Interleukin-6/STAT pathway is responsible for the induction of gene expression of REG Iα, a new auto-antigen in Sjögren׳s syndrome patients, in salivary duct epithelial cells

The regenerating gene, , was originally isolated from a rat regenerating islet cDNA library, and its human homolog was named . Recently, we reported that mRNA as well as its product were overexpressed in ductal epithelial cells in the minor salivary glands of Sjögren׳s syndrome (SS) patients. This study was undertaken to elucidate the role of cytokines and the subsequent intracellular mechanism for induction of in the salivary glands of SS patients. We prepared a reporter plasmid containing promoter (-1190/+26) upstream of a luciferase reporter gene. The promoter plasmid was introduced by lipofection into human NS-SV-DC and rat A5 salivary ductal cells. The cells were treated with interleukin (IL)-6, IL-8, and a combination of the two. Thereafter transcriptional activity of was measured by luciferase assay. We found that IL-6 stimulation, but not IL-8, significantly enhanced the promoter activity in salivary ductal cells. Deletion analysis revealed that the region of -141 to -117 of the gene was responsible for the promoter activation by IL-6, which contains a consensus sequence for signal transduction and activation of transcription (STAT). The introduction of siRNA for human STAT3 abolished IL-6-induced transcription. These results showed that IL-6 stimulation induced transcription through STAT3 activation and binding to the consensus sequence of promoter in salivary ductal cells. This IL-6/STAT dependent induction might play a role in the pathogenesis of SS.