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The Production and Function of Endogenous Interleukin-10 in Intestinal Epithelial Cells and Gut Homeostasis

2021; Elsevier BV; Volume: 12; Issue: 4 Linguagem: Inglês

10.1016/j.jcmgh.2021.07.005

ISSN

2352-345X

Autores

Huong D. Nguyen, Hanan M. Aljamaei, Andrew W. Stadnyk,

Tópico(s)

Helicobacter pylori-related gastroenterology studies

Resumo

The healthy gut is achieved and maintained through a balanced relationship between the mucosal immune system, microbial communities resident in the lumen, and the intestinal epithelium. The intestinal epithelium plays an exceptionally important role in harmonizing the interaction between the host immunity and the luminal residents, as this selectively permeable barrier separates but also allows interchange between the 2 environments. Interleukin (IL)-10 has been well established to play an important role in maintaining gut homeostasis by imparting diverse effects on a variety of cell types in this relationship. In the intestine, the source and the target of IL-10 include leukocytes and epithelial cells. Given that both the epithelium and IL-10 are essential players in supporting homeostasis, we discuss the relationship between these 2 factors, focusing on epithelial sources of IL-10 and the effects of IL-10 on the intestinal epithelium. Insight into this relationship reveals an important aspect of the innate immune function of intestinal epithelial cells. The healthy gut is achieved and maintained through a balanced relationship between the mucosal immune system, microbial communities resident in the lumen, and the intestinal epithelium. The intestinal epithelium plays an exceptionally important role in harmonizing the interaction between the host immunity and the luminal residents, as this selectively permeable barrier separates but also allows interchange between the 2 environments. Interleukin (IL)-10 has been well established to play an important role in maintaining gut homeostasis by imparting diverse effects on a variety of cell types in this relationship. In the intestine, the source and the target of IL-10 include leukocytes and epithelial cells. Given that both the epithelium and IL-10 are essential players in supporting homeostasis, we discuss the relationship between these 2 factors, focusing on epithelial sources of IL-10 and the effects of IL-10 on the intestinal epithelium. Insight into this relationship reveals an important aspect of the innate immune function of intestinal epithelial cells. SummaryThis review discusses the effect of interleukin-10 on the intestinal epithelium and the potential role of epithelial-derived interleukin-10 in gut homeostasis. This review discusses the effect of interleukin-10 on the intestinal epithelium and the potential role of epithelial-derived interleukin-10 in gut homeostasis. The intestinal epithelium, as a single contiguous layer of columnar cells, is the body's largest mucosal surface.1Helander H.F. Fändriks L. Surface area of the digestive tract-revisited.Scand J Gastroenterol. 2014; 49: 681-689Crossref PubMed Scopus (356) Google Scholar With the apical side facing the lumen and the basal side in contact with a basement membrane resting on the lamina propria, the epithelium is the bridge between lumen contents and the leukocytes of the lamina propria.2Allaire J.M. Crowley S.M. Law H.T. Chang S.-Y. Ko H.-J. Vallance B.A. The intestinal epithelium: central coordinator of mucosal immunity.Trends Immunol. 2018; 39: 677-696Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar In the small intestine, the epithelium is folded into crypts and villi, and is composed of immature dividing cells and mature cell types including enterocytes, enteroendocrine cells, Tuft cells, microfold cells (M cells), goblet cells, and Paneth cells.2Allaire J.M. Crowley S.M. Law H.T. Chang S.-Y. Ko H.-J. Vallance B.A. The intestinal epithelium: central coordinator of mucosal immunity.Trends Immunol. 2018; 39: 677-696Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar The large intestine lacks villi, but both undifferentiated and differentiated cell types are present, with the relative abundances of differentiated cell types differing between the small and large intestines.2Allaire J.M. Crowley S.M. Law H.T. Chang S.-Y. Ko H.-J. Vallance B.A. The intestinal epithelium: central coordinator of mucosal immunity.Trends Immunol. 2018; 39: 677-696Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar The epithelium is continually renewed by stem cells residing at the crypt bases.3Krndija D. Marjou F. El Guirao B. Richon S. Leroy O. Bellaiche Y. Hannezo E. Vignjevic D.M. Active cell migration is critical for steady-state epithelial turnover in the gut.Science. 2019; 365: 705-710Crossref PubMed Scopus (57) Google Scholar The epithelium limits macromolecules and microbial entry into the mucosa by forming an intercellular network of tight junctions between cells.4Buckley A. Turner J.R. Cell biology of tight junction barrier regulation and mucosal disease.Cold Spring Harb Perspect Biol. 2018; 10: a029314Crossref PubMed Scopus (177) Google Scholar Cells secrete mucus and antimicrobial products, and transport immunoglobulins into the mucus, limiting intestinal infiltration by microbes.5Thoo L. Noti M. Krebs P. Keep calm: the intestinal barrier at the interface of peace and war.Cell Death Dis. 2019; 10: 849Crossref PubMed Scopus (32) Google Scholar Meanwhile, the adaptive immune system defaults to promote antigen tolerogenic responses. Thus, gut homeostasis depends on the interplay between innate and adaptive immunity, acting against the luminal microbiota.6Vivier E. Artis D. Colonna M. Diefenbach A. Di Santo J.P. Eberl G. Koyasu S. Locksley R.M. McKenzie A.N.J. Mebius R.E. Powrie F. Spits H. Innate Lymphoid Cells: 10 years on.Cell. 2018; 174: 1054-1066Abstract Full Text Full Text PDF PubMed Scopus (657) Google Scholar,7Zhou L. Sonnenberg G.F. Essential immunological orchestrators of intestinal homeostasis.Sci Immunol. 2018; 3eaao1605Crossref PubMed Scopus (35) Google Scholar Much of this regulation is achieved through the secretion of soluble cytokines, including interleukin (IL)-10. IL-10, first reported as human cytokine synthesis inhibitory factor,8Fiorentino D.F. Bond M.W. Mosmann T.R. Two types of mouse t helper cell: IV. Th2 clones secrete a factor that inhibits cytokine production by Thl clones.J Exp Med. 1989; 170: 2081-2095Crossref PubMed Scopus (2424) Google Scholar is now a well-studied immunomodulator. As the descriptive name implies, the anti-inflammatory effects of IL-10 are attributed to suppressing secretion of many proinflammatory cytokines and chemokines, including interferon gamma (IFN-γ), tumor necrosis factor (TNF), IL-1α/β, and others, from a variety of cell types.9Abrams J. Figdor C.G. De Waal Malefyt R. Bennett B. De Vries J.E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes.J Exp Med. 1991; 174: 1209-1220Crossref PubMed Scopus (3308) Google Scholar IL-10 also induces secretion of anti-inflammatory molecules such as the IL-1 receptor antagonist, soluble TNF receptor, and IL-27, which contribute to an anti-inflammatory milieu.10Akdis C.A. Blaser K. Mechanisms of interleukin-10-mediated immune suppression.Immunology. 2001; 103: 131-136Crossref PubMed Scopus (278) Google Scholar Besides manipulating the production of secreted products, IL-10 can exert direct effects on effector cells including preventing the stimulation of naïve CD4+ T cells, inhibiting maturation of dendritic cells and repressing activation and proliferation of macrophages.11Minton K. Immune regulation: IL-10 targets macrophage metabolism.Nat Rev Immunol. 2017; 17: 345Crossref PubMed Scopus (7) Google Scholar With such an array of direct and indirect impacts, IL-10 may well be the master regulator of the anti-inflammatory response in the intestines. The pivotal role that IL-10 plays in balancing intestinal homeostasis was unequivocally demonstrated by the discovery that the lack of IL-10 predisposes to enterocolitis.12Kühn R. Löhler J. Rennick D. Rajewsky K. Müller W. Interleukin-10-deficient mice develop chronic enterocolitis.Cell. 1993; 75: 263-274Abstract Full Text PDF PubMed Scopus (3526) Google Scholar This profound outcome was validated in humans, in which mutations in IL-10 or IL-10 receptor (IL-10R) resulted in inflammatory bowel disease (IBD).13Franke A. Balschun T. Karlsen T.H. Sventoraityte J. Nikolaus S. Mayr G. Domingues F.S. Albrecht M. Nothnagel M. Ellinghaus D. Sina C. Onnie C.M. Weersma R.K. Stokkers P.C.F. Wijmenga C. Gazouli M. Strachan D. McArdle W.L. Vermeire S. Rutgeerts P. Rosenstiel P. Krawczak M. Vatn M.H. Mathew C.G. Schreiber S. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility.Nat Genet. 2008; 40: 1319-1323Crossref PubMed Scopus (466) Google Scholar,14Engelhardt K.R. Shah N. Faizura-Yeop I. Kocacik Uygun D.F. Frede N. Muise A.M. Shteyer E. Filiz S. Chee R. Elawad M. Hartmann B. Arkwright P.D. Dvorak C. Klein C. Puck J.M. Grimbacher B. Glocker E.O. Clinical outcome in IL-10- and IL-10 receptor-deficient patients with or without hematopoietic stem cell transplantation.J Allergy Clin Immunol. 2013; 131: 825-830Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar Noteworthy, the "cure" for patients was to restore expression in leukocytes through stem cell or bone marrow transplantation.15Kotlarz D. Beier R. Murugan D. Diestelhorst J. Jensen O. Boztug K. Pfeifer D. Kreipe H. Pfister E.D. Baumann U. Puchalka J. Bohne J. Egritas O. Dalgic B. Kolho K.L. Sauerbrey A. Buderus S. Güngör T. Enninger A. Koda Y.K.L. Guariso G. Weiss B. Corbacioglu S. Socha P. Uslu N. Metin A. Wahbeh G.T. Husain K. Ramadan D. Al-Herz W. Grimbacher B. Sauer M. Sykora K.W. Koletzko S. Klein C. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy.Gastroenterology. 2012; 143: 347-355Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar,16Murugan D. Albert M.H. Langemeier J. Bohne J. Puchalka J. Järvinen P.M. Hauck F. Klenk A.K. Prell C. Schatz S. Diestelhorst J. Sciskala B. Kohistani N. Belohradsky B.H. Müller S. Kirchner T. Walter M.R. Bufler P. Muise A.M. Snapper S.B. Koletzko S. Klein C. Kotlarz D. Very early onset inflammatory bowel disease associated with aberrant trafficking of IL-10R1 and cure by T cell replete haploidentical bone marrow transplantation.J Clin Immunol. 2014; 34: 331-339Crossref PubMed Scopus (44) Google Scholar Resolving the deficiency with leukocyte transplants not only confirms the importance of IL-10 in gut health, but also suggests that there is a significant population of IL-10–producing and IL-10–responsive leukocytes in the gut. IL-10 was first identified as a product of mouse CD4+ Th2 lymphocytes, regulating the secretion of cytokines by Th1 cells.8Fiorentino D.F. Bond M.W. Mosmann T.R. Two types of mouse t helper cell: IV. Th2 clones secrete a factor that inhibits cytokine production by Thl clones.J Exp Med. 1989; 170: 2081-2095Crossref PubMed Scopus (2424) Google Scholar Since that discovery, depending on the stimulation, IL-10 can be secreted by many leukocytes including subsets of T cells, B cells, macrophages/monocytes, innate lymphoid cells, and others.17Moore K.W. O'Garra A. De Waal Malefyt R. Vieira P. Mosmann T.R. Interleukin-10.Annu Rev Immunol. 1993; 11: 165-190Crossref PubMed Scopus (2350) Google Scholar,18Mosser D.M. Zhang X. Interleukin-10: new perspectives on an old cytokine.Immunol Rev. 2008; 226: 205-218Crossref PubMed Scopus (734) Google Scholar Most cells that produce IL-10 also possess the IL-10R, which suggests that IL-10 is likely acting in an autocrine fashion.19Shouval D.S. Ouahed J. Biswas A. Goettel J.A. Horwitz B.H. Klein C. Muise A.M. Snapper S.B. Interleukin 10 receptor signaling: master regulator of intestinal mucosal homeostasis in mice and humans.Adv Immunol. 2014; 122: 177-210Crossref PubMed Scopus (164) Google Scholar In fact, systemically administered IL-10 has a very short half-life,20Schreiber S. Fedorak R.N. Nielsen O.H. Wild G. Williams C.N. Nikolaus S. Jacyna M. Lashner B.A. Gangl A. Rutgeerts P. Isaacs K. Van Deventer S.J.H. Koningsberger J.C. Cohard M. LeBeaut A. Hanauer S.B. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease.Gastroenterology. 2000; 119: 1461-1472Abstract Full Text Full Text PDF PubMed Scopus (420) Google Scholar suggesting that autocrine and paracrine roles are critical. Early studies identified the major source of IL-10 in the healthy small intestine to be intraepithelial lymphocytes (IELs), specifically type 1 T regulatory (Treg) cells.21Kamanaka M. Kim S.T. Wan Y.Y. Sutterwala F.S. Lara-Tejero M. Galán J.E. Harhaj E. Flavell R.A. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse.Immunity. 2006; 25: 941-952Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar However, in a recent study, a small subset of type 2 innate lymphoid cells, in the lamina propria, was shown to secrete IL-10, at steady state and following stimulation with IL-2, IL-4, IL-10, IL-27, and the neuropeptide neuromedin U.22Bando J.K. Gilfillan S. Di Luccia B. Fachi J.L. Sécca C. Cella M. Colonna M. ILC2s are the predominant source of intestinal ILC-derived IL-10.J Exp Med. 2020; 217e20191520Crossref PubMed Google Scholar Contrasting the small intestine, colonic lamina propria T cells produce IL-10 upon activation, but few produce IL-10 constitutively, casting doubt on the magnitude of the contribution of lymphocytes during steady state.21Kamanaka M. Kim S.T. Wan Y.Y. Sutterwala F.S. Lara-Tejero M. Galán J.E. Harhaj E. Flavell R.A. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse.Immunity. 2006; 25: 941-952Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar, 22Bando J.K. Gilfillan S. Di Luccia B. Fachi J.L. Sécca C. Cella M. Colonna M. ILC2s are the predominant source of intestinal ILC-derived IL-10.J Exp Med. 2020; 217e20191520Crossref PubMed Google Scholar, 23Melgar S. Yeung M.M.W. Bas A. Forsberg G. Suhr O. Öberg Å. Hammarström S. Danielsson Å. Hammarström M.L. Over-expression of interleukin 10 in mucosal T cells of patients with active ulcerative colitis.Clin Exp Immunol. 2003; 134: 127-137Crossref PubMed Scopus (121) Google Scholar, 24Braunstein J. Qiao L. Autschbach F. Schürmann G. Meuer S. T cells of the human intestinal lamina propria are high producers of interleukin-10.Gut. 1997; 41: 215-220Crossref PubMed Scopus (89) Google Scholar, 25Ebert E.C. Mehta V. Das K.M. Activation antigens on colonic T cells in inflammatory bowel disease: effects of IL-10.Clin Exp Immunol. 2005; 140: 157-165Crossref PubMed Scopus (8) Google Scholar Unlike lymphocytes, IL-10 production from macrophages occurs in both small and large intestine.26Morhardt T.L. Hayashi A. Ochi T. Quirós M. Kitamoto S. Nagao-Kitamoto H. Kuffa P. Atarashi K. Honda K. Kao J.Y. Nusrat A. Kamada N. IL-10 produced by macrophages regulates epithelial integrity in the small intestine.Sci Rep. 2019; 9: 1223Crossref PubMed Scopus (28) Google Scholar,27Krause P. Morris V. Greenbaum J.A. Park Y. Bjoerheden U. Mikulski Z. Muffley T. Shui J.W. Kim G. Cheroutre H. Liu Y.C. Peters B. Kronenberg M. Murai M. IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis.Nat Commun. 2015; 6: 7055Crossref PubMed Scopus (71) Google Scholar Importantly, it was also demonstrated that although IELs and type 2 innate lymphoid cells make IL-10 in the healthy gut, resident macrophages becomes the dominant source during acute inflammation of both intestines.26Morhardt T.L. Hayashi A. Ochi T. Quirós M. Kitamoto S. Nagao-Kitamoto H. Kuffa P. Atarashi K. Honda K. Kao J.Y. Nusrat A. Kamada N. IL-10 produced by macrophages regulates epithelial integrity in the small intestine.Sci Rep. 2019; 9: 1223Crossref PubMed Scopus (28) Google Scholar,27Krause P. Morris V. Greenbaum J.A. Park Y. Bjoerheden U. Mikulski Z. Muffley T. Shui J.W. Kim G. Cheroutre H. Liu Y.C. Peters B. Kronenberg M. Murai M. IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis.Nat Commun. 2015; 6: 7055Crossref PubMed Scopus (71) Google Scholar The stimuli leading to macrophage secretion of IL-10 come from both endogenous (eg, secondary bile acids)28Biagioli M. Carino A. Cipriani S. Francisci D. Marchianò S. Scarpelli P. Sorcini D. Zampella A. Fiorucci S. The bile acid receptor GPBAR1 regulates the M1/M2 phenotype of intestinal macrophages and activation of GPBAR1 rescues mice from murine colitis.J Immunol. 2017; 199: 718-733Crossref PubMed Scopus (99) Google Scholar and exogenous (eg, microbial metabolites) factors.29Hayashi A. Sato T. Kamada N. Mikami Y. Matsuoka K. Hisamatsu T. Hibi T. Roers A. Yagita H. Ohteki T. Yoshimura A. Kanai T. A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice.Cell Host Microbe. 2013; 13: 711-722Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Considering that the intestines contain the largest pool of IL-10–producing macrophages in the body,30Murray P.J. Understanding and exploiting the endogenous interleukin-10/STAT3-mediated anti-inflammatory response.Curr Opin Pharmacol. 2006; 6: 379-386Crossref PubMed Scopus (301) Google Scholar it is reasonable to presume this source is important in the regulation of intestinal homeostasis. Mucosal leukocytes are not the only source of IL-10. There is evidence of constitutive and stimulated secretion of IL-10 from intestinal fibroblasts, thought to preserve mucosal T cell viability.31Ina K. Kusugami K. Kawano Y. Nishiwaki T. Wen Z. Musso A. West G.A. Ohta M. Goto H. Fiocchi C. Intestinal fibroblast--derived IL-10 increases survival of mucosal T cells by inhibiting growth factor deprivation- and Fas-mediated apoptosis.J Immunol. 2005; 175: 2000-2009Crossref PubMed Scopus (17) Google Scholar,32Pang G. Couch L. Batey R. Clancy R. Cripps A. GM-CSF, IL-1α, IL-1β, IL-6, IL-8, IL-10, ICAM-1 and VCAM-1 gene expression and cytokine production in human duodenal fibroblasts stimulated with lipopolysaccharide, IL-1α and TNF-α.Clin Exp Immunol. 1994; 96: 437-443Crossref PubMed Scopus (139) Google Scholar Last, intestinal epithelial cells (IECs) also reportedly produce and secrete IL-10. One approach to identifying constitutive cell sources of IL-10, whether mucosal or extraintestinal, is to examine germ-free animals or following antibiotic treatments. Studies indicate that IL-10 production in the intestines of germ-free mice and broad-spectrum antibiotic-treated mice is either similar or reduced compared with conventionally raised mice.33Kennedy E.A. King K.Y. Baldridge M.T. Mouse microbiota models: Comparing germ-free mice and antibiotics treatment as tools for modifying gut bacteria.Front Physiol. 2018; 9: 1534Crossref PubMed Scopus (136) Google Scholar It was also reported that Treg cells from germ-free mice expressed less IL-10 compared with cells from conventionally raised mice.34Strauch U.G. Obermeier F. Grunwald N. Gürster S. Dunger N. Schultz M. Griese D.P. Mähler M. Schölmerich J. Rath H.C. Influence of intestinal bacteria on induction of regulatory T cells: Lessons from a transfer model of colitis.Gut. 2005; 54: 1546-1552Crossref PubMed Scopus (123) Google Scholar Another noteworthy report showed that germ-free mice possess a population of splenic plasmacytes that secrete IL-10.35Fillatreau S. Natural regulatory plasma cells.Curr Opin Immunol. 2018; 55: 62-66Crossref PubMed Scopus (20) Google Scholar The speculation was that these cells are a T cell–independent response by B cells, intended to regulate autoreactivity.35Fillatreau S. Natural regulatory plasma cells.Curr Opin Immunol. 2018; 55: 62-66Crossref PubMed Scopus (20) Google Scholar In addition to constitutive or intrinsic secretion is the idea that microbes stimulate IL-10.26Morhardt T.L. Hayashi A. Ochi T. Quirós M. Kitamoto S. Nagao-Kitamoto H. Kuffa P. Atarashi K. Honda K. Kao J.Y. Nusrat A. Kamada N. IL-10 produced by macrophages regulates epithelial integrity in the small intestine.Sci Rep. 2019; 9: 1223Crossref PubMed Scopus (28) Google Scholar,36Rutz S. Ouyang W. Regulation of interleukin-10 and interleukin-22 expression in T helper cells.Curr Opin Immunol. 2011; 23: 605-612Crossref PubMed Scopus (56) Google Scholar, 37Ueda Y. Kayama H. Jeon S.G. Kusu T. Isaka Y. Rakugi H. Yamamoto M. Takeda K. Commensal microbiota induce LPS hyporesponsiveness in colonic macrophages via the production of IL-10.Int Immunol. 2010; 22: 953-962Crossref PubMed Scopus (92) Google Scholar, 38Quiros M. Nishio H. Neumann P.A. Siuda D. Brazil J.C. Azcutia V. Hilgarth R. O'Leary M.N. Garcia-Hernandez V. Leoni G. Feng M. Bernal G. Williams H. Dedhia P.H. Gerner-Smidt C. Spence J. Parkos C.A. Denning T.L. Nusrat A. Macrophage-derived IL-10 mediates mucosal repair by epithelial WISP-1 signaling.J Clin Invest. 2017; 127: 3510-3520Crossref PubMed Scopus (73) Google Scholar Bacteroides fragilis polysaccharide A reportedly drives IL-10 production by CD4+ T cells at a level sufficient to protect mice from colitis.39Mazmanian S.K. Round J.L. Kasper D.L. A microbial symbiosis factor prevents intestinal inflammatory disease.Nature. 2008; 453: 620-625Crossref PubMed Scopus (1558) Google Scholar Colonization by clusters IV and XIVa of Clostridium-induced IL-10–secreting Treg cells and prevented colitis.40Atarashi K. Tanoue T. Shima T. Imaoka A. Kuwahara T. Momose Y. Cheng G. Yamasaki S. Saito T. Ohba Y. Taniguchi T. Takeda K. Hori S. Ivanov I.I. Umesaki Y. Itoh K. Honda K. Induction of colonic regulatory T cells by indigenous Clostridium species.Science. 2011; 331: 337-341Crossref PubMed Scopus (2296) Google Scholar,41Furusawa Y. Obata Y. Fukuda S. Endo T.A. Nakato G. Takahashi D. Nakanishi Y. Uetake C. Kato K. Kato T. Takahashi M. Fukuda N.N. Murakami S. Miyauchi E. Hino S. Atarashi K. Onawa S. Fujimura Y. Lockett T. Clarke J.M. Topping D.L. Tomita M. Hori S. Ohara O. Morita T. Koseki H. Kikuchi J. Honda K. Hase K. Ohno H. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells.Nature. 2013; 504: 446-450Crossref PubMed Scopus (2438) Google Scholar The mechanism proved to be indirect, as Faecalibacterium prausnitzii (Clostridium IV) induced secretion of IL-10 among an array of Treg-polarizing molecules in dendritic cells, which in turn induced secretion by colonic Treg cells.42Alameddine J. Godefroy E. Papargyris L. Sarrabayrouse G. Tabiasco J. Bridonneau C. Yazdanbakhsh K. Sokol H. Altare F. Jotereau F. Faecalibacterium prausnitzii skews human DC to prime IL10-producing T cells through TLR2/6/JNK signaling and IL-10, IL-27, CD39, and IDO-1 induction.Front Immunol. 2019; 10: 143Crossref PubMed Scopus (31) Google Scholar,43Rossi O. Van Berkel L.A. Chain F. Tanweer Khan M. Taverne N. Sokol H. Duncan S.H. Flint H.J. Harmsen H.J.M. Langella P. Samsom J.N. Wells J.M. Faecalibacterium prausnitzii A2-165 has a high capacity to induce IL-10 in human and murine dendritic cells and modulates T cell responses.Sci Rep. 2016; 6: 18507Crossref PubMed Scopus (103) Google Scholar Bifidobacterium breve had a similar effect.44Jeon S.G. Kayama H. Ueda Y. Takahashi T. Asahara T. Tsuji H. Tsuji N.M. Kiyono H. Ma J.S. Kusu T. Okumura R. Hara H. Yoshida H. Yamamoto M. Nomoto K. Takeda K. Probiotic Bifidobacterium breve induces IL-10-producing Tr1 cells in the colon.PLoS Pathog. 2012; 8e1002714Crossref PubMed Scopus (209) Google Scholar Clostridium butyricum, on the other hand, induced IL-10 production in macrophages, to an extent that attenuated colitis.29Hayashi A. Sato T. Kamada N. Mikami Y. Matsuoka K. Hisamatsu T. Hibi T. Roers A. Yagita H. Ohteki T. Yoshimura A. Kanai T. A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice.Cell Host Microbe. 2013; 13: 711-722Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar Finally, the gut microbiota promoted expansion of IL-10–producing B cells in the colonic lamina propria.45Mishima Y. Oka A. Liu B. Herzog J.W. Eun C.S. Fan T.J. Bulik-Sullivan E. Carroll I.M. Hansen J.J. Chen L. Wilson J.E. Fisher N.C. Ting J.P.Y. Nochi T. Wahl A. Victor Garcia J. Karp C.L. Balfour Sartor R. Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10-producing regulatory B cells.J Clin Invest. 2019; 129: 3702-3716Crossref PubMed Scopus (54) Google Scholar Collectively, these observations implicate gut microbes causally in the production of IL-10, through effects on multiple cell types, presumably contributing to homeostasis. The membrane-bound IL-10R is a tetramer consisting of 2 α (IL-10R1) and 2 β (IL-10R2) chains.46Kotenko S.V. Krause C.D. Izotova L.S. Pollack B.P. Wu W. Pestka S. Identification and functional characterization of a second chain of the interleukin-10 receptor complex.EMBO J. 1997; 16: 5894-5903Crossref PubMed Scopus (322) Google Scholar IL-10R1 is specific to IL-10 while IL-10R2 has a lower affinity and shares roles in receptor complexes for other cytokines including IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, IL-29, and IFN-λ.47Commins S. Steinke J.W. Borish L. The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29.J Allergy Clin Immunol. 2008; 121: 1108-1111Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar Notwithstanding the plentiful evidence for IL-10 acting on leukocytes to achieve homeostasis, there is evidence that IL-10R is expressed in IECs. In mice, IL-10R messenger RNA (mRNA) for both subunits was detected from freshly isolated cells of murine intestines.48Denning T.L. Campbell N.A. Song F. Garofalo R.P. Klimpel G.R. Reyes V.E. Ernst P.B. Expression of IL-10 receptors on epithelial cells from the murine small and large intestine.Int Immunol. 2000; 12: 133-139Crossref PubMed Scopus (75) Google Scholar These authors also reported surface expression detected by flow cytometry and labeled ligand binding in the murine small intestinal mode-K and colonic MCA-38 cell lines.48Denning T.L. Campbell N.A. Song F. Garofalo R.P. Klimpel G.R. Reyes V.E. Ernst P.B. Expression of IL-10 receptors on epithelial cells from the murine small and large intestine.Int Immunol. 2000; 12: 133-139Crossref PubMed Scopus (75) Google Scholar Hasnain et al49Hasnain S.Z. Tauro S. Das I. Tong H. Chen A.H. Jeffery P.L. McDonald V. Florin T.H. McGuckin M.A. IL-10 promotes production of intestinal mucus by suppressing protein misfolding and endoplasmic reticulum stress in goblet cells.Gastroenterology. 2013; 144: 357-368Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar provided immunofluorescent data localizing IL-10R1 on goblet cells of the mouse distal colon; consequently, they pursued functional studies with the goblet cell-differentiated LS174T colon carcinoma cell line. Regarding expression in the human intestines, Bourreille et al50Bourreille A. Segain J.P. Raingeard de la Blétière D. Siavoshian S. Vallette G. Galmiche J.P. Blottière H.M. Lack of interleukin 10 regulation of antigen presentation-associated molecules expressed on colonic epithelial cells.Eur J Clin Invest. 1999; 29: 48-55Crossref PubMed Scopus (20) Google Scholar detected IL-10R1 mRNA in healthy colonic epithelial cells and the human cell line SW1116 but surprisingly in neither HT-29 nor T84.50Bourreille A. Segain J.P. Raingeard de la Blétière D. Siavoshian S. Vallette G. Galmiche J.P. Blottière H.M. Lack of interleukin 10 regulation of antigen presentation-associated molecules expressed on colonic epithelial cells.Eur J Clin Invest. 1999; 29: 48-55Crossref PubMed Scopus (20) Google Scholar On the other hand, IFN-γ was shown to induce apical IL-10R1 expression on T84 cells and apical expression was detected in the distal colon of dextran sodium sulfate (DSS)–inflamed mice, coincidental with peak IFN-γ levels.51Kominsky D.J. Campbell E.L. Ehrentraut S.F. Wilson K.E. Kelly C.J. Glover L.E. Collins C.B. Bayless A.J. Saeedi B. Dobrinskikh E. Bowers B.E. MacManus C.F. Müller W. Colgan S.P. Bruder D. IFN-γ–mediated induction of an apical IL-10 receptor on polarized intestinal epithelia.J Immunol. 2014; 192: 1267-1276Crossref PubMed Scopus (57) Google Scholar Mice with an IEC-specific IL-10R1 Cre/flox knockdown had more permeable intestines prior to DSS, and were more susceptible to the DSS, indicating that IL-10 acting on the colonic epithelium is critical to protection, although the study did not address whether the receptors were apical or otherwise.51Kominsky D.J. Campbell E.L. Ehrentraut S.F. Wilson K.E. Kelly C.J. Glover L.E. Collins C.B. Bayless A.J. Saeedi B. Dobrinskikh E. Bowers B.E. MacManus C.F. Müller W. Colgan S.P. Bruder D. IFN-γ–mediated induction of an apical IL-10 receptor on polarized intestinal epithelia.J Immunol. 2014; 192: 1267-1276Crossref PubMed Scopus (57) Google Scholar With regard to humans, apical IL-10R1 was reported only on IECs from IBD biopsies, inferring the expression was induced.51Kominsky D.J. Campbell E.L. Ehrentraut S.F. Wilson K.E. Kelly C.J. Glover L.E. Collins C.B. Bayless A.J. Saeedi B. Dobrinskikh E. Bowers B.E. MacManus C.F. Müller W. Colgan S.P. Bruder D. IFN-γ–mediated induction of an apical IL-10 receptor on polarized intestinal epithelia.J Immunol. 2014; 192: 1267-1276Crossref PubMed Scopus (57) Google Scholar Thus, at least in the colon, there is evidence that IEC apical IL-10R can be induced. Focusing on the possible stimuli for steady-state (including apical) expression, metabolites found in the gut were shown to induce the expression of the IL-10R on IECs.51Kominsky D.J. Campbell E.L. Ehrentraut S.F. Wilson K.E. Kelly C.J. Glover L.E. Collins C.B. Bayless A.J. Saeedi B. Dobrinskikh E. Bowers B.E. MacManus C.F. Müller W. Colgan S.P. Bruder D. IFN-γ–mediated induction of an apical IL-10 receptor on polarized intestinal epithelia.J Immunol. 2014; 192: 1267-1276Cro

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