Synergistic Activations ofREG IαandREG IβPromoters by IL-6 and Glucocorticoids through JAK/STAT Pathway in Human PancreaticβCells

Abstract

Reg(Regenerating gene) gene was originally isolated from rat regenerating islets and its encoding protein was revealed as an autocrine/paracrine growth factor forβcells. RatReggene is activated in inflammatory conditions forβcell regeneration. In human, although five functionalREGfamily genes (REG Iα, REG Iβ, REG III, HIP/PAP, andREG IV) were isolated, their expressions inβcells under inflammatory conditions remained unclear. In this study, we found that combined addition of IL-6 and dexamethasone (Dx) inducedREG IαandREG Iβexpression in human 1.1B4βcells. Promoter assay revealed that a signal transducer and activator of transcription- (STAT-) binding site in each promoter ofREG Iα(TGCCGGGAA) andREG Iβ(TGCCAGGAA) was essential for the IL-6+Dx-induced promoter activation. A Janus kinase 2 (JAK2) inhibitor significantly inhibited the IL-6+Dx-inducedREG IαandREG Iβtranscription. Electrophoretic mobility shift assay and chromatin immunoprecipitation revealed that IL-6+Dx stimulation increased STAT3 binding to theREG Iαpromoter. Furthermore, small interfering RNA-mediated targeting of STAT3 blocked the IL-6+Dx-induced expression ofREG IαandREG Iβ. These results indicate that the expression ofREG IαandREG Iβshould be upregulated in humanβcells under inflammatory conditions through the JAK/STAT pathway.