TGF-beta production regulates the development of the 2,4,6-trinitrophenol-conjugated keyhole limpet hemocyanin-induced colonic inflammation in IL-2-deficient mice.
A severe, Th1-mediated experimental colitis with similarities to inflammatory bowel disease in humans can be induced by a single injection of 2,4,6-trinitrophenol (TNP)-substituted protein plus adjuvant in IL-2-/- mice. To determine the early events involved in the pathogenesis of IL-2-/-colitis, we compared the function of lamina propria (LP) T cells from IL-2-/- and IL-2+/+ mice subjected to disease-inducing (TNP-conjugated keyhole limpet hemocyanin [TNP-KLH]) and disease-inhibiting (anti-CD3) immunization protocols. We show that LP T cells in TNP-KLH-immunized IL-2-/- mice fail to produce TGF-beta early (day 2), whereas LP T cells in TNP-KLH-immunized IL-2+/+ mice exhibit an approximately eightfold rise in TGF-beta secretion. The critical importance of local TGF-beta production was further substantiated by the following findings. 1) LP T cells from TNP-KLH-immunized IL-2-/- mice administered anti-CD3 (i.p.) exhibit a significant rise in TGF-beta, production but fail to produce IFN-gamma, and such mice do not develop colitis. 2) TNP-KLH-immunized IL-2-/- mice administered anti-CD3 and coadministered anti-TGF-beta mAb again give rise to IFN-gamma-producing LP cells, and such mice develop colitis. 3) TNP-KLH-immunized IL-2+/+ mice administered anti-TGF-beta mAb exhibit pockets of mononuclear cell infiltrates in the LP. These results indicate that the disposition of IL-2-/- mice to develop chronic colonic inflammation is due to a Th1 cell response in the LP that is not appropriately counter-regulated by the production of the suppressor cytokine, TGF-beta.
Lúdvíksson
B R
BR
Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.
Ehrhardt
R O
RO
Strober
W
W
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D017252:CD3 Complex / Q000276:immunology; D003092:Colitis / Q000209:etiology* / Q000276:immunology / Q000517:prevention & control; D005260:Female; D006241:Haptens; D006433:Hemocyanins / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000172:deficiency* / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis / Q000172:deficiency; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010851:Picrates / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000172:deficiency
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D006241:Haptens; D007376:Interleukin-2; D010851:Picrates; D016212:Transforming Growth Factor beta; C054401:trinitrophenyl keyhole limpet hemocyanin; D015847:Interleukin-4; D006433:Hemocyanins; C005858:picric acid