TGF-BETA PRODUCTION REGULATES THE DEVELOPMENT OF THE 2,4,6-TRINITROPHENOL-CONJUGATED KEYHOLE LIMPET HEMOCYANIN-INDUCED COLONIC INFLAMMATIONIN IL-2-DEFICIENT MICE
Br. Ludviksson et al., TGF-BETA PRODUCTION REGULATES THE DEVELOPMENT OF THE 2,4,6-TRINITROPHENOL-CONJUGATED KEYHOLE LIMPET HEMOCYANIN-INDUCED COLONIC INFLAMMATIONIN IL-2-DEFICIENT MICE, The Journal of immunology, 159(7), 1997, pp. 3622-3628
A severe, Th1-mediated experimental colitis with similarities to infla
mmatory bowel disease in humans can be induced by a single injection o
f 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-induci
ng (TNP-conjugated keyhole limpet hemocyanin (TNP-KLH)) and disease-in
hibiting (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 impor
tance of local TGF-beta production was further substantiated by the fo
llowing findings, 1) LP T cells from TNP-KLH-immunized IL-2(-/-) mice
administered anti-CD3 (i.p.) exhibit a significant rise in TGF-beta pr
oduction but fail to produce IFN-gamma, and such mice do not develop c
olitis. 2) TNP-KLH-immunized IL-2(-/-) mice administered anti-CD3 and
coadministered anti-TGF-beta mAb again give rise to IFN-gamma-producin
g 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 dispositi
on of IL-2(-/-) mice to develop chronic colonic inflammation is due to
a Th1 cell response in the LP that is not appropriately counter-regul
ated by the production of the suppressor cytokine, TGF-beta.