The interrelated roles of TGF-beta and IL-10 in the regulation of experimental colitis.
In the present study, we define the relation between TGF-beta and IL-10 in the regulation of the Th1-mediated inflammation occurring in trinitrobenzene sulfonic acid (TNBS)-colitis. In initial studies, we showed that the feeding of trinitrophenol-haptenated colonic protein to SJL/J mice induces CD4(+) regulatory T cells that transfer protection from induction of TNBS-colitis, and that such protection correlates with cells producing TGF-beta, not IL-10. Further studies in which SJL/J mice were fed haptenated colonic protein, and then administered either anti-TGF-beta or anti-IL-10 at the time of subsequent TNBS administration per rectum, showed that while both Abs abolished protection, anti-TGF-beta administration prevented TGF-beta secretion, but left IL-10 secretion intact; whereas anti-IL-10 administration prevented both TGF-beta secretion and IL-10 secretion. Thus, it appeared that the protective effect of IL-10 was an indirect consequence of its effect on TGF-beta secretion. To establish this point further, we conducted adoptive transfer studies and showed that anti-IL-10 administration had no effect on induction of TGF-beta producing T cells in donor mice. However, it did inhibit their subsequent expansion in recipient mice, probably by regulating the magnitude of the Th1 T cell response which would otherwise inhibit the TGF-beta response. Therefore, these studies suggest that TGF-beta production is a primary mechanism of counter-regulation of Th1 T cell-mediated mucosal inflammation, and that IL-10 is necessary as a secondary factor that facilitates TGF-beta production.
Fuss
Ivan J
IJ
Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. ifuss@niaid.nih
Boirivant
Monica
M
Lacy
Brian
B
Strober
Warren
W
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000502:physiology*; D000284:Administration, Oral; D000285:Administration, Rectal; D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003092:Colitis / Q000139:chemically induced / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D003106:Colon / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D006241:Haptens / Q000008:administration & dosage; D016753:Interleukin-10 / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010851:Picrates / Q000008:administration & dosage; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D006241:Haptens; D010851:Picrates; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D014302:Trinitrobenzenesulfonic Acid; C005858:picric acid