Reciprocal regulation of the survival and apoptosis of Th17 and Th1 cells in the colon

Abstract

Background: The immediate early response gene X-1 (IEX-1) is a stress-inducible gene involved in the regulation of cell growth, apoptosis and inflammation. Methods: Acute colitis was induced by treatment of IEX-1 knockout (KO) and wild type (WT) control mice with dextran sulfate sodium (DSS), whereas chronic colitis was induced in Rag-/- mice by adoptive transfer of CD4 +CD45RB hi T cells isolated from the two strains of mice. The diseases and responses of lamina propria lymphocytes were analyzed in the mice. Results: IEX-1 KO mice produced IL-17 in the colon significantly greater than WT control mice following DSS treatment owing to better survival and differentiation of both IL-17-secreting γδ T cells and Th17 cells. The altered level of IL-17 production contributed critically to the reduced colon inflammation in IEX-1 KO mice, and administration of neutralizing anti-IL-17 antibody increased susceptibility of the animal to the disease. Strikingly, in contrast to the better survival of T cells producing IL-17, lack of IEX-1 enhanced apoptosis in proinflammatory T cells producing interferon gamma (IFN-γ). Enhanced apoptosis in Th1 cells and better survival of Th17 cells may both result in a delayed onset of colitis in Rag-/- mice receiving pathogenic CD4 +CD45RB hi T cells isolated from IEX-1 KO animals compared to those mice transferred with WT counterparts Conclusions: The present study demonstrates the refractoriness of IEX-1 knockout (KO) mice to DSS-induced colitis and diminished pathogenesis of IEX-1-deficient CD4 +CD45RB hi T cells. These data demonstrate that IEX-1 reciprocally regulates T-cell survival and apoptosis in a subset-dependent fashion. Inhibition of IEX-1 may thus offer novel strategies for colitis treatment by simultaneous induction of apoptosis in proinflammatory Th1 cells while promoting the survival and differentiation of a protective T-cell subset. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.