Peroxisome proliferator-activated receptor gamma agonist ligands stimulate a Th2 cytokine response and prevent acute colitis

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ), a member of a nuclear transcription factor family, has been previously demonstrated to have antiinflammatory activity. The effects of PPARγ activation in the development of an immune response are less well characterized. Through evaluation of PPARγ heterozygote mice (PPARyγ+/-) and specific PPARγ agonist ligand binding, we evaluated the immunologic effects of PPARγ activation in a well-described model of colitis. Increased susceptibility to dextran sodium sulfate (DSS)-induced colitis as defined by body weights, histologic injury, and survival was observed in the PPARγ+/- mice in comparison to wild-type mice. Three different PPARγ ligands (troglitazone, pioglitazone, and rosiglitazone) demonstrated beneficial dose-related treatment effects when administered prior to the onset of colitis. However, no protection was observed when PPARγ ligand activation occurred after the onset of colitis. The reduction in DSS-induced inflammation noted with PPARγ ligand treatment was associated with decreased interferon-gamma and tumor necrosis factor-alpha and increased interleukin (IL)-4 and IL-10 levels as assessed by quantitative reverse transcriptase-polymerase chain reaction. Consistent with this shift towards a T helper (Th2) cytokine dominance, PPARγ ligand treatment stimulated increased GATA-3 expression. These results indicate that the protective effects exhibited by PPARγ ligands in intestinal inflammation may be due to immune deviation away from Th1 and towards Th2 cytokine production.