Glucocorticoid (GC) regulation of Th1 and Th2 transcription factors (TF)

ANA C. LIBERMAN, EDUARDO ARZT,

Buenos Aires, Argentina

Congreso; 3RD Latin American Congress on Autoimmunity (LACA); 2009

TF T-bet and GATA-3 are pivotal for the acquisition of Th1 or Th2 phenotype, respectively. GC regulate both Th1 and Th2 cytokines and favor a shift towards Th2 differentiation. We describe for the first time GC regulation of these master TF. GC inhibit T-bet transcriptional activity by a transrepression mechanism involving glucocorticoid receptor (GR) physical interaction with T-bet. This interaction also blocks GR-dependent transcription. The mechanism underlying T-bet inhibition further involves reduction of T-bet binding to DNA. The first zinc finger region of GR is required for T-bet inhibition. The inhibition of T-bet by GC plays an important role in mediating the inhibition of IFN-g gene expression, hallmark of Th1-mediated immunity. GC also inhibit GATA-3 transcriptional activity. This mechanism does not involve physical interaction between the GR and GATA-3, nor reduction of GATA-3 binding to DNA, as described for T-bet. Instead, GC inhibit GATA-3 activity by inhibition of p38 MAPK induced GATA-3 phosphorylation. Finally, GATA-3 inhibition impacts on interleukin-5 gene, a central Th2 cytokine. Consistent with its immunosuppressive action, GC inhibit both Th1 and Th2 master TF but favor Th2 activity. These different molecular mechanisms provide a rationale for dissecting GC targeting on Th1/Th2 cells and its role in autoimmune processes.