Intestinal antiinflammatory effects of thiazolidenedione peroxisome proliferator-activated receptor-γ ligands on T helper type 1 chemokine regulation include nontranscriptional control mechanisms

Crohn's disease is associated with an excessive T helper (T,) type 1 inflammatory immune response. Reducing the influx of disease-associated CD4+ T(H)1 cells into the inflamed intestine is likely to be beneficial in preventing a disease flare-up and even possibly in reducing the effect of acute disease. Thiazolidenedione (TZD) ligands, which activate peroxisome proliferator-activated receptor-gamma (PPARgamma), have been shown to reduce T(H)1 inflammation in murine models of colitis, primarily in a preventative fashion. To determine whether PPARgamma ligands reduce this inflammation in part by reducing T(H)1 chemoattractant levels in vivo, the TZD pioglitazone was tested for its effects on a T(H)1 chemokine (CXCL10) in 2 models of colitis (i.e., dextran sodium sulfate and 2,4,6-dinitrobenzene sulfonic acid-mediated colitis). In both models, CXCL10 levels were significantly reduced by pioglitazone. Because TZDs can affect gene expression either directly, by regulating the binding of PPARgamma to consensus promoter elements, or indirectly, by modulating other signaling pathways that can affect gene transcription, the regulation of CXCL10 by TZDs was investigated in vitro in both HT-29 colon epithelial cells and THP-1 monocyte/macrophage cells. TZDs significantly reduced CXCL10 protein levels from activated HT-29 cells and THP-1-derived macrophages in a dose-dependent manner at nanomolar concentrations. However, TZDs did not affect messenger RNA levels or nuclear factor-kappaB activation at these concentrations in these cells. These findings imply the existence of a novel posttranscriptional regulatory antinflammatory mechanism by TZDs that is not associated with reductions in nuclear factor-kappaB activation.