Distinct apoptotic machinery and selective gene regulation by glucocorticoids in Th17 cells (P1294)

Abstract

Abstract Glucocorticoids (GCs) are extensively used in the treatment of inflammatory disorders and surprisingly, are ineffective in suppressing Th17 responses. We sought to determine the mechanisms underlying the insensitivity of Th17 cells to GCs. We found that in vitro polarized murine Th1 and Th2 cells, but not Th17 cells, were sensitive to GC-induced apoptosis as determined by various apoptotic markers such as annexin-V staining. At the mRNA level, GCs suppressed IL-4 and IFN-γ, and unexpectedly IL-22 but not IL-17 (A and F). Despite the distinct GC responses, Th1, Th2, and Th17 cells showed similar levels of GC receptor (GR) isoforms. Using PCR array to survey 84 genes involved in apoptosis, we found significant differences in the apoptotic machinery between Th1 and Th17 cells. Th17 cells showed increased expression of anti-apoptotic survivin and Bfl-1 whereas Th1 cells showed increased expression of pro-apoptotic Bim, Fas ligand, caspase 1, and death receptor 5. GCs induced Bim in both Th1 and Th17 cells while the same treatment decreased the expression of Nod1 and Bcl-xL in Th1 but not Th17 cells. Altered apoptotic machinery and differences in genes regulated after GC treatment may underlie the inability of GCs to induce apoptosis in Th17 cells. These studies on the mechanisms underlying the selective insensitivity of Th17 cells to GCs may provide a basis for improved treatment regimens for severe asthma and other Th17-mediated disorders.