Oral mucosal epithelia as other types of mucosal epithelia are known traditionally as protective tissues. In the present mini-review, attempts were made to introduce oral epithelia as non-lymphoid, non-myeloid tissue with immune potentials. Today, opinions holds the believe that oral epithelial cells have TLR system and can recognize microbial invaders. Microbial invaders in turn, induce epithelia to produce pro-inflammatory TH1, TH2 cytokines and Chemokines. The induction processes described as species and strain specific. Natural epithelial cytokine production has been assured by a number of in-vitro models. Oral epithelial cytokine interplayed several immune functions like regulation of local immune responses, mediate autoimmune disease and induce tissue damage in case of increased secretion. They express multi-factorial influences on mucosal immune compartment, be an integral part of the local innate immune responses and might have a future implication in vaccine immunity.

Keywords: cytokine, epithelia, immune response, microbiome, toll-like receptor

OMC, oral mucosal compartment; OMM, oral mucous membrane; OEC, oral epithelial cytokines; EC, epithelial cells

Overview: The epithelial tissue lining the oral cavity is now being considered as an integral part of the oral innate immune system and displayed a multi-factorial influences on the oral mucosal immunity. Among these influences epithelial cell produced cytokines and chemokines.¹ The aim of the present mini-review is confined onto the oral epithelial cytokines.

Oral Topography: Stomium, oral cavity or mouth is situated at the port of entry of the gastro-intestinal tract, as a cavity. It is enclosed on the sides by lips and checks, above by the soft and hard plates and below by the floor of the mouth and the tongue. The lips are lined on the outside by skin and on the inside by mucous membrane. Small glands are situated beneath the mucous membrane and there are many bundles of muscles within the lips. The palate is divided into hard and soft. The hard palate at the front of the mouth and the soft at the back. The bones of the hard palate are covered by thick layer of firm soft tissue. The soft palate connects with the passageway from the mouth to the throat. It is continue with tissues en-circuling the opening of the pharynx. The floor of the mouth lies in horse-shoe around the tongue. Near the front end are the openings of the sub-mandibular salivary glands.^2‒4

Oral Mucosal Compartment (OMC): The OMC is formed from mucosa associated lymphoid tissues beneath the mucosal membranes of the gum, Periodontium, salivary glands and tonsils⁵ (Table 1).

Oral Mucous Membrane (OMM): The basic elements of the mucous membrane are formed from an epithelium ⁶. OMM covers gingival surface, gingival part of the periodontium, tongue, salivary glands as well as tonsils. The epithelia of such mucous membrane can be keratinized, para-keratinized and non-keratinized with most evident type, the stratified Squamous epithelium⁷ (Table 1). The immune functions of the mucous membrane are; mechanical barrier, lubrication, site for mucosal IgA and trapper of the microbial invaders^7,8 (Table 1).

Epithelia is the plural of the singular epithelium. They are specialized layers that covered the external surface of the organs forming the body. An epithelium constitutes a sheet of cells lining close together with distinct biochemical, functional and structural domains that confer polarity, sideness to the epithelia. Epithelia are avascular and receive nourishment through diffusion of the molecules via basal lamina. Their functions can be; trans-cellular transport, secretion of hormones mucous and proteins as well as, selective permeability.⁷

Epithelia have lateral epithelial surface and apical epithelial surface. The lateral surface contains specialized junctions that produce adhesions between cells and restrict movement of matters into and out of the lamina .Basal epithelial surfaces are formed from an extracellular supportive structure the basal lamina, Hemidesmosomes and basal plasma membrane in-foldings. While apical surfaces posses specialized structures like micro-vili, sterio-cilia and cilia.^7,8

Two non-immune mediated diseases involving epithelia; the immotile cilia syndrome and the epithelial cell tumors, carcinoma and adeno-carcinoma. A third immune mediated autoimmune disease the Bullous pemphigoid also involves epithelia.^7‒9

In the immunologic sense, the epithelia played several functions of immune nature like; Mechanical barrier, trapping, innate immune recognition, innate immune response and cytokine production (Table 2).

Nomenclature

Before scientists be able to coin the term “cytokines” several names have been used to assign them as noted in Table 3.

Nature

Cytokines are secreted regulator proteins that have pleotropic regulatory effects on haemopoietic and non-haemopoietic cells. They are synthesized and secreted by every nucleated cell of the body.¹⁰ Cytokines include; Interleukins, tumor necrotic factors, growth factors and interferons. The boarders of the cytokine world are ill-defined and rather un-stable (Table 4). The basic functional features of cytokine action is the network signal language fashion.^10,11

The oral cytokines and chemokines are either of systemic or local secreted origins. They have numerous immunologic and non-immunologic functions such as: Immune responses, immunoglobulin class switching, inflammatory responses, cell growth, cell differentiation and expansion.¹² Excessive cytokine production affects tissue damages.^13,14

Classification

Cytokine can be classified in accordance with various criteria like; structure, capacity to interact with different classes of receptors and functions.¹² In structural sense, cytokines have been classified according to their overall three dimensional structure and their receptor structure (Table 5 & 6). When cytokine structure and functions have been studied in details as a results six families are evident as; Interleukine family, hemo-poietin family, interferon family, tumor necrosis factor family, interleukine 17 family and chemokine family.¹⁰

Oral Epithelial Cytokines (OEC)

The oral epithelial cells recognize microbial invaders through their TLRs. The invaders or their subunits can stimulate epithelial cell to produce cytokines. The profiles of such cytokines can match that of natural immune cells, TH1, TH2 cytokines and chemokines. The mode of synthesis and release are through either constitutive or inductive pathways.^14,15

OEC have been described as species and strain dependent manner. They may take part in; Regulation of local oral immune responses, augment epithelial cells to secret more cytokines, mediate autoimmune responses and activate neutrophil. OEC can inhibit fungal growth, potentiate virulence of some fungi. Lipopolysacchrides, lipotichoic acid and peptidoglycan potentiate oral epithelial cells to secret cytokines, initiate and perpetuate oral mucosal inflammation and/or tissue damage in cases of excessive secretion.^16‒19 Epithelial cells (EC) are important elements of the innate immune system. EC from periodontal pocket are integral part of the immune system in the oral cavity.¹⁸

INF g primed EC precondition them for stimulation by microbial component through up-regulation of their TLR system.¹⁹ Cytokines and chemokines are involved in the interaction between gum epithelial cell and dendritic cells (DCs). The responses are bacterio-specific differential and coordinated regulation between gingival EC and DCs may be important in regulation of innate hemostasis and responses to pathogens in the oral cavity.¹ Polymorph nuclear cell induce protective type TH1 cytokines epithelial response in an in-vitro model of oral candidiasis.¹⁶

The infection of oral epithelial cells with C. albicans augments the antifungal activity of neutrophil.¹⁷ Microbial but not the vaccine components initiate immune responses. Such responses will lead to the development of TNF alpha and mediate autoimmune inflammatory disease in the submandibular glands, in which the microbial subunits induce the release of TNF alpha that triggers the secretion of IL8 from ECs.²⁰

In the cellular immune-biologic sense, there is a theme²¹ of a tripartite local reaction that occurred between the oral epithelial cells with the oral resident microbiome and the OECs with the invading dental microbial pathogen. The local microbiome did an interplay with the oral immune compartment and has been reviewed.^5,21,22 So as that interplay, the OECs face and interact with commensal part of the local microbiome and established a state of harmony.²³ While, the OECs recognize and interact with the pathogenic microbe such interaction may lead to initiation of the innate inflammatory cytokine and antimicrobial peptide productions.^24,25 Parallel to these events, the pathogen may establish an intracellular persistence within the oral epithelial cells (As in case of Porphyromonas gingivalis). Thus, the net functional outcomes of OECs in such interplay are; Recognition, respond to, pro-inflammatory and inflammatory cytokine production and intracellular persistence of some dental pathogen like P. gingivalis. Such intracellular persistence might contribute in case of its course of chronicity to cellular hypersensitivity, and autoimmune reactions.^26,27 (Table 7).

Primary epithelial cell culture (ECC):

The epithelial layer from hard palate of the mouth biopsied by specialist. It is macerated, washed and treated with trypsin or collagenase for relatively short time to free the cells from the tissue remnants and mucus. Epithelial cells are, washed, centrifuged and suspended into tissue culture medium which support their growth. The cell suspension is dispensed in tubes and bottles where cells can adhere to the wall and grown into a monolayer. These monolayer cultures are found to be devoid of CD14 and did not enhance for production of IL8 and GMCSF when stimulated by LPS and LTA. While when treated with INFg for three days, they will secret IL8 and GMCF in response to LPS and LAT.^28,29

An in vitro oral epithelial model

A tissue engineered model of oral cavity epithelium has been developed. Oral bacteria are used to induce the epithelia to produce pro-inflammatory cytokines and compared to that of sub-emerged epithelial monolayer. The epi-oral Epi-oral tissue model was characterized for keratin and beta defensine evaluations by RT-PCR after exposure to bacteria and TNF alpha cytokines in the medium. The epi-oral responses were compared to the response of traditional sub-emerged oral epithelial culture.Better cytokine responses were noted by the epi-oral model.³⁰

An in-vitro model for host-parasite interactions

Gingival epithelial primary culture was prepared as a monolayer. This monolayer was exposed to bio-film of plaque forming dental bacteria. The bio-film-monolayer culture system was incubated for certain time period. Bio-film invoked apoptosis in epithelial cells, triggering the release of pro-inflammatory cytokines and in parallel seen induced degradation of the cytokine by the action of the bio-film generating enzymes.³¹

Oral mucosal epithelium is being introduced into the world of immune function. They interplayed functional roles in both natural (innate) and adapted oral mucosal immune responses. Such responses are concerning, cytokines, chemokines and TLR system functions as well as they might have implications in vaccine local and/or systemic immune responses.

None.

Author declares there are no conflicts of interest.

None.

1. Yin L, Chino T, Horst OV, et al. Differential and coordinated expression of defensins and cytokines by gingival epithelial cells and dendritic cells in response to oral bacteria, BMC Immunol. 2010;11:37.
2. Wistreich GA, Lechtman MD. Oral Microbiology. (3rd edn), Mac million Publishing Co INC., New York. 1982. p.582‒595.
3. Ross PW. Infection of the mouth. Clinical Bacteriology, Churchilli-Living stone, Edinberg, London. 1979. p.80‒88.
4. Samaranayake LP, Jones BM. Essentials of Microbiology For Dentistery. (2nd edn), Churchill-Livingstone, London. 2002. p.205‒252.
5. Shnawa IMS. The interplay of the local microbiome with oral mucosal compartment. Am J Biomed and LifeSience. 2015;3(4‒1):17‒19.
6. Lever JD. Introducing Anatomy. William Heinemann Medical Books Ltd., London. 1980. p.245‒272.
7. Gartner LP, Hiatt JL, Strum JM. Cell Biology and Histology. (4th edn), Lippincott Williams and Wilikins, Science Review, Philideliphia. 2003. p.62‒72.
8. Ross MH, Kaya GI, Pawlina W. Histology, A Text And Atlas with Cell And Molecular Biology, (4th edn), Lippincott Williams And Wilkins, Philadelphia, USA. 2013. p.19‒78.
9. DiFiore MSH. An Atlas of Human Histology. (3rd edn), Henry Kimpton, London. 1967. p.16‒29.
10. Owen JA, Punt J, Stranford SA, et al. Kuby Immunology. (7th edn), Mecmillian, England. 2013. p.105‒140.
11. Abbas AK, LichtmanAH, Pillal S. Cellular and Molecular Immunology. (8th edn), Elsevier Saunders, Canada. 2015. p.289‒314.
12. Montovani A, Dinarello CA, Ghezzi P. Pharmacology of Cytokines. Oxford university Press, Oxford, USA. 2000. p.1‒20.
13. Theze J . The cytokine network and Immune Functions. Oxford University Press, Oxford, USA. 1999. p.1‒13.
14. Paul WE. Fundamental Immunology. (5th edn), Williams and Wilkins, Philadelphia, USA. 2003. p.685‒841.
15. Steel C, Fidel PL Jr. Cytokine and Chemokine produced by oral and vaginal epithelial cells in response to Candida albicans. Infect Immun. 2002;70(2):577‒583.
16. Schaller M, Boeld U, Oberbauer S, et al. Polymorphonuclear leukocytes induce protective Th1 type cytokine response in an in-vitro model of oral candidiasis. Microbiol. 2014;150(9):2807‒2813.
17. Dongari - Begtzoglou A. Fungal Immunology. In: Haffnage GB & Fidel PC (Eds.), organ Perspective. 2015; 13‒36.
18. Madianos PN, Kinane DF, Sandros J, et al. Cytokine response of oral epithelial cells to Poryphymonas gingivalis infection. J Dent Res. 2000;79(10):1808‒1814.
19. Uehara A, Gugawara S, Takada H. Priming of human oral epithelial eclls by INFg to secret cytokine in response and LPS, LTA, and peptidoglycan. Med Microbiol. 2002;51(8):626‒634.
20. Ohata K, Ishida Y, Fukui A, et al. TLR expression and TLR mediate IL8 production by human sub-mandibular gland epithelial cells. Mol Med Rep. 2014;10(5):2377‒2382.
21. Yilmaz O. The chornichle of Porphyromonas gingivalis: The microbiome,the human epithelia, and their interplay. Microbiol . 2008;154:2897‒2903.
22. Wade WG. Oral microbiome in health and disease. Pharmacol Res. 2013;69(1):137‒143.
23. Marsh PD. Dental plaque as biofilm and microbial community implications for health and disease. BMC Oral Health. 2006;6(Suppl 1):S14.
24. Hesagawa Y, Tribble GD, Baker HV, et al. Role of Prophyromonas gingivalis SerB in gingival epithelial cell cytoskeleton remodeling and cytokine production. Infect Immun. 2008;76(6):2420‒2427.
25. Marshal RI. Gingival defensines: Linking innate and adaptive immune responses to dental plaque. Periodontol. 2004;35:14‒20.
26. Colombo AV, da Silva CM, Haffajee A, et al. Identification of intracellular oral species within human cervicular epithelial cell from subject with chronic periodontitis by fluorescence in situ hyberdization. J Periodontal Res. 2007;42(3): 236‒243.
27. Colombo AV, Silva CM, Haffajee A, et al. Identification of oral bacteria associated with cervicular epithelial cells from chronic periodontitis lesion. J Med Microbiol. 2006;55(Pt 5):609‒615.
28. Shnawa IMS. Oral mucosal immune tolerance versus immune silencing. AM J Biomed Lif Sci . 2015;3(4‒1):7‒9.
29. Versteeg J. A Colour Atlas of Virology. Wolf Medical Publication Ltd., Netherland. 1985. p.98‒99.
30. Mat Tek Cooporation. Automated barrier of an in-vitro oral epithelial model. Mat Tek Cooporation, USA. 2015.
31. Guggenhhiem B, Gmur R, Galicia JC, et al. In vitro modeling of host-parasite interactions: The sub-gingival bio-film challenge of primary human epithelial cells. BMC Microbiol. 2009;9:280.