Interleukin 17C: Is It A Host Defense Factor In The Oral Innate Immunity?
Takahiro Chino* and Ryan Yu
Department of Biomedical Sciences, University of the Pacific, Arthur A. Dugoni School of Dentistry, USA
Submission: February 04, 2017; Published: March 09, 2017
*Corresponding author: NTakahiro Chino, DDS, MSD, PhD, Department of Biomedical Sciences University of the Pacific, Arthur A. Dugoni School of Dentistry 155 5th St., San Francisco, California, USA 94103, Tel:451-929-3301 ; Fax: 415-929-6564 ; Email:tchino@pacific.edu
How to cite this article: Chino T, Yu R. Interleukin 17C: Is It A Host Defense Factor In The Oral Innate Immunity?. Adv Dent & Oral Health. 2017; 4(3):555630. DOI: 10.19080/ADOH.2017.04.555631
Abstract
Toll-like receptors (TLRs) expressed on oral epithelial cells (OECs) enable rapid response to microorganisms by secreting antimicrobial peptides as well as cytokines that play pivotal roles in antimicrobial immunity. Several lines of investigation have revealed that cytokines play important roles not only in tissue homeostasis, but also in the pathogenesis of infectious disease including periodontitis. OECs also express receptors for a number of different cytokines. Thus, cytokines secreted by OECs may play an autocrine role or may influence adjacent non-epithelial cells. IL-17C, a member of the IL-17 cytokine family, is mainly produced by epithelial cells. Its role in the gut- immune system has recently been proposed, however, the biological significance of IL-17C and its receptor on OECs in the maintenance of oral mucosal homeostasis and pathogenesis of periodontitis has not been systematically investigated. This mini review will give a current understanding of immunomodulatory roles of IL-17C to maintain mucosal homeostasis, including oral cavity.
Keywords: Interleukin-17C; β-defensin; Oral mucosa; Innate immunity
Introduction
The oral cavity harbors a diverse and complex microbial community. The oral microbial flora contains approximately 500 species, and is composed of both commensal and pathogenic species [1]. Bacteria accumulate on both the hard and soft oral tissues in a sessile biofilm. In this highly antigenic environment, oral mucosal tissue must maintain tolerance to commensal bacteria and other molecules, such as proteins in food. Under certain circumstances, however, the oral bacterial flora can induce an immune response resulting in inflammatory manifestations, such as periodontitis.
Oral innate immunity
The mucosal surface of the oral cavity is protected primarily by secretory components of the salivary glands and oral epithelium. Saliva contains an array of molecules that play vital roles in the innate and adaptive host defense mechanisms [2]. Innate host defense factors in saliva function to promote bacterial agglutination, inhibit bacterial growth, inhibit bacterial proteases, or prevent bacteria from cell wall synthesis. Secretory IgA is the major antibody in saliva and specifically binds to target antigens.
The oral epithelium functions as the first line of defense against invading microorganisms to maintain oral mucosal homeostasis. Toll-like receptors (TLRs) expressed on oral epithelial cells (OECs) enable rapid response to microorganisms by secreting chemokines, cytokines and antimicrobial peptides that play pivotal roles in antimicrobial immunity [3]. For example, ligation of TLR9 by CpG induced IL-8 expression in gingival epithelial cells [4]. IL-8 is a chemoattractant for neutrophils, recruiting them to the site of infection. OECs also express receptors for a number of different cytokines. Thus, cytokines secreted by OECs may play an autocrine role or may influence adjacent non-epithelial cells. In addition, cytokines and other molecules in saliva [5] may stimulate OECs to secrete cytokines, chemokines, and antimicrobial peptides. Periodontal disease is a type of chronic, destructive, inflammatory disease resulting from a polymicrobial disruption of the oral mucosal homeostasis [6].
The β-defensins are antimicrobial peptides that possess a broad spectrum of activity against both Gram-negative and Gram-positive bacteria as well as some fungi and viruses [7,8]. In addition to their direct antimicrobial activity, human β-defensins (hBDs) also directly stimulate antigen- presenting dendritic cells and memory T cells, and thus can link innate and adaptive immune responses [3,9-11]. Human β-defensin 1 (hBD1) is constitutively expressed by OECs, while the expression of hBD2 and hBD3 is inducible. Epithelial cells produce hBD2 and hBD3 following stimulation with microorganisms (Gram-negative, Gram-positive bacteria and Candida albicans) or cytokines such as TNF-α and IL-1β [3,12-14].
IL-17C
IL-17C, a member of the IL-17 cytokine family, is mainly produced by epithelial cells [15,16]. Colon and tracheal epithelial cells as well as epidermal keratinocytes revealed enhanced secretion of IL-17C in response to heat-killed Escherichia coli. Moreover, TLR2 and TLR5 ligands, and cytokines, such as TNF-α and IL-1β, also regulate the expression of IL-17C in colon epithelial cells and epidermal keratinocytes, respectively [16]. IL- 17C binds to the IL-17RA/IL-17RE receptor complex expressed on the epithelial cells, resulting in the recruitment of adapter molecule, Act1, to the receptor complex. This triggers the NFκB activation, leading to the expression of target gene that plays a role in the innate host defense mechanism [15-17]. IL-17C also plays a role in T cell polarization. IL-17C binding to IL-17RE directs the differentiation of CD4+ T cells into Th17 populations [18].
recombinant human (rh) IL-17C enhanced hBD2 secretion [16]. Mice lacking IL-17C revealed exacerbated dextran sodium sulfate (DSS) induced colitis associated with degraded expression of tight junction protein in colonic epithelial cells [17]. On the contrary, mice lacking IL-17C were partially resistant to experimental autoimmune encephalomyelitis (EAE) [18], indicating that IL-17C is a key molecule for the pathogenesis of EAE. This can be explained, at least in part, by the difference in the cell type predominates in the disease. DSS-induced colitis is a disease model of innate immunity [19], while EAE is Th17 mediated condition [18]. Taken together, IL-17C can be either anti- or pro-inflammator cytokine. IL-17C exerts its anti-inflammatory function in the innate immunity. It functions as pro- inflammatory cytokine in the adaptive immunity. However, the biological significance of IL-17C and its receptor on OECs in maintaining oral mucosal homeostasis and pathogenesis of periodontitis has not been systematically investigated.
Hypothetical model of IL-17C in oral innate immunity
Intestinal homeostasis mediated by IL-17C has been wellstudied. However, the biological significance of IL-17C and its receptor on OECs in maintaining oral mucosal homeostasis and pathogenesis of periodontitis has not been systematically investigated. Recent study showed the slight immunoreactivity against IL-17C in healthy oral epithelium [20]. In addition, OECs expressed IL-17C, IL-17RA, and IL-17RE mRNA. Our preliminary data showed that IL-17C was secreted by OECs in response to TLR ligands. These data suggests that IL-17C is constitutively expressed by OECs and bacterial challenge enhances its expression. Since IL- 17C induces hBD2 from keratinocytes, we hypothesize that IL-17C binds back to OECs in autocrine and/or paracrine manner, leading to hBD2 secretion from these cells (Figure 1).
Conclusion
IL-17C is one of the key regulatory molecules to maintain homeostasis of intestinal mucosa and we proposed its role in oral innate immunity. The experiments have been underway to investigate whether or not IL-17C secreted by OECs play a role in maintaining oral mucosal homeostasis.
Acknowledgement
This work was supported in part by a Research Pilot Project Award 03-Activity 092 (T. Chino) from University of the Pacific, Arthur A. Dugoni School of Dentistry,
References
- Paster BJ, Boches SK, Galvin JL, Ericson RE, Lau CN, et al. (2001) Bacterial diversity in human subgingival plaque. J Bacteriol 183(12): 3770-3783.
- Gorr SU (2009) Antimicrobial peptides of the oral cavity. Periodontol 2000(51): 152-180.
- Yin L, Chino T, Horst OV, Hacker BM, Clark EA, et al. (2010) Differential and coordinated expression of defensins and cytokines by gingival epithelial cells and dendritic cells in response to oral bacteria. BMC Immunol 11: 37.
- Kim Y, Jo AR, Jang DH, Cho YJ, Chun J, et al. (2012) Toll-like receptor 9 mediates oral bacteria- induced IL-8 expression in gingival epithelial cells. Immunol Cell Biol 90(6): 655-663.
- Takayama A, Satoh A, Ngai T, Nishimura T, Ikawa K, et al. (2003) Augmentation of Actinobacillus actinomycetemcomitans invasion of human oral epithelial cells and up-regulation of interleukin-8 production by saliva CD14. Infect Immun 71(10): 5598-5604.
- Bartold PM, Van Dyke TE (2013) Periodontitis: a host-mediated disruption of microbial homeostasis. Unlearning learned concepts. Periodontol 2000 62 (1): 203-217.
- Ganz T (2003) Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 3: 710-720.
- Nuding S, Zabel LT, Enders C, Porter E, Fellermann K, et al. (2009) Antibacterial activity of human defensins on anaerobic intestinal bacterial species: a major role of HBD-3. Microbes Infect 11(3): 384- 393.
- Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, et al. (1999) Betadefensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 286(5439): 525-528.
- Yang D, Biragyn A, Hoover DM, Lubkowski J, Oppenheim JJ (2004) Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense. Annu Rev Immunol 22: 181-215.
- Brogden KA, Heidari M, Sacco RE, Palmquist D, Guthmiller JM, et al. (2003) Defensin-induced adaptive immunity in mice and its potential in preventing periodontal disease. Oral Microbiol Immunol 18(2): 95-99.
- Mathews M, Jia HP, Guthmiller JM, Losh G, Graham S, et al. (1999) Production of beta-defensin antimicrobial peptides by the oral mucosa and salivary glands. Infect Immun 67(6): 2740-2745.
- Krisanaprakornkit S, Kimball JR, Weinberg A, Darveau RP, Bainbridge BW, et al. (2000) Inducible expression of human beta-defensin 2 by Fusobacterium nucleatum in oral epithelial cells: multiple signaling pathways and role of commensal bacteria in innate immunity and the epithelial barrier. Infect Immun 68(5): 2907-2915.
- Liu AY, Destoumieux D, Wong AV, Park CH, Valore EV, et al. (2002) Human beta-defensin-2 production in keratinocytes is regulated by interleukin-1, bacteria, and the state of differentiation. J Invest Dermatol 118(2): 275-281.
- Song X, Zhu S, Shi P, Liu Y, Shi Y, et al. (2011) IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens. Nat Immunol 12(12): 1151-1158.
- Ramirez-Carrozzi V, Sambandam A, Luis E, Lin Z, Jeet S, et al. (2011) IL-17C regulates the innate immune function of epithelial cells in an autocrine manner. Nat Immunol 12(12): 1159-1166.
- Reynolds JM, Martinez GJ, Nallaparaju KC, Chang SH, Wang YH, et al. (2012) Cutting edge: regulation of intestinal inflammation and barrier function by IL-17C. J Immunol 189(9): 4226-4230.
- Chang SH, Reynolds JM, Pappu BP, Chen G, Martinez GJ, et al. (2011) Interleukin-17C promotes Th17 cell responses and autoimmune disease via interleukin-17 receptor E Immunity 35(4): 611-621.
- Kim YS, Lee MH, Ju AS, Rhee KJ (2011) Th17 responses are not induced in dextran sodium sulfate model of acute colitis. Immune Netw 11(6): 416-419.
- Al-Samadi A, Kouri VP, Salem A, Ainola M, Kaivosoja E, et al. (2014) IL-17C and its receptor IL-17RA/IL-17RE identify human oral epithelial cell as an inflammatory cell in recurrent aphthous ulcer. J Oral Pathol Med 43(2): 117-124.