Advances in Animal and Veterinary Sciences

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AAVS_Nexus 661

 

 

Review Article

 

Biology, Expression, and Regulation of Host Defense Peptides: A Minireview

 

Lakshmi Tulasi Sunkara1, Amanda Renee Curtis1, Guolong Zhang1, 2, 3*

1Department of Animal Science; 2Department of Biochemistry and Molecular Biology; 3Department of Physiological Sciences, Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078, USA.

 

Abstract | Host defence peptides (HDPs) represent a diverse group of small peptides generally consisting of less than 100 amino acid residues with a net positive charge. HDPs are synthesized preferably by phagocytes in the circulation, skin keratinocytes, and mucosal epithelial cells of the digestive, respiratory, and urogenital tracts. As important effector molecules of innate immunity, HDPs are quickly mobilized to fight off infections. In addition to direct antimicrobial activities, HDPs impact positively on wound healing, inflammation resolution, and development of adaptive immunity. Besides infection and inflammation, many HDPs were found recently to be induced by a large number of dietary compounds such as vitamins D, short-chain fatty acids, histone deacetylase inhibitors, zinc, and certain phytochemicals in humans and several other animal species such as poultry. Further investigations on the dietary modulation of HDP synthesis may lead to the development of a novel antibiotic-free approach to disease control and prevention with applications in both the livestock and poultry industry and human health.

 

Keywords | Host defence peptides, Antimicrobial resistance, Immune modulation, Antibiotic alternatives, Innate immunity

 

Editor | Muhammad Munir (DVM, PhD), Avian Viral Diseases Program, Compton Laboratory, Newbury, Berkshire, RG20 7NN, UK.

Special Issue | 3(2015) “Poultry diseases and the strategies for their control and prevention”

Received | June 04, 2015; Revised | June 20, 2015; Accepted | June 21, 2015; Published | June 29, 2015

*Correspondence | Guolong Zhang, Oklahoma State University, Stillwater, USA; Email: zguolon@okstate.edu

Citation | Sunkara LT, Curtis AR, Zhang G (2015). Biology, expression, and regulation of host defense peptides: A minireview. Adv. Anim. Vet. Sci. 3(3s): 9-20.

DOI | http://dx.doi.org/10.14737/journal.aavs/2015/3.3s.9.20

ISSN (Online) | 2307-8316; ISSN (Print) | 2309-3331

Copyright © 2015 Sunkara et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

 

INTRODUCTION

 

Innate immunity is the first line of host defense and crucial to protect all living organisms against microbial invasions (Linde et al., 2008; Steinstraesser et al., 2011). As critical effector molecules of the innate immune system, host defense peptides (HDPs), also known as antimicrobial peptides, have been discovered in nearly all forms of life (Zasloff, 2002; Zhang and Sunkara, 2014). HDPs are strategically expressed in leukocytes as well as mucosal epithelial cells lining the respiratory, gastrointestinal and urogenital systems of their host (Zhang and Sunkara, 2014). They are synthesized as peptide precursors and enzymatically processed to release biologically active, mature peptides (Steinstraesser et al., 2011; Zasloff, 2002). Most mature HDPs consist of 12 to100 amino acids rich in cationic residues and are largely amphipathic (Wang, 2014). They directly kill a myriad of microbes ranging from Gram-positive and Gram-negative bacteria to fungi, protozoa, parasites, enveloped viruses, and even cancerous cells. Additionally, many HDPs have a profound impact on the regulation of inflammation, wound healing, and adaptive immunity (Hilchie et al., 2013; Yeung et al., 2011). Because of these pleotropic activities, these HDPs are being actively explored as novel antimicrobials for disease control and prevention particularly against drug-resistant microbes (Hancock et al., 2012).

 

CLASSIFICATION OF HDPs

 

Nearly 2,500 HDPs have been reported in bacteria, protozoa, fungi, plants, and animals (Fjell et al., 2007; Wang et al., 2009). Based on their structures, HDPs are broadly classified into four major groups including the peptides adopting largely an α-helical, β-sheet, a loop or flexible structure (Pasupuleti et al., 2012; Yeung et al., 2011). The loop structure of HDPs is mainly due to the presence of a disulfide bond, whereas flexible structures result from enrichment of certain amino acids such as arginine, histidine, proline, and tryptophan. Cathelicidins and defensins represent two major families of HDPs found in vertebrates (Sang and Blecha, 2009; Sorensen et al., 2008; van Dijk et al., 2011). Cathelicidins were first isolated from bovine neutrophils as cyclic dodecapeptides (Romeo et al., 1988). Since then, cathelicidins have been found in not only mammals but also in fish, snakes, and birds (Chang et al., 2006; Gennaro and Zanetti, 2000; Lynn et al., 2004; Uzzell et al., 2003; van Dijk et al., 2005; Xiao et al., 2006; Zhao et al., 2008). The name cathelicidin was coined from the presence of a highly conserved cathelin domain in the N-terminal region. The C-terminal regions of cathelicidins are highly variable among species and possess different biological functions (Gennaro and Zanetti, 2000; Kolls et al., 2008). A large group of cathelicidin genes are encoded in the porcine, ovine, and bovine genomes; however, only a single cathelicidin gene exists in rodents, dogs, primates, and humans (Steinstraesser et al., 2011; van Dijk et al., 2011). Four cathelicidin genes were found recently in chickens (Goitsuka et al., 2007; Xiao et al., 2006).

 

Defensins, present in plants, invertebrates and vertebrates, are rich in cysteines and comprised of 3-4 disulfide bonds (Carvalho-Ade and Gomes, 2009; Strominger, 2009; van Dijk et al., 2008). Most vertebrate defensins consist of a signal peptide, proregion and cationic mature peptide with six conserved cysteine residues forming three intramolecular disulfide bridges creating a “defensin-like” fold (Hiemstra, 2007; Lehrer and Ganz, 2002). Based on the spacing pattern and pairing of cysteine residues, vertebrate defensins are classified into three major subfamilies namely α-, β-, and θ- defensins (Hiemstra, 2007). The disulfide bridges are formed between C1-C6, C2-C4, and C3-C5 in α-defensins, whereas C1-C5, C2-C4, and C3-C6 are paired in β-defensins, and C1-C6, C2-C5 and C3-C4 paired in θ-defensins. Triple-stranded, anti-parallel β-sheet structures are present in α- and β-defensins, while θ-defensins are composed of circular double-stranded β-sheets (Selsted, 2004; Selsted and Ouellette, 2005; Steinstraesser et al., 2011; van Dijk et al., 2008).

 

As important effector molecules of innate immunity, cathelicidins and defensins are produced strategically by leukocytes, skin keratinocytes, and mucosal epithelial cells of respiratory, gastrointestinal, and urogenital tracts (Brown and Hancock, 2006; Hancock and Scott, 2000). In humans, cathelicidin LL-37 is mainly found in both leukocytes and epithelial cells, while α- and θ-defensins are commonly expressed in neutrophils and paneth cells of the small intestine, and the primary source of β-defensins are mucosal epithelia and skin (Easton et al., 2009; Lehrer, 2004). HDP precursors are processed post translationally by different proteolytic enzymes to become biologically active (Auvynet and Rosenstein, 2009; Zanetti et al., 1995). For example, human α-defensin HD5 is synthesized by intestinal Paneth cells and processed by trypsin (Oppenheim, 2003). Human cathelicidin LL-37 is further processed by serine proteases like proteinase 3 in neutrophils and kallikreins 5 and 7 in the skin (Guani-Guerra et al., 2010; Sorensen et al., 2001), whereas elastase is a main enzyme responsible for cleavage of cathelicidin precursors in cattle and pigs (Panyutich et al., 1997; Scocchi et al., 1992; Zanetti et al., 1991).

 

ANTIMICROBIAL PROPERTIES OF HDPs

 

HDPs are broad-spectrum natural antibiotics that kill or suppress the growth of a wide range of bacteria, mycobacteria, fungi, parasites, and certain enveloped viruses (Bernard and Gallo, 2011). They kill microbes by physical disruption of membranes or by nonspecific inhibition of cellular transcription and translation (Yeung et al., 2011). Cationic HDPs initially accumulate and electrostatically interact with anionic membrane components such as lipopolysaccharides (LPS) of Gram-negative bacteria and lipoteichoic acid (LTA) of Gram-positive bacteria. Penetration into negatively charged phospholipids of microbial membranes resulting in membrane perturbation and leakage of intracellular contents, ultimately leading to cell death (Hale and Hancock, 2007; Zasloff, 2002). Because it is very difficult for microbes to change the overall negative charge of their membrane phospholipids, development of resistance against HDPs is extremely rare (Yeaman and Yount, 2003). Preferred disruption of microbial, but not host, membranes is believed to be due to the differences between prokaryotic and eukaryotic cell membrane properties. While the former is heavily negatively charged with high transmembrane potential (-140 mV), the latter is largely uncharged with a high cholesterol content and low transmembrane potential of approximately -15 mV (Huang et al., 2010; Yount and Yeaman, 2005). The mechanism of pore formation on microbial membranes varies among individual HDPs. Depending upon the net charge and spatial structure, HDPs permeate membranes via “barrel-stave”, “toroidal-pore”, “molecular electroporation”, “sinking raft”, or “carpet-wormhole” mechanisms (Oren and Shai, 1998; Palffy et al., 2009; van Dijk et al., 2008).

 

In addition to direct disruption of membranes, certain HDPs, particularly α- and θ-defensins, suppress viral proliferation by acting as collectins. For example, retrocyclins (primate θ-defensins) bind to glycoproteins (gp41 and gp120) of HIV as well as CD4 of host immune cells and prevent viral entry by blocking the conformational change of gp41, which is required for attachment and fusion of viruses with host cells (Penberthy et al., 2011). Similarly, human α-defensins (HNP1, -2, and -3) bind to envelop glycoprotein B of herpes simplex virus to suppress viral entry into the host cells (Hazrati et al., 2006). Because of these diverse interactions with microbes, it is extremely difficult for microbes to develop resistance against HDPs.

 

ANTIINFLAMMATORY EFFECTS OF HDPs

 

Besides antimicrobial properties, HDPs suppress inflammation and protect the host from excessive production of proinflammatory mediators triggered by microbial products. HDPs are capable of neutralizing bacterial endotoxins, inhibiting proinflammatory cytokine production, inducing antiinflammatory cytokines, and preventing activation of classical and lectin complement cascades (Choi et al., 2012; Easton et al., 2009; Groeneveld et al., 2007). For example, human cathelicidin LL-37 binds to and neutralizes LPS and LTA, thereby abolishing the production of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6, while also stimulating the expression of antiinflammatory cytokines such as IL-10 (Mookherjee et al., 2006; Mookherjee and Hancock, 2007; Ruan et al., 2013; Scott et al., 2011; Suphasiriroj et al., 2013). In addition, LL-37 inhibits IFN-γ-induced cell activation, proliferation, and production of proinflammatory and Th1-polarizing cytokines and antibodies in antigen- presenting cells (Nijnik et al., 2009). In a murine infection model, LL-37 protects mice from septic shock induced by Pseudomonas aeruginosa (Kirikae et al., 1998). It also promotes secondary necrosis of apoptotic neutrophils without causing loss of membrane integrity or provoking inflammatory response of macrophages (Li et al., 2009b). Likewise, chicken cathelicidin fowlicidin-1 prevents LPS-induced production of nitric oxide and TNF-α (Bommineni et al., 2010). Porcine cathelicidin PR-39 inhibits the production of reactive oxygen species, while bovine cathelicidin BAMP-28 induces apoptosis of activated lymphocytes (Brown and Hancock, 2006).

 

Similar to cathelicidins, defensins also inhibit production of proinflammatory cytokines by binding to microbial membranes, surface adhesins, and bacterial toxins as well as by surpressing their attachment to host cells (Kohlgraf et al., 2010). For example, human α-defensin HNP1 attenuates LPS-mediated production of proinflammatory cytokines such as IL-1β from monocytes (Shi et al., 2007). HNP2 and HNP3 reduce production of several proinflammatory cytokines including IL-1 β, IL-6, IL-8 and TNF-α from LPS-stimulated human monocyte-derived macrophages (Miles et al., 2009). Human β defensin(HBD)-3 also abrogates the induction of IL-6, and TNF-α from human myeloid dendritic cells stimulated with Porphyromonas gingivalis (Pingel et al., 2008). Moreover, there is evidence that expression of human α- and β-defensins is reduced in inflammatory diseases like Crohn’s disease, emphasizing the role of defensins in regulation of inflammation (Guani-Guerra et al., 2010; Salzman, 2010).

 

IMMUNOMODULATORY ACTIVITIES OF HDPs

 

HDPs have the capacity to directly kill pathogens, but their antimicrobial activity is often diminished in biological fluids in the presence of monovalent and divalent cations, serum, and polyanionic molecules like glycosaminoglycans (Bowdish et al., 2005). Several HDPs, albeit with extremely weak or no antibacterial activities, have been found to still protect the host from infections, implying a host defense role other than directly killing bacteria (Brown and Hancock, 2006; Jenssen and Hancock, 2010; Yeung et al., 2011). In fact, HDPs promote diverse immunomodulatory functions by stimulating the production of chemokines and cytokines, and by regulating complement activation, promoting wound healing, and by acting as chemoattractants (Pundir and Kulka, 2010; van Dijk et al., 2011; Yeung et al., 2011). For example, Human β-defensins (HBD1 and HBD3) chemoattract immature dendritic cells and memory T cells, while human α-defensins are chemotactic to naïve T cells (Auvynet and Rosenstein, 2009). Similarly, HNP1-3 and HBD3-4 stimulate migration of neutrophils and monocytes, whereas LL-37 and HNP1-3 are chemotactic to mast cells and induce degranulation to release histamine and prostaglandin-2, respectively (Auvynet and Rosenstein, 2009). HDPs also induce production of various pro-inflammatory cytokines such as IL-1β, TNF-α and IL-6 as well as chemokines such as IL-8 and monocyte chemotactic protein-1 from mononuclear phagocytes and epithelial cells (Auvynet and Rosenstein, 2009; van Dijk et al., 2009).

 

In addition to modulation of host immunity, HDPs enhance wound healing. HDPs promote re-epithelialization, angiogenesis and vascularization by inducing proliferation of epithelial cells and vascular endothelial cells and chemoattracting fibroblasts and macrophages (Steinstraesser et al., 2011). LL-37 was shown to enhance the closure of wounds in human corneal epithelial cells and in high-glucose-attenuated porcine corneal epithelial cells (Yin and Yu, 2010). HDPs enhance synthesis of growth factors and cytokines in keratinocytes and epithelial cells that are essential for wound repair (Yeung et al., 2011). For example, human LL-37 and HBDs enhances IL-18 secretion from keratinocytes (Niyonsaba et al., 2005). HBD2 and HBD-3 are also actively involved in re-epithelialization of damaged skin (Steinstraesser et al., 2008). Porcine PR-39 is involved in wound healing by increasing the expression of extracellular matrix proteoglycans such as syndecan-1 and 4, which are important for activation of many growth factors (Gallo et al., 1994). Given such an array of immunomodulatory properties of HDPs, it is highly desirable to harness these properties for antimicrobial therapies to boost host immunity without directly acting on microbes, thereby minimizing the risk of developing resistance (Finlay and Hancock, 2004).

 

TRANSCRIPTIONAL REGULATION OF HDPs

 

HDP Regulation in Humans

Expression of many HDPs can be induced in response to infection and inflammation. Human cathelicidin LL-37 expression is induced in response to Gram-negative bacteria such as Salmonella enterica serovar Dublin, and enteroinvasive Escherichia coli in human colonic epithelium (Hase et al., 2002), Helicobacter pylori in human gastric epithelial cells (Hase et al., 2003), and Pseudomonas aeruginosa in corneal epithelium (Gao et al., 2010). Likewise, the synthesis of LL-37 is increased in response to Gram-positive bacteria including S. aureus in keratinocytes (Midorikawa et al., 2003), Mycobacterium species in human alveolar macrophages, monocytes, neutrophils and epithelial cells (Mendez-Samperio et al., 2008; Rivas-Santiago et al., 2008), LPS and LTA in sinus epithelial cells (Nell et al., 2004), flagellin in corneal epithelial cells (Gao et al., 2010). On the other hand, Shigella dysenteriae, Vibrio cholera (Islam et al., 2001) and Nisseria gonorrhoeae (Bergman et al., 2005) downregulate LL-37 expression in intestinal epithelial cells. In addition, stressors like injury (Dorschner et al., 2001), endoplasmic reticulum stress (Park et al., 2011), and inflammatory disorders (Frohm et al., 1997) also enhance LL-37 expression in keratinocytes. Moreover, various proinflammatory cytokines (IL-1α, IL-6, and IL-17) (Erdag and Morgan, 2002; Lande et al., 2007; Peric et al., 2008) and growth factors (insulin-like growth factor 1 and transforming growth factor-α and -β1) (Sorensen et al., 2003) promote LL-37 expression in skin epithelial cells, while proinflammatory cytokines display no effect on colonic epithelium (Hase et al., 2002). IL-10 and IL-13 also suppress LL-37 expression in the skin (Kolls et al., 2008), and IL-18 stimulates LL-37 expression in colonic epithelial cells (McDonald et al., 2006).

 

Neutrophil-derived human α-defensins are mostly constitutively expressed but inducible in a few cases such as pulmonary tuberculosis, septicemia, and bacterial meningitis (Ashitani et al., 2002; Ashitani et al., 2000; Panyutich et al., 1993). Similarly, IL-18 and viral infections like hepatitis C increase α-defensin expression in intestinal cells and in peripheral blood mononuclear cells, respectively (Aceti et al., 2006; McDonald et al., 2006). HBD1 expression is primarily constitutive, but induced by LPS, and IFN-γ in certain antigen-presenting cells, and repressed by Shigella dyserteriae, Vibrio cholera and bacterial exotoxins (Chakraborty et al., 2008; Duits et al., 2002; Islam et al., 2001). The expression of HBD2-4 is upregulated by various stimulants including bacteria, and bacterial products, and cytokines such as IL-1α, IL-1β, IL-22, IL-17A, TNF-α, and IFN-γ in keratinocytes (Harder et al., 2004). HBD2 and HBD3 are also inducible in Campylobacter jejuni-treated intestinal epithelial cells (Zilbauer et al., 2005). Viral infections including HIV-1 and Rhinovirus-16 enhance HBD2 and HBD3 expression in epithelial cells (Lehrer, 2004). Cryptosporidium parvum upregulates HBD2, but down-regulates HBD1 with no effect on HBD3 expression in colonic epithelial cells (Zaalouk et al., 2004).

 

Apart from infection and stress, human LL-37 is also induced by several dietary factors including short-chain fatty acids, flavones, zinc, and vitamin D3. For example, short-chain fatty acids such as butyrate and propionate induce LL-37 expression in human intestinal and hepatic cells as well as lung epithelial cells by acting as histone deacetylase (HDAC) inhibitors (Kida et al., 2006; Schauber et al., 2004; Schauber et al., 2003). Other HDAC inhibitors including 4-phenylbutyrate and trichostatin (TSA) are also able to augment LL-37 expression in epithelial and monocytic cells (Schauber et al., 2004; Schauber et al., 2003; Steinmann et al., 2009). Other fatty acids including valerate, hexanoate and heptanoate appear to be more potent in inducing LL-37 than butyrate in human colonic and monocytic cells (Jiang et al., 2013). Besides fatty acids, vitamin D3 stimulates LL-37 synthesis in lung epithelial cells, keratinocytes, and monocytes, but not in colonic epithelial cells (Hansdottir et al., 2008; Peric et al., 2009; Schauber et al., 2006; Schauber et al., 2008). In addition, zinc has the capacity to enhance LL-37 expression in human intestinal epithelial cells (Talukder et al., 2011). LL-37 expression is also augmented by various cyclic adenosine monophosphate (cAMP) signaling agonists in mucosal epithelial cells (Chakraborty et al., 2009).

 

Human neutrophil α-defensins are induced by 2-arachidonoyl-glycerol and arachidonic acid and the induction is correlated with increased antimicrobial activities of neutrophils against E. coli, S. aureus, herpes simplex virus (HSV)-1, and respiratory syncytial virus (RSV) (Chouinard et al., 2013). Human HBD1 expression is mostly constitutive in response to infection, but can be modulated by dietary compounds such as apicidin, butyrate, depudecin, MS-275 and valproic acid in human lung epithelial cell lines through inhibition of HDAC1 (Kallsen et al., 2012). Another HDAC inhibitor and butyrate analog, 4-phenylbutyrate stimulates the expression of HBD1, but not HBD2-4 in human lung epithelial cells (Steinmann et al., 2009). However, 4-phenylbutyrate fails to induce HBD1 in monocytic cells in the same study (Steinmann et al., 2009), suggesting that HDP regulation is both gene- and cell-specific.

 

HDAC inhibitors such as TSA, butyrate, and sulforaphane are also capable of enhancing HBD2 expression in human colonic epithelial cells (Schwab et al., 2008). Free fatty acids such as lauric acid, palmitic acid, and oleic acid enhance the antimicrobial activity of sebocytes against Propionibacterium acnes by upregulation of HBD2 (Nakatsuji et al., 2010). Zinc and several probiotic bacterial strains have also been found to upregulate HBD2 expression (Di Cagno et al., 2010; Putaala et al., 2010; Schlee et al., 2008). It is likely that probiotics and prebiotics stimulate bacterial fermentation of short-chain fatty acids, which in turn promote HDP synthesis, host immunity, and disease resistance.

 

HDP Regulation in other Species Including Poultry

Mouse cathelicidin CRAMP expression is enhanced in the skin in response to injury and mild UV irradiation and in mast cells by LPS stimulation (Dorschner et al., 2001; Hong et al., 2008; Li et al., 2009a). Mouse intestinal α-defensins (cryptidins) are also induced in response to Toxoplasma gondi via TLR9-dependent pathway (Foureau et al., 2010). Mouse β-defensin 3 (MBD3) are augmented in the esophagus and tongue by E. coli, and MBD2 expression are triggered in the skin by UV irradiation (Ahrens et al., 2011). In contrast, MBD1 expression is inhibited by Cryptosporidium parvum (Burd et al., 2002; Hong et al., 2008; Zaalouk et al., 2004). In rats, neuropathogenic E. coli enhances the expression of intestinal α-defensins (Birchenough et al., 2013), and methicillin-resistant Staphylococcus aureus enhanced the rat β-Defensin 3 (RBD3) expression in the lung (Wu et al., 2011). In response to intestinal ischemia or injury, RBD2 is stimulated in the lung as well (Liu et al., 2009). Similarly, Actinobacillus actinomycetemcomitans increases RBD1 and RBD2 expression in gingival epithelia (Kurland et al., 2006). Testicular and epididymal β-defensins are enhanced in rats treated with LPS (Biswas and Yenugu, 2013, 2011). In rabbits, oral supplementation of butyrate or 4-phenylbutyrate alleviates clinical symptoms of dysentery in shigellosis infections through upregulation of cathelicidin expression in the colon and lung epithelia (Raqib et al., 2006; Sarker et al., 2011).

 

Like their mammalian counter parts, porcine cathelicidins such as protegrins and PR-39 show an increased expression in porcine bone marrow cells in response to different Salmonella strains, LPS, and IL-6 (Wu et al., 2011; Zhang et al., 1997). In addition, PR-39 is increased in mucosal and lymphatic tissues of the respiratory tract in pigs chronically, but not acutely infected with Actinobacillus pleuropneumoniae (Hennig-Pauka et al., 2012). Porcine β-defensin 2 (PBD2) expression is enhanced in intestinal epithelial cells exposed to live Salmonella, but not heat-killed or colistin-treated bacteria (Veldhuizen et al., 2006). Likewise, Salmonella enteritidis infection stimulates PBD1 gene expression (Veldhuizen et al., 2006; Veldhuizen et al., 2009), while PBD1 is upregulated and PBD2 is down-regulated in intestinal epithelial cells treated with Fusarium toxin (Wan et al., 2013). Treatment of primary tracheal epithelial cells with LPS or canine respiratory coronavirus or parainfluenza virus has led to a decreased expression of several canine β-defensins (Erles and Brownlie, 2010).

 

In ruminant animals, E. coli or LPS stimulation of neutrophils results in an increased production of bovine cathelicidin Bac-5 (Tomasinsig et al., 2002). Furthermore, bovine HDPs such as TAP, LAP, and BBD5 are upregulated in response to infections, particularly in the mammary, lung, and uterine tissues (Meade et al., 2014). Several bovine β-defensins are also increased in response to inflammation and infection (Das et al., 2008; Russell et al., 1996; Stolzenberg et al., 1997). Similarly, S. aureus or LPS treatment of umbilical endothelial cells potentiates the expression of bovine LAP, BBD1 and BBD4 through autocrine production of TNF-α (Alva-Murillo et al., 2012b). Intrauterine infusion of E. coli in goats results in up-regulation of β-defensin 2 gene expression (Shao et al., 2012), whereas infection of intestinal epithelial cells with Eimeria spp leads to down-regulation of the goat β-defensin 2 gene (Ibarra-Velarde and Alcala-Canto, 2007). In sheep, SBD1 is increased with parainfluenza virus type 3 infection and decreased by Mannheimia haemolytica, with no difference in gene expression observed with SBD2 (Ackermann et al., 2004).

 

In avian species, HDPs are also differentially expressed in response to infectious agents and inflammatory mediators (Cuperus et al., 2013; Zhang and Sunkara, 2014). For example, several chicken cathelicidins are augmented in response to S. typhimurium in cecal tonsils, and down-regulated by Camphylobacter jejuni in peripheral blood leukocytes and Eimeria praecox in small intestine (Akbari et al., 2008; Meade et al., 2009; Sumners et al., 2011). Chicken β-defensins are also regulated by Haemophilus paragallinarum in the trachea (AvBD3) and by Salmonella typhimurium (AvBD1, 2, 5, and 6) in cecal tonsils (Akbari et al., 2008; Zhao et al., 2001).

 

Dietary compounds has also been found to regulate HDPs expression in non-human species. For example, fatty acids such as butyrate, propionate and hexanoate have been shown to increase the expression of several bovine β-defensins in primary mammary epithelial cells and inhibit both internalization and infection of Staphylococcus aureus (Alva-Murillo et al., 2012a). In contrast, the expression of bovine LAP, TAP, and BBD4 is decreased in rumen epithelia when infused with butyrate (Baldwin et al., 2012). Oleic acid induces MBD4 in the hair follicle sebaceous glands of ear skin in mice (Nakatsuji et al., 2010). Lysozyme-digested probiotics increases mouse CRAMP expression in macrophages and protects rats against sepsis (Bu et al., 2006). Free fatty acids with 3-8 carbons are able to induce porcine HDPs such as PBD2, PBD3, PEP2C, and protegrins in intestinal epithelial cells, alveolar macrophages, and primary monocytes (Zeng et al., 2013). PBD2 is induced in the ileum of pigs administered with a probiotic, Lactobacillus rhamnosus (Li et al., 2012).

 

In animal agriculture, particularly in poultry, organic acids including butyrate and propionate have been used for decades and shown an overall improved resistance to S. enteritidis (Van Immerseel et al., 2006) and Clostridium perfringens (Timbermont et al., 2010). Many antibacterial mechanisms of organic acids have been proposed, including a reduction of intestinal pH, direct antibacterial activities, and suppression of bacterial attachment to host intestinal cells (Gantois et al., 2006; Van Immerseel et al., 2004; Van Immerseel et al., 2003; Van Immerseel et al., 2006). Augmenting HDP synthesis and host immunity has also been proposed as a new mode of action of organic acids, which often contain short-chain fatty acids that have been revealed to be strong inducers of chicken HDPs both in vitro and in vivo (Sunkara et al., 2011; Sunkara et al., 2012). A combination of three short-chain fatty acids, namely butyrate, acetate and propionate, could synergistically induce chicken HDP expression and clearance of Salmonella in the cecum of chickens (Sunkara et al., 2012). A phytochemical, forskolin, also synergizes with butyrate in enhancing chicken HDP expression both in vitro and in vivo (Sunkara et al., 2012; Sunkara et al., 2014).

 

CONCLUSIONS

 

HDPs are important effector molecules of innate immunity, possessing a myriad of beneficial functions with potent antimicrobial, antiinflammatory, and immunomodulatory activities. HDPs are mobilized quickly in response to infection and inflammation. A growing body of evidence suggests that dietary factors including vitamin D3, short-chain fatty acids, zinc, certain amino acids, and phytochemicals are capable of inducing HDP synthesis in humans and other animal species like cattle, pigs, sheep and poultry, suggesting the potential of using these HDP-inducing compounds for immune augmentation and disease resistance. Dietary modulation of the endogenous HDP synthesis may be further explored as a novel antibiotic-free strategy for disease prevention and control for both human and animal health including poultry.

 

ACKNOWLEDGMENTS

 

We thank all the members of the Zhang Laboratory for their valuable contributions to successfully complete different research projects in studying HDP modulation. The research on host defence peptides in different animals in the Zhang Laboratory is supported by the U.S. Department of Agriculture grant (2008-35204-04544), Oklahoma Center for the Advancement of Science and Technology grants HR07-113, HR12-051, AR07.2-087 and AR12.2-077), and Oklahoma Agricultural Experiment Station project (H-2811). The funders has no role in preparation of this review article.

 

CONFLICTS OF INTEREST

 

The authors have declared no conflict of interest.

 

Author’s Contribution

 

Lakshmi Tulasi Sunkara and Amanda Renee Curits drafted the manuscript and Guolong Zhang drafted and revised the manuscript.

 

REFERENCES

 

  • Aceti A, Mangoni ML, Pasquazzi C, Fiocco D, Marangi M, Miele R, Zechini B, Borro M, Versace I, Simmaco M (2006). Alpha-defensin increase in peripheral blood mononuclear cells from patients with hepatitis C virus chronic infection. J. Viral Hepat. 13(12): 821-827. http://dx.doi.org/10.1111/j.1365-2893.2006.00762.x
  • Ackermann MR, Gallup JM, Zabner J, Evans RB, Brockus CW, Meyerholz DK, Grubor B, Brogden KA (2004). Differential expression of sheep beta-defensin-1 and -2 and interleukin 8 during acute Mannheimia haemolytica pneumonia. Microb. Pathog. 37(1): 21-27. http://dx.doi.org/10.1016/j.micpath.2004.04.003
  • Ahrens K, Schunck M, Podda GF, Meingassner J, Stuetz A, Schroder JM, Harder J, Proksch E (2011). Mechanical and metabolic injury to the skin barrier leads to increased expression of murine beta-defensin-1, -3, and -14. J. Invest. Dermatol. 131(2): 443-452. http://dx.doi.org/10.1038/jid.2010.289
  • Akbari MR, Haghighi HR, Chambers JR, Brisbin J, Read LR, Sharif S (2008). Expression of antimicrobial peptides in cecal tonsils of chickens treated with probiotics and infected with Salmonella enterica serovar typhimurium. Clin. Vaccine Immunol. 15(11): 1689-1693. http://dx.doi.org/10.1128/CVI.00242-08
  • Alva-Murillo N, Ochoa-Zarzosa A, Lopez-Meza JE (2012a). Short chain fatty acids (propionic and hexanoic) decrease Staphylococcus aureus internalization into bovine mammary epithelial cells and modulate antimicrobial peptide expression. Vet. Microbiol. 155(2-4): 324-331. http://dx.doi.org/10.1016/j.vetmic.2011.08.025
  • Alva-Murillo N, Tellez-Perez AD, Sagrero-Cisneros E, Lopez-Meza JE, Ochoa-Zarzosa A (2012b). Expression of antimicrobial peptides by bovine endothelial cells. Cell Immunol. 280(1): 108-112. http://dx.doi.org/10.1016/j.cellimm.2012.11.016
  • Ashitani J, Mukae H, Hiratsuka T, Nakazato M, Kumamoto K, Matsukura S (2002). Elevated levels of alpha-defensins in plasma and BAL fluid of patients with active pulmonary tuberculosis. Chest. 121(2): 519-526. http://dx.doi.org/10.1378/chest.121.2.519
  • Ashitani J, Nakazato M, Mukae H, Taniguchi H, Date Y, Matsukura S (2000). Recombinant granulocyte colony-stimulating factor induces production of human neutrophil peptides in lung cancer patients with neutropenia. Regul. Pept. 95(1-3): 87-92. http://dx.doi.org/10.1016/S0167-0115(00)00158-0
  • Auvynet C, Rosenstein Y (2009). Multifunctional host defense peptides: antimicrobial peptides, the small yet big players in innate and adaptive immunity. FEBS J. 276(22): 6497-6508. http://dx.doi.org/10.1111/j.1742-4658.2009.07360.x
  • Baldwin RLt, Wu S, Li W, Li C, Bequette BJ, Li RW (2012). Quantification of Transcriptome Responses of the Rumen Epithelium to Butyrate Infusion using RNA-seq Technology. Gene Regul. Syst. Bio. 6: 67-80.
  • Bergman P, Johansson L, Asp V, Plant L, Gudmundsson GH, Jonsson AB, Agerberth B (2005). Neisseria gonorrhoeae downregulates expression of the human antimicrobial peptide LL-37. Cell Microbiol. 7(7): 1009-1017. http://dx.doi.org/10.1111/j.1462-5822.2005.00530.x
  • Bernard JJ, Gallo RL (2011). Protecting the boundary: the sentinel role of host defense peptides in the skin. Cell Mol. Life Sci. 68(13): 2189-2199. http://dx.doi.org/10.1007/s00018-011-0712-8
  • Birchenough GM, Johansson ME, Stabler RA, Dalgakiran F, Hansson GC, Wren BW, Luzio JP, Taylor PW (2013). Altered innate defenses in the neonatal gastrointestinal tract in response to colonization by neuropathogenic Escherichia coli. Infect. Immun. 81(9): 3264-3275. http://dx.doi.org/10.1128/IAI.00268-13
  • Biswas B, Yenugu S (2013). Lipopolysaccharide induces epididymal and testicular antimicrobial gene expression in vitro: insights into the epigenetic regulation of sperm-associated antigen 11e gene. Immunogenetics. 65(4): 239-253. http://dx.doi.org/10.1007/s00251-013-0681-1
  • Biswas B, Yenugu S (2011). Antimicrobial responses in the male reproductive tract of lipopolysaccharide challenged rats. Am. J. Reprod. Immunol. 65(6): 557-568. http://dx.doi.org/10.1111/j.1600-0897.2010.00937.x
  • Bommineni YR, Achanta M, Alexander J, Sunkara LT, Ritchey JW, Zhang G (2010). A fowlicidin-1 analog protects mice from lethal infections induced by methicillin-resistant Staphylococcus aureus. Peptides. 31(7): 1225-1230. http://dx.doi.org/10.1016/j.peptides.2010.03.037
  • Bowdish DM, Davidson DJ, Lau YE, Lee K, Scott MG, Hancock RE (2005). Impact of LL-37 on anti-infective immunity. J, Leukoc, Biol. 77(4): 451-459. http://dx.doi.org/10.1189/jlb.0704380
  • Brown KL, Hancock RE (2006). Cationic host defense (antimicrobial) peptides. Curr. Opin. Immunol. 18(1): 24-30. http://dx.doi.org/10.1016/j.coi.2005.11.004
  • Bu HF, Wang X, Zhu YQ, Williams RY, Hsueh W, Zheng X, Rozenfeld RA, Zuo XL, Tan XD (2006). Lysozyme-modified probiotic components protect rats against polymicrobial sepsis: role of macrophages and cathelicidin-related innate immunity. J. Immunol. 177(12): 8767-8776. http://dx.doi.org/10.4049/jimmunol.177.12.8767
  • Burd RS, Furrer JL, Sullivan J, Smith AL (2002). Murine beta-defensin-3 is an inducible peptide with limited tissue expression and broad-spectrum antimicrobial activity. Shock. 18(5): 461-464. http://dx.doi.org/10.1097/00024382-200211000-00013
  • Carvalho Ade O, Gomes VM (2009). Plant defensins--prospects for the biological functions and biotechnological properties. Peptides. 30(5): 1007-1020. http://dx.doi.org/10.1016/j.peptides.2009.01.018
  • Chakraborty K, Ghosh S, Koley H, Mukhopadhyay AK, Ramamurthy T, Saha DR, Mukhopadhyay D, Roychowdhury S, Hamabata T, Takeda Y, Das S (2008). Bacterial exotoxins downregulate cathelicidin (hCAP-18/LL-37). and human beta-defensin 1 (HBD-1) expression in the intestinal epithelial cells. Cell Microbiol. 10(12): 2520-2537. http://dx.doi.org/10.1111/j.1462-5822.2008.01227.x
  • Chakraborty K, Maity PC, Sil AK, Takeda Y, Das S (2009). cAMP stringently regulates human cathelicidin antimicrobial peptide expression in the mucosal epithelial cells by activating cAMP-response element-binding protein, AP-1, and inducible cAMP early repressor. J. Biol. Chem. 284(33): 21810-21827. http://dx.doi.org/10.1074/jbc.M109.001180
  • Chang CI, Zhang YA, Zou J, Nie P, Secombes CJ (2006). Two cathelicidin genes are present in both rainbow trout (Oncorhynchus mykiss) and atlantic salmon (Salmo salar). Antimicrob. Agents Chemother. 50(1): 185-195. http://dx.doi.org/10.1128/AAC.50.1.185-195.2006
  • Choi KY, Chow LN, Mookherjee N (2012). Cationic host defence peptides: multifaceted role in immune modulation and inflammation. J, Innate Immun. 4(4): 361-370. http://dx.doi.org/10.1159/000336630
  • Chouinard F, Turcotte C, Guan X, Larose MC, Poirier S, Bouchard L, Provost V, Flamand L, Grandvaux N, Flamand N (2013). 2-Arachidonoyl-glycerol- and arachidonic acid-stimulated neutrophils release antimicrobial effectors against E. coli, S. aureus, HSV-1, and RSV. J. Leukoc Biol. 93(2): 267-276. http://dx.doi.org/10.1189/jlb.0412200
  • Cuperus T, Coorens M, van Dijk A, Haagsman HP (2013). Avian host defense peptides. Dev. Comp. Immunol. 41(3): 352-369. http://dx.doi.org/10.1016/j.dci.2013.04.019
  • Das H, Swamy N, Sahoo G, Ahmed SU, More T (2008). Beta-defensin antibiotic peptides in the innate immunity of the buffalo: in vivo and in vitro studies. Altern. Lab. Anim. 36(4): 429-440.
  • Di Cagno R, Mazzacane F, Rizzello CG, De Angelis M, Giuliani G, Meloni M, De Servi B, Gobbetti M (2010). Synthesis of gamma-aminobutyric acid (GABA). by Lactobacillus plantarum DSM19463: functional grape must beverage and dermatological applications. Appl. Microbiol. Biotechnol. 86(2): 731-741. http://dx.doi.org/10.1007/s00253-009-2370-4
  • Dorschner RA, Pestonjamasp VK, Tamakuwala S, Ohtake T, Rudisill J, Nizet V, Agerberth B, Gudmundsson GH, Gallo RL (2001). Cutaneous injury induces the release of cathelicidin anti-microbial peptides active against group A Streptococcus. J. Invest. Dermatol. 117(1): 91-97. http://dx.doi.org/10.1046/j.1523-1747.2001.01340.x
  • Duits LA, Ravensbergen B, Rademaker M, Hiemstra PS, Nibbering PH (2002). Expression of beta-defensin 1 and 2 mRNA by human monocytes, macrophages and dendritic cells. Immunology. 106(4): 517-525. http://dx.doi.org/10.1046/j.1365-2567.2002.01430.x
  • Easton DM, Nijnik A, Mayer ML, Hancock RE (2009). Potential of immunomodulatory host defense peptides as novel anti-infectives. Trends Biotechnol. 27(10): 582-590. http://dx.doi.org/10.1016/j.tibtech.2009.07.004
  • Erdag G, Morgan JR (2002). Interleukin-1alpha and interleukin-6 enhance the antibacterial properties of cultured composite keratinocyte grafts. Ann. Surg. 235(1): 113-124. http://dx.doi.org/10.1097/00000658-200201000-00015
  • Erles K, Brownlie J (2010). Expression of beta-defensins in the canine respiratory tract and antimicrobial activity against Bordetella bronchiseptica. Vet. Immunol. Immunopathol. 135(1-2): 12-19. http://dx.doi.org/10.1016/j.vetimm.2009.10.025
  • Finlay BB, Hancock RE (2004). Can innate immunity be enhanced to treat microbial infections? Nat. Rev. Microbiol. 2(6): 497-504. http://dx.doi.org/10.1038/nrmicro908
  • Fjell CD, Hancock RE, Cherkasov A (2007). AMPer: a database and an automated discovery tool for antimicrobial peptides. Bioinformatics. 23(9): 1148-1155. http://dx.doi.org/10.1093/bioinformatics/btm068
  • Foureau DM, Mielcarz DW, Menard LC, Schulthess J, Werts C, Vasseur V, Ryffel B, Kasper LH, Buzoni-Gatel D (2010). TLR9-dependent induction of intestinal alpha-defensins by Toxoplasma gondii. J. Immunol. 184(12): 7022-7029. http://dx.doi.org/10.4049/jimmunol.0901642
  • Frohm M, Agerberth B, Ahangari G, Stahle-Backdahl M, Liden S, Wigzell H, Gudmundsson GH (1997). The expression of the gene coding for the antibacterial peptide LL-37 is induced in human keratinocytes during inflammatory disorders. J. Biol. Chem. 272(24): 15258-15263. http://dx.doi.org/10.1074/jbc.272.24.15258
  • Gallo RL, Ono M, Povsic T, Page C, Eriksson E, Klagsbrun M, Bernfield M (1994). Syndecans, cell surface heparan sulfate proteoglycans, are induced by a proline-rich antimicrobial peptide from wounds. Proc. Natl. Acad. Sci. USA. 91(23): 11035-11039. http://dx.doi.org/10.1073/pnas.91.23.11035
  • Gantois I, Ducatelle R, Pasmans F, Haesebrouck F, Hautefort I, Thompson A, Hinton JC, Van Immerseel F (2006). Butyrate specifically down-regulates salmonella pathogenicity island 1 gene expression. Appl. Environ. Microbiol. 72(1): 946-949. http://dx.doi.org/10.1128/AEM.72.1.946-949.2006
  • Gao N, Kumar A, Jyot J, Yu FS (2010). Flagellin-induced corneal antimicrobial peptide production and wound repair involve a novel NF-kappaB-independent and EGFR-dependent pathway. PLoS One. 5(2): e9351. http://dx.doi.org/10.1371/journal.pone.0009351
  • Gennaro R, Zanetti M (2000). Structural features and biological activities of the cathelicidin-derived antimicrobial peptides. Biopolymers. 55(1): 31-49. http://dx.doi.org/10.1002/1097-0282(2000)55:1<31::AID-BIP40>3.0.CO;2-9
  • Goitsuka R, Chen CL, Benyon L, Asano Y, Kitamura D, Cooper MD (2007). Chicken cathelicidin-B1, an antimicrobial guardian at the mucosal M cell gateway. Proc. Natl. Acad. Sci. USA. 104(38): 15063-15068. http://dx.doi.org/10.1073/pnas.0707037104
  • Groeneveld TW, Ramwadhdoebe TH, Trouw LA, van den Ham DL, van der Borden V, Drijfhout JW, Hiemstra PS, Daha MR, Roos A (2007). Human neutrophil peptide-1 inhibits both the classical and the lectin pathway of complement activation. Mol. Immunol. 44(14): 3608-3614. http://dx.doi.org/10.1016/j.molimm.2007.03.003
  • Guani-Guerra E, Santos-Mendoza T, Lugo-Reyes SO, Teran LM (2010). Antimicrobial peptides: general overview and clinical implications in human health and disease. Clin. Immunol. 135(1): 1-11. http://dx.doi.org/10.1016/j.clim.2009.12.004
  • Hale JD, Hancock RE (2007). Alternative mechanisms of action of cationic antimicrobial peptides on bacteria. Expert Rev. Anti. Infect. Ther. 5(6): 951-959. http://dx.doi.org/10.1586/14787210.5.6.951
  • Hancock RE, Nijnik A, Philpott DJ (2012). Modulating immunity as a therapy for bacterial infections. Nat. Rev. Microbiol. 10(4): 243-254. http://dx.doi.org/10.1038/nrmicro2745
  • Hancock RE, Scott MG (2000). The role of antimicrobial peptides in animal defenses. Proc. Natl. Acad. Sci. USA. 97(16): 8856-8861. http://dx.doi.org/10.1073/pnas.97.16.8856
  • Hansdottir S, Monick MM, Hinde SL, Lovan N, Look DC, Hunninghake GW (2008). Respiratory epithelial cells convert inactive vitamin D to its active form: potential effects on host defense. J. Immunol. 181(10): 7090-7099. http://dx.doi.org/10.4049/jimmunol.181.10.7090
  • Harder J, Meyer-Hoffert U, Wehkamp K, Schwichtenberg L, Schroder JM (2004). Differential gene induction of human beta-defensins (hBD-1, -2, -3, and -4). in keratinocytes is inhibited by retinoic acid. J. Invest. Dermatol. 123(3): 522-529. http://dx.doi.org/10.1111/j.0022-202X.2004.23234.x
  • Hase K, Eckmann L, Leopard JD, Varki N, Kagnoff MF (2002). Cell differentiation is a key determinant of cathelicidin LL-37/human cationic antimicrobial protein 18 expression by human colon epithelium. Infect. Immun. 70(2): 953-963. http://dx.doi.org/10.1128/IAI.70.2.953-963.2002
  • Hase K, Murakami M, Iimura M, Cole SP, Horibe Y, Ohtake T, Obonyo M, Gallo RL, Eckmann L, Kagnoff MF (2003). Expression of LL-37 by human gastric epithelial cells as a potential host defense mechanism against Helicobacter pylori. Gastroenterology. 125(6): 1613-1625. http://dx.doi.org/10.1053/j.gastro.2003.08.028
  • Hazrati E, Galen B, Lu W, Wang W, Ouyang Y, Keller MJ, Lehrer RI, Herold BC (2006). Human alpha- and beta-defensins block multiple steps in herpes simplex virus infection. J. Immunol. 177(12): 8658-8666. http://dx.doi.org/10.4049/jimmunol.177.12.8658
  • Hennig-Pauka I, Koch R, Hoeltig D, Gerlach GF, Waldmann KH, Blecha F, Brauer C, Gasse H (2012). PR-39, a porcine host defence peptide, is prominent in mucosa and lymphatic tissue of the respiratory tract in healthy pigs and pigs infected with Actinobacillus pleuropneumoniae. BMC Res. Notes. 5: 539. http://dx.doi.org/10.1186/1756-0500-5-539
  • Hiemstra PS (2007). The role of epithelial beta-defensins and cathelicidins in host defense of the lung. Exp. Lung Res. 33(10): 537-542. http://dx.doi.org/10.1080/01902140701756687
  • Hilchie AL, Wuerth K, Hancock RE (2013). Immune modulation by multifaceted cationic host defense (antimicrobial) peptides. Nat. Chem. Biol. 9(12): 761-768. http://dx.doi.org/10.1038/nchembio.1393
  • Hong SP, Kim MJ, Jung MY, Jeon H, Goo J, Ahn SK, Lee SH, Elias PM, Choi EH (2008). Biopositive effects of low-dose UVB on epidermis: coordinate upregulation of antimicrobial peptides and permeability barrier reinforcement. J. Invest. Dermatol. 128(12): 2880-2887. http://dx.doi.org/10.1038/jid.2008.169
  • Huang Y, Huang J, Chen Y (2010). Alpha-helical cationic antimicrobial peptides: relationships of structure and function. Protein Cell. 1(2): 143-152. http://dx.doi.org/10.1007/s13238-010-0004-3
  • Ibarra-Velarde F, Alcala-Canto Y (2007). Downregulation of the goat beta-defensin-2 gene by IL-4 in caprine intestinal epithelial cells infected with Eimeria spp. Parasitol. Res. 101(3): 613-618. http://dx.doi.org/10.1007/s00436-007-0523-x
  • Islam D, Bandholtz L, Nilsson J, Wigzell H, Christensson B, Agerberth B, Gudmundsson G (2001). Downregulation of bactericidal peptides in enteric infections: a novel immune escape mechanism with bacterial DNA as a potential regulator. Nat. Med. 7(2): 180-185. http://dx.doi.org/10.1038/84627
  • Jenssen H, Hancock RE (2010). Therapeutic potential of HDPs as immunomodulatory agents. Methods Mol. Biol. 618: 329-347. http://dx.doi.org/10.1007/978-1-60761-594-1_20
  • Jiang WY, Sunkara LT, Zeng XF, Deng Z, Myers SM, Zhang GL (2013). Differential regulation of human cathelicidin LL-37 by free fatty acids and their analogs. Peptides. 50: 129-138. http://dx.doi.org/10.1016/j.peptides.2013.10.008
  • Kallsen K, Andresen E, Heine H (2012). Histone deacetylase (HDAC). 1 controls the expression of beta defensin 1 in human lung epithelial cells. PLoS One. 7(11): e50000. http://dx.doi.org/10.1371/journal.pone.0050000
  • Kida Y, Shimizu T, Kuwano K (2006). Sodium butyrate up-regulates cathelicidin gene expression via activator protein-1 and histone acetylation at the promoter region in a human lung epithelial cell line, EBC-1. Mol. Immunol. 43(12): 1972-1981. http://dx.doi.org/10.1016/j.molimm.2005.11.014
  • Kirikae T, Hirata M, Yamasu H, Kirikae F, Tamura H, Kayama F, Nakatsuka K, Yokochi T, Nakano M (1998). Protective effects of a human 18-kilodalton cationic antimicrobial protein (CAP18).-derived peptide against murine endotoxemia. Infect. Immun. 66(5): 1861-1868.
  • Kohlgraf KG, Pingel LC, Dietrich DE, Brogden KA (2010). Defensins as anti-inflammatory compounds and mucosal adjuvants. Future Microbiol. 5(1): 99-113. http://dx.doi.org/10.2217/fmb.09.104
  • Kolls JK, McCray PB, Jr., Chan YR (2008). Cytokine-mediated regulation of antimicrobial proteins. Nat. Rev. Immunol. 8(11): 829-835. http://dx.doi.org/10.1038/nri2433
  • Kurland AR, Schreiner H, Diamond G (2006). In vivo beta-defensin gene expression in rat gingival epithelium in response to Actinobacillus actinomycetemcomitans infection. J. Periodontal. Res. 41(6): 567-572. http://dx.doi.org/10.1111/j.1600-0765.2006.00909.x
  • Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, Cao W, Su B, Nestle FO, Zal T, Mellman I, Schroder JM, Liu YJ, Gilliet M (2007). Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 449(7162): 564-569. http://dx.doi.org/10.1038/nature06116
  • Lehrer RI (2004). Primate defensins. Nat Rev Microbiol. 2(9): 727-738. http://dx.doi.org/10.1038/nrmicro976
  • Lehrer RI, Ganz T (2002). Cathelicidins: a family of endogenous antimicrobial peptides. Curr. Opin. Hematol. 9(1): 18-22. http://dx.doi.org/10.1097/00062752-200201000-00004
  • Li G, Domenico J, Jia Y, Lucas JJ, Gelfand EW (2009a). NF-kappaB-dependent induction of cathelicidin-related antimicrobial peptide in murine mast cells by lipopolysaccharide. Int. Arch. Allergy Immunol. 150(2): 122-132. http://dx.doi.org/10.1159/000218115
  • Li HN, Barlow PG, Bylund J, Mackellar A, Bjorstad A, Conlon J, Hiemstra PS, Haslett C, Gray M, Simpson AJ, Rossi AG, Davidson DJ (2009b). Secondary necrosis of apoptotic neutrophils induced by the human cathelicidin LL-37 is not proinflammatory to phagocytosing macrophages. J. Leukoc Biol. 86(4): 891-902. http://dx.doi.org/10.1189/jlb.0209050
  • Li XQ, Zhu YH, Zhang HF, Yue Y, Cai ZX, Lu QP, Zhang L, Weng XG, Zhang FJ, Zhou D, Yang JC, Wang JF (2012). Risks associated with high-dose Lactobacillus rhamnosus in an Escherichia coli model of piglet diarrhoea: intestinal microbiota and immune imbalances. PLoS One. 7(7): e40666. http://dx.doi.org/10.1371/journal.pone.0040666
  • Linde A, Ross CR, Davis EG, Dib L, Blecha F, Melgarejo T (2008). Innate immunity and host defense peptides in veterinary medicine. J. Vet. Int. Med. 22(2): 247-265. http://dx.doi.org/10.1111/j.1939-1676.2007.0038.x
  • Liu KX, Chen SQ, Zhang H, Guo JY, Li YS, Huang WQ (2009). Intestinal ischaemia/reperfusion upregulates beta-defensin-2 expression and causes acute lung injury in the rat. Injury. 40(9): 950-955. http://dx.doi.org/10.1016/j.injury.2009.01.103
  • Lynn DJ, Higgs R, Gaines S, Tierney J, James T, Lloyd AT, Fares MA, Mulcahy G, O’Farrelly C (2004). Bioinformatic discovery and initial characterisation of nine novel antimicrobial peptide genes in the chicken. Immunogenetics. 56(3): 170-177. http://dx.doi.org/10.1007/s00251-004-0675-0
  • McDonald V, Pollok RC, Dhaliwal W, Naik S, Farthing MJ, Bajaj-Elliott M (2006). A potential role for interleukin-18 in inhibition of the development of Cryptosporidium parvum. Clin. Exp. Immunol. 145(3): 555-562. http://dx.doi.org/10.1111/j.1365-2249.2006.03159.x
  • Meade KG, Cormican P, Narciandi F, Lloyd A, O’Farrelly C (2014). Bovine beta-defensin gene family: opportunities to improve animal health? Physiol. Genomics. 46(1): 17-28. http://dx.doi.org/10.1152/physiolgenomics.00085.2013
  • Meade KG, Narciandi F, Cahalane S, Reiman C, Allan B, O’Farrelly C (2009). Comparative in vivo infection models yield insights on early host immune response to Campylobacter in chickens. Immunogenetics. 61(2): 101-110. http://dx.doi.org/10.1007/s00251-008-0346-7
  • Mendez-Samperio P, Miranda E, Trejo A (2008). Expression and secretion of cathelicidin LL-37 in human epithelial cells after infection by Mycobacterium bovis Bacillus Calmette-Guerin. Clin. Vac. Immunol. 15(9): 1450-1455. http://dx.doi.org/10.1128/CVI.00178-08
  • Midorikawa K, Ouhara K, Komatsuzawa H, Kawai T, Yamada S, Fujiwara T, Yamazaki K, Sayama K, Taubman MA, Kurihara H, Hashimoto K, Sugai M (2003). Staphylococcus aureus susceptibility to innate antimicrobial peptides, beta-defensins and CAP18, expressed by human keratinocytes. Infect. Immun. 71(7): 3730-3739. http://dx.doi.org/10.1128/IAI.71.7.3730-3739.2003
  • Miles K, Clarke DJ, Lu W, Sibinska Z, Beaumont PE, Davidson DJ, Barr TA, Campopiano DJ, Gray M (2009). Dying and necrotic neutrophils are anti-inflammatory secondary to the release of alpha-defensins. J. Immunol. 183(3): 2122-2132. http://dx.doi.org/10.4049/jimmunol.0804187
  • Mookherjee N, Brown KL, Bowdish DM, Doria S, Falsafi R, Hokamp K, Roche FM, Mu R, Doho GH, Pistolic J, Powers JP, Bryan J, Brinkman FS, Hancock RE (2006). Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. J. Immunol. 176(4): 2455-2464. http://dx.doi.org/10.4049/jimmunol.176.4.2455
  • Mookherjee N, Hancock RE (2007). Cationic host defence peptides: innate immune regulatory peptides as a novel approach for treating infections. Cell Mol. Life Sci. 64(7-8): 922-933. http://dx.doi.org/10.1007/s00018-007-6475-6
  • Nakatsuji T, Kao MC, Zhang L, Zouboulis CC, Gallo RL, Huang CM (2010). Sebum free fatty acids enhance the innate immune defense of human sebocytes by upregulating beta-defensin-2 expression. J. Invest. Dermatol. 130(4): 985-994. http://dx.doi.org/10.1038/jid.2009.384
  • Nell MJ, Tjabringa GS, Vonk MJ, Hiemstra PS, Grote JJ (2004). Bacterial products increase expression of the human cathelicidin hCAP-18/LL-37 in cultured human sinus epithelial cells. FEMS Immunol. Med. Microbiol. 42(2): 225-231. http://dx.doi.org/10.1016/j.femsim.2004.05.013
  • Nijnik A, Pistolic J, Wyatt A, Tam S, Hancock RE (2009). Human cathelicidin peptide LL-37 modulates the effects of IFN-gamma on APCs. J. Immunol. 183(9): 5788-5798. http://dx.doi.org/10.4049/jimmunol.0901491
  • Niyonsaba F, Ushio H, Nagaoka I, Okumura K, Ogawa H (2005). The human beta-defensins (-1, -2, -3, -4). and cathelicidin LL-37 induce IL-18 secretion through p38 and ERK MAPK activation in primary human keratinocytes. J. Immunol. 175(3): 1776-1784. http://dx.doi.org/10.4049/jimmunol.175.3.1776
  • Oppenheim JJ, Biragyn A, Kwak LW, Yang D (2003). Roles of antimicrobial peptides such as defensins in innate and adaptive immunity. Ann. Rheum. Dis. 62(Suppl II): 217–221. http://dx.doi.org/10.1136/ard.62.suppl_2.ii17
  • Oren Z, Shai Y (1998). Mode of action of linear amphipathic alpha-helical antimicrobial peptides. Biopolymers. 47(6): 451-463. http://dx.doi.org/10.1002/(SICI)1097-0282(1998)47:6<451::AID-BIP4>3.0.CO;2-F
  • Palffy R, Gardlik R, Behuliak M, Kadasi L, Turna J, Celec P (2009). On the physiology and pathophysiology of antimicrobial peptides. Mol. Med. 15(1-2): 51-59.
  • Panyutich A, Shi J, Boutz PL, Zhao C, Ganz T (1997). Porcine polymorphonuclear leukocytes generate extracellular microbicidal activity by elastase-mediated activation of secreted proprotegrins. Infect. Immun. 65(3): 978-985.
  • Panyutich AV, Panyutich EA, Krapivin VA, Baturevich EA, Ganz T (1993). Plasma defensin concentrations are elevated in patients with septicemia or bacterial meningitis. J. Lab. Clin. Med. 122(2): 202-207.
  • Park K, Elias PM, Oda Y, Mackenzie D, Mauro T, Holleran WM, Uchida Y (2011). Regulation of cathelicidin antimicrobial peptide expression by an endoplasmic reticulum (ER). stress signaling, vitamin D receptor-independent pathway. J. Biol. Chem. 286(39): 34121-34130. http://dx.doi.org/10.1074/jbc.M111.250431
  • Pasupuleti M, Schmidtchen A, Malmsten M (2012). Antimicrobial peptides: key components of the innate immune system. Crit. Rev. Biotechnol. 32(2): 143-171. http://dx.doi.org/10.3109/07388551.2011.594423
  • Penberthy WT, Chari S, Cole AL, Cole AM (2011). Retrocyclins and their activity against HIV-1. Cell Mol. Life Sci. 68(13): 2231-2242. http://dx.doi.org/10.1007/s00018-011-0715-5
  • Peric M, Koglin S, Dombrowski Y, Gross K, Bradac E, Buchau A, Steinmeyer A, Zugel U, Ruzicka T, Schauber J (2009). Vitamin D analogs differentially control antimicrobial peptide/”alarmin” expression in psoriasis. PLoS One. 4(7): e6340. http://dx.doi.org/10.1371/journal.pone.0006340
  • Peric M, Koglin S, Kim SM, Morizane S, Besch R, Prinz JC, Ruzicka T, Gallo RL, Schauber J (2008). IL-17A enhances vitamin D3-induced expression of cathelicidin antimicrobial peptide in human keratinocytes. J. Immunol. 181(12): 8504-8512. http://dx.doi.org/10.4049/jimmunol.181.12.8504
  • Pingel LC, Kohlgraf KG, Hansen CJ, Eastman CG, Dietrich DE, Burnell KK, Srikantha RN, Xiao X, Belanger M, Progulske-Fox A, Cavanaugh JE, Guthmiller JM, Johnson GK, Joly S, Kurago ZB, Dawson DV, Brogden KA (2008). Human beta-defensin 3 binds to hemagglutinin B (rHagB): a non-fimbrial adhesin from Porphyromonas gingivalis, and attenuates a pro-inflammatory cytokine response. Immunol. Cell. Biol. 86(8): 643-649. http://dx.doi.org/10.1038/icb.2008.56
  • Pundir P, Kulka M (2010). The role of G protein-coupled receptors in mast cell activation by antimicrobial peptides: is there a connection? Immunol. Cell. Biol. 88(6): 632-640. http://dx.doi.org/10.1038/icb.2010.27
  • Putaala H, Barrangou R, Leyer GJ, Ouwehand AC, Hansen EB, Romero DA, Rautonen N (2010). Analysis of the human intestinal epithelial cell transcriptional response to Lactobacillus acidophilus, Lactobacillus salivarius, Bifidobacterium lactis and Escherichia coli. Benef. Microbes. 1(3): 283-295. http://dx.doi.org/10.3920/BM2010.0003
  • Raqib R, Sarker P, Bergman P, Ara G, Lindh M, Sack DA, Nasirul Islam KM, Gudmundsson GH, Andersson J, Agerberth B (2006). Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic. Proc. Natl. Acad. Sci. USA. 103(24): 9178-9183. http://dx.doi.org/10.1073/pnas.0602888103
  • Rivas-Santiago B, Hernandez-Pando R, Carranza C, Juarez E, Contreras JL, Aguilar-Leon D, Torres M, Sada E (2008). Expression of cathelicidin LL-37 during Mycobacterium tuberculosis infection in human alveolar macrophages, monocytes, neutrophils, and epithelial cells. Infect. Immun. 76(3): 935-941. http://dx.doi.org/10.1128/IAI.01218-07
  • Romeo D, Skerlavaj B, Bolognesi M, Gennaro R (1988). Structure and bactericidal activity of an antibiotic dodecapeptide purified from bovine neutrophils. J. Biol. Chem. 263(20): 9573-9575.
  • Ruan Y, Shen T, Wang Y, Hou M, Li J, Sun T (2013). Antimicrobial peptide LL-37 attenuates LTA induced inflammatory effect in macrophages. Int. Immunopharmacol. 15(3): 575-580. http://dx.doi.org/10.1016/j.intimp.2013.01.012
  • Russell JP, Diamond G, Tarver AP, Scanlin TF, Bevins CL (1996). Coordinate induction of two antibiotic genes in tracheal epithelial cells exposed to the inflammatory mediators lipopolysaccharide and tumor necrosis factor alpha. Infect. Immun. 64(5): 1565-1568.
  • Salzman NH (2010). Paneth cell defensins and the regulation of the microbiome: detente at mucosal surfaces. Gut. Microbes. 1(6): 401-406. http://dx.doi.org/10.4161/gmic.1.6.14076
  • Sang Y, Blecha F (2009). Porcine host defense peptides: expanding repertoire and functions. Dev. Comp. Immunol. 33(3): 334-343. http://dx.doi.org/10.1016/j.dci.2008.05.006
  • Sarker P, Ahmed S, Tiash S, Rekha RS, Stromberg R, Andersson J, Bergman P, Gudmundsson GH, Agerberth B, Raqib R (2011). Phenylbutyrate counteracts Shigella mediated downregulation of cathelicidin in rabbit lung and intestinal epithelia: a potential therapeutic strategy. PLoS One. 6(6): e20637. http://dx.doi.org/10.1371/journal.pone.0020637
  • Schauber J, Dorschner RA, Yamasaki K, Brouha B, Gallo RL (2006). Control of the innate epithelial antimicrobial response is cell-type specific and dependent on relevant microenvironmental stimuli. Immunology. 118(4): 509-519. http://dx.doi.org/10.1111/j.1365-2567.2006.02399.x
  • Schauber J, Iffland K, Frisch S, Kudlich T, Schmausser B, Eck M, Menzel T, Gostner A, Luhrs H, Scheppach W (2004). Histone-deacetylase inhibitors induce the cathelicidin LL-37 in gastrointestinal cells. Mol. Immunol. 41(9): 847-854. http://dx.doi.org/10.1016/j.molimm.2004.05.005
  • Schauber J, Oda Y, Buchau AS, Yun QC, Steinmeyer A, Zugel U, Bikle DD, Gallo RL (2008). Histone acetylation in keratinocytes enables control of the expression of cathelicidin and CD14 by 1,25-dihydroxyvitamin D3. J. Invest. Dermatol. 128(4): 816-824. http://dx.doi.org/10.1038/sj.jid.5701102
  • Schauber J, Svanholm C, Termen S, Iffland K, Menzel T, Scheppach W, Melcher R, Agerberth B, Luhrs H, Gudmundsson GH (2003). Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways. Gut. 52(5): 735-741. http://dx.doi.org/10.1136/gut.52.5.735
  • Schlee M, Harder J, Koten B, Stange EF, Wehkamp J, Fellermann K (2008). Probiotic lactobacilli and VSL#3 induce enterocyte beta-defensin 2. Clin. Exp. Immunol. 151(3): 528-535. http://dx.doi.org/10.1111/j.1365-2249.2007.03587.x
  • Schwab M, Reynders V, Loitsch S, Steinhilber D, Schroder O, Stein J (2008). The dietary histone deacetylase inhibitor sulforaphane induces human beta-defensin-2 in intestinal epithelial cells. Immunology. 125(2): 241-251. http://dx.doi.org/10.1111/j.1365-2567.2008.02834.x
  • Scocchi M, Skerlavaj B, Romeo D, Gennaro R (1992). Proteolytic cleavage by neutrophil elastase converts inactive storage proforms to antibacterial bactenecins. Eur. J. Biochem. 209(2): 589-595. http://dx.doi.org/10.1111/j.1432-1033.1992.tb17324.x
  • Scott A, Weldon S, Buchanan PJ, Schock B, Ernst RK, McAuley DF, Tunney MM, Irwin CR, Elborn JS, Taggart CC (2011). Evaluation of the ability of LL-37 to neutralise LPS in vitro and ex vivo. PLoS One. 6(10): e26525. http://dx.doi.org/10.1371/journal.pone.0026525
  • Selsted ME (2004). Theta-defensins: cyclic antimicrobial peptides produced by binary ligation of truncated alpha-defensins. Curr. Protein Pept. Sci. 5(5): 365-371. http://dx.doi.org/10.2174/1389203043379459
  • Selsted ME, Ouellette AJ (2005). Mammalian defensins in the antimicrobial immune response. Nat. Immunol. 6(6): 551-557. http://dx.doi.org/10.1038/ni1206
  • Shao CY, Wang H, Meng X, Zhu JQ, Wu YQ, Li JJ (2012). Characterization of the innate immune response in goats after intrauterine infusion of E. coli using histopathological, cytologic and molecular analyses. Theriogenology. 78(3): 593-604. http://dx.doi.org/10.1016/j.theriogenology.2012.03.005
  • Shi J, Aono S, Lu W, Ouellette AJ, Hu X, Ji Y, Wang L, Lenz S, van Ginkel FW, Liles M, Dykstra C, Morrison EE, Elson CO (2007). A novel role for defensins in intestinal homeostasis: regulation of IL-1beta secretion. J. Immunol. 179(2): 1245-1253. http://dx.doi.org/10.4049/jimmunol.179.2.1245
  • Sorensen OE, Borregaard N, Cole AM (2008). Antimicrobial peptides in innate immune responses. Contrib. Microbiol. 15: 61-77. http://dx.doi.org/10.1159/000136315
  • Sorensen OE, Cowland JB, Theilgaard-Monch K, Liu L, Ganz T, Borregaard N (2003). Wound healing and expression of antimicrobial peptides/polypeptides in human keratinocytes, a consequence of common growth factors. J. Immunol. 170(11): 5583-5589. http://dx.doi.org/10.4049/jimmunol.170.11.5583
  • Sorensen OE, Follin P, Johnsen AH, Calafat J, Tjabringa GS, Hiemstra PS, Borregaard N (2001). Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood. 97(12): 3951-3959. http://dx.doi.org/10.1182/blood.V97.12.3951
  • Steinmann J, Halldorsson S, Agerberth B, Gudmundsson GH (2009). Phenylbutyrate induces antimicrobial peptide expression. Antimicrob. Agents Chemother. 53(12): 5127-5133. http://dx.doi.org/10.1128/AAC.00818-09
  • Steinstraesser L, Koehler T, Jacobsen F, Daigeler A, Goertz O, Langer S, Kesting M, Steinau H, Eriksson E, Hirsch T (2008). Host defense peptides in wound healing. Mol. Med. 14(7-8): 528-537. http://dx.doi.org/10.2119/2008-00002
  • Steinstraesser L, Kraneburg U, Jacobsen F, Al-Benna S (2011). Host defense peptides and their antimicrobial-immunomodulatory duality. Immunobiology. 216(3): 322-333. http://dx.doi.org/10.1016/j.imbio.2010.07.003
  • Stolzenberg ED, Anderson GM, Ackermann MR, Whitlock RH, Zasloff M (1997). Epithelial antibiotic induced in states of disease. Proc. Natl. Acad. Sci. USA. 94(16): 8686-8690. http://dx.doi.org/10.1073/pnas.94.16.8686
  • Strominger JL (2009). Animal antimicrobial peptides: ancient players in innate immunity. J. Immunol. 182(11): 6633-6634. http://dx.doi.org/10.4049/jimmunol.0990038
  • Sumners LH, Miska KB, Jenkins MC, Fetterer RH, Cox CM, Kim S, Dalloul RA (2011). Expression of toll-like receptors and antimicrobial peptides during Eimeria praecox infection in chickens. Exp. Parasitol. 127(3): 714-718. http://dx.doi.org/10.1016/j.exppara.2010.12.002
  • Sunkara LT, Achanta M, Schreiber NB, Bommineni YR, Dai G, Jiang W, Lamont S, Lillehoj HS, Beker A, Teeter RG, Zhang G (2011). Butyrate enhances disease resistance of chickens by inducing antimicrobial host defense peptide gene expression. PLoS One. 6(11): e27225. http://dx.doi.org/10.1371/journal.pone.0027225
  • Sunkara LT, Jiang W, Zhang G (2012). Modulation of antimicrobial host defense peptide gene expression by free fatty acids. PLoS One. 7(11): e49558. http://dx.doi.org/10.1371/journal.pone.0049558
  • Sunkara LT, Zeng X, Curtis AR, Zhang G (2014). Cyclic AMP synergizes with butyrate in promoting beta-defensin 9 expression in chickens. Mol. Immunol. 57(2): 171-180. http://dx.doi.org/10.1016/j.molimm.2013.09.003
  • Suphasiriroj W, Mikami M, Shimomura H, Sato S (2013). Specificity of antimicrobial peptide LL-37 to neutralize periodontopathogenic lipopolysaccharide activity in human oral fibroblasts. J. Periodontol. 84(2): 256-264. http://dx.doi.org/10.1902/jop.2012.110652
  • Talukder P, Satho T, Irie K, Sharmin T, Hamady D, Nakashima Y, Kashige N, Miake F (2011). Trace metal zinc stimulates secretion of antimicrobial peptide LL-37 from Caco-2 cells through ERK and p38 MAP kinase. Int. Immunopharmacol. 11(1): 141-144. http://dx.doi.org/10.1016/j.intimp.2010.10.010
  • Timbermont L, Lanckriet A, Dewulf J, Nollet N, Schwarzer K, Haesebrouck F, Ducatelle R, Van Immerseel F (2010). Control of Clostridium perfringens-induced necrotic enteritis in broilers by target-released butyric acid, fatty acids and essential oils. Avian Pathol. 39(2): 117-121. http://dx.doi.org/10.1080/03079451003610586
  • Tomasinsig L, Scocchi M, Di Loreto C, Artico D, Zanetti M (2002). Inducible expression of an antimicrobial peptide of the innate immunity in polymorphonuclear leukocytes. J. Leukoc Biol. 72(5): 1003-1010.
  • Uzzell T, Stolzenberg ED, Shinnar AE, Zasloff M (2003). Hagfish intestinal antimicrobial peptides are ancient cathelicidins. Peptides. 24(11): 1655-1667. http://dx.doi.org/10.1016/j.peptides.2003.08.024
  • van Dijk A, Molhoek EM, Bikker FJ, Yu PL, Veldhuizen EJ, Haagsman HP (2011). Avian cathelicidins: paradigms for the development of anti-infectives. Vet. Microbiol. 153(1-2): 27-36. http://dx.doi.org/10.1016/j.vetmic.2011.03.028
  • van Dijk A, Tersteeg-Zijderveld MH, Tjeerdsma-van Bokhoven JL, Jansman AJ, Veldhuizen EJ, Haagsman HP (2009). Chicken heterophils are recruited to the site of Salmonella infection and release antibacterial mature Cathelicidin-2 upon stimulation with LPS. Mol. Immunol. 46(7): 1517-1526. http://dx.doi.org/10.1016/j.molimm.2008.12.015
  • van Dijk A, Veldhuizen EJ, Haagsman HP (2008). Avian defensins. Vet. Immunol. Immunopathol. 124(1-2): 1-18. http://dx.doi.org/10.1016/j.vetimm.2007.12.006
  • van Dijk A, Veldhuizen EJ, van Asten AJ, Haagsman HP (2005). CMAP27, a novel chicken cathelicidin-like antimicrobial protein. Vet. Immunol. Immunopathol. 106(3-4): 321-327. http://dx.doi.org/10.1016/j.vetimm.2005.03.003
  • Van Immerseel F, De Buck J, Boyen F, Bohez L, Pasmans F, Volf J, Sevcik M, Rychlik I, Haesebrouck F, Ducatelle R (2004). Medium-chain fatty acids decrease colonization and invasion through hilA suppression shortly after infection of chickens with Salmonella enterica serovar Enteritidis. Appl. Environ. Microbiol. 70(6): 3582-3587. http://dx.doi.org/10.1128/AEM.70.6.3582-3587.2004
  • Van Immerseel F, De Buck J, Pasmans F, Velge P, Bottreau E, Fievez V, Haesebrouck F, Ducatelle R (2003). Invasion of Salmonella enteritidis in avian intestinal epithelial cells in vitro is influenced by short-chain fatty acids. Int. J. Food Microbiol. 85(3): 237-248. http://dx.doi.org/10.1016/S0168-1605(02)00542-1
  • Van Immerseel F, Russell JB, Flythe MD, Gantois I, Timbermont L, Pasmans F, Haesebrouck F, Ducatelle R (2006). The use of organic acids to combatSalmonellain poultry: a mechanistic explanation of the efficacy. Avian Pathol. 35(3): 182-188. http://dx.doi.org/10.1080/03079450600711045
  • Veldhuizen EJ, Hendriks HG, Hogenkamp A, van Dijk A, Gaastra W, Tooten PC, Haagsman HP (2006). Differential regulation of porcine beta-defensins 1 and 2 upon Salmonella infection in the intestinal epithelial cell line IPI-2I. Vet. Immunol. Immunopathol. 114(1-2): 94-102. http://dx.doi.org/10.1016/j.vetimm.2006.07.012
  • Veldhuizen EJ, Koomen I, Ultee T, van Dijk A, Haagsman HP (2009). Salmonella serovar specific upregulation of porcine defensins 1 and 2 in a jejunal epithelial cell line. Vet. Microbiol. 136(1-2): 69-75. http://dx.doi.org/10.1016/j.vetmic.2008.09.072
  • Wan ML, Woo CS, Allen KJ, Turner PC, El-Nezami H (2013). Modulation of porcine beta-defensins 1 and 2 upon individual and combined Fusarium toxin exposure in a swine jejunal epithelial cell line. Appl. Environ. Microbiol. 79(7): 2225-2232. http://dx.doi.org/10.1128/AEM.03277-12
  • Wang G (2014). Human antimicrobial peptides and proteins. Pharmaceuticals (Basel). 7(5): 545-594. http://dx.doi.org/10.1007/s12602-014-9159-1
  • Wang G, Li X, Wang Z (2009). APD2: the updated antimicrobial peptide database and its application in peptide design. Nucleic Acid. Res. 37(Database issue): D933-937. http://dx.doi.org/10.1088/0022-3727/42/11/115405
  • Wu H, Zhang G, Minton JE, Ross CR, Blecha F (2000). Regulation of cathelicidin gene expression: induction by lipopolysaccharide, interleukin-6, retinoic acid, and Salmonella enterica serovar typhimurium infection. Infect. Immun. 68(10): 5552-5558. http://dx.doi.org/10.1163/156855800744610
  • Wu Q, Gui P, Yao S, Zhu H, Li J, Li Y (2011). Expression of beta-defensin-3 in lungs of immunocompetent rats with methicillin-resistant Staphylococcus aureus ventilator-associated pneumonia. J. Surg. Res. 169(2): 277-283. http://dx.doi.org/10.1016/j.jss.2009.12.012
  • Xiao Y, Cai Y, Bommineni YR, Fernando SC, Prakash O, Gilliland SE, Zhang G (2006). Identification and functional characterization of three chicken cathelicidins with potent antimicrobial activity. J. Biol. Chem. 281(5): 2858-2867. http://dx.doi.org/10.1074/jbc.M507180200
  • Yang D, Chertov O, Oppenheim JJ (2001). Participation of mammalian defensins and cathelicidins in anti-microbial immunity: receptors and activities of human defensins and cathelicidin (LL-37). J. Leukoc Biol. 69(5): 691-697.
  • Yeaman MR, Yount NY (2003). Mechanisms of antimicrobial peptide action and resistance. Pharmacol. Rev. 55(1): 27-55. http://dx.doi.org/10.1124/pr.55.1.2
  • Yeung ATY, Gellatly SL, Hancock REW (2011). Multifunctional cationic host defence peptides and their clinical applications. Cell Mol. Life Sci. 68(13): 2161-2176. http://dx.doi.org/10.1007/s00018-011-0710-x
  • Yin J, Yu FS (2010). LL-37 via EGFR transactivation to promote high glucose-attenuated epithelial wound healing in organ-cultured corneas. Invest. Ophthalmol. Vis. Sci. 51(4): 1891-1897. http://dx.doi.org/10.1167/iovs.09-3904
  • Yount NY, Yeaman MR (2005). Immunocontinuum: perspectives in antimicrobial peptide mechanisms of action and resistance. Protein Pept. Lett. 12(1): 49-67. http://dx.doi.org/10.2174/0929866053405959
  • Zaalouk TK, Bajaj-Elliott M, George JT, McDonald V (2004). Differential regulation of beta-defensin gene expression during Cryptosporidium parvum infection. Infect. Immun. 72(5): 2772-2779. http://dx.doi.org/10.1128/IAI.72.5.2772-2779.2004
  • Zanetti M, Gennaro R, Romeo D (1995). Cathelicidins: a novel protein family with a common proregion and a variable C-terminal antimicrobial domain. FEBS Lett. 374(1): 1-5. http://dx.doi.org/10.1016/0014-5793(95)01050-O
  • Zanetti M, Litteri L, Griffiths G, Gennaro R, Romeo D (1991). Stimulus-induced maturation of probactenecins, precursors of neutrophil antimicrobial polypeptides. J. Immunol. 146(12): 4295-4300.
  • Zasloff M (2002). Antimicrobial peptides of multicellular organisms. Nature. 415(6870): 389-395. http://dx.doi.org/10.1038/415389a
  • Zeng X, Sunkara LT, Jiang W, Bible M, Carter S, Ma X, Qiao S, Zhang G (2013). Induction of porcine host defense Peptide gene expression by short-chain Fatty acids and their analogs. PLoS One. 8(8): e72922. http://dx.doi.org/10.1371/journal.pone.0072922
  • Zhang G, Ross CR, Dritz SS, Nietfeld JC, Blecha F (1997). Salmonella infection increases porcine antibacterial peptide concentrations in serum. Clin. Diagn. Lab. Immunol. 4(6): 774-777.
  • Zhang G, Sunkara LT (2014). Avian antimicrobial host defense peptides: from biology to therapeutic applications. Pharmaceuticals (Basel). 7(3): 220-247. http://dx.doi.org/10.3390/ph7030220
  • Zhao C, Nguyen T, Liu L, Sacco RE, Brogden KA, Lehrer RI (2001). Gallinacin-3, an inducible epithelial beta-defensin in the chicken. Infect. Immun. 69(4): 2684-2691. http://dx.doi.org/10.1128/IAI.69.4.2684-2691.2001
  • Zhao H, Gan TX, Liu XD, Jin Y, Lee WH, Shen JH, Zhang Y (2008). Identification and characterization of novel reptile cathelicidins from elapid snakes. Peptides. 29(10): 1685-1691. http://dx.doi.org/10.1016/j.peptides.2008.06.008
  • Zilbauer M, Dorrell N, Boughan PK, Harris A, Wren BW, Klein NJ, Bajaj-Elliott M (2005). Intestinal innate immunity to Campylobacter jejuni results in induction of bactericidal human beta-defensins 2 and 3. Infect. Immun. 73(11): 7281-7289. http://dx.doi.org/10.1128/IAI.73.11.7281-7289.2005
  •