Significance of Interleukin-6/STAT Pathway for the Gene Expression of REG Iα, a New Autoantigen in Sjögren's Syndrome Patients, in Salivary Duct Epithelial Cells.
The regenerating gene, Reg, was originally isolated from a rat regenerating islet complementary DNA (cDNA) library, and its human homologue was named REG Iα. Recently, we reported that REG Iα messenger RNA (mRNA), as well as its product, was overexpressed in ductal epithelial cells in the salivary glands of Sjögren's syndrome patients. Furthermore, autoantibodies against REG Iα were found in the sera of Sjögren's syndrome patients, and the patients who were positive for the anti-REG Iα antibody showed significantly lower saliva secretion than antibody-negative patients. We found the mechanism of REG Iα induction in salivary ductal epithelial cells. Reporter plasmid containing REG Iα promoter (-1190/+26) upstream of a luciferase gene was introduced into human NS-SV-DC and rat A5 salivary ductal cells. The cells were treated with several cytokines (interleukin (IL)-6, IL-8, etc.), upregulated in Sjögren's syndrome salivary ducts, and the transcriptional activity was measured. IL-6 stimulation significantly enhanced the REG Iα promoter activity in both cells. Deletion analysis revealed that the -141∼-117 region of the REG Iα gene was responsible for the promoter activation by IL-6, which contains a consensus sequence for signal transducer and activator of transcription (STAT) binding. The introduction of small interfering RNA for human STAT3 abolished IL-6-induced REG Iα transcription. These results indicated that IL-6 stimulation induced REG Iα transcription through STAT3 activation and binding to the REG Iα promoter in salivary ductal cells. This dependence of REG Iα induction upon IL-6/STAT in salivary duct epithelial cells may play an important role in the pathogenesis/progression of Sjögren's syndrome.
['Fujimura|Takanori|T|', 'Fujimoto|Takashi|T|', 'Itaya-Hironaka|Asako|A|', 'Miyaoka|Tomoko|T|', 'Yoshimoto|Kiyomi|K|', 'Sakuramoto-Tsuchida|Sumiyo|S|', 'Yamauchi|Akiyo|A|', 'Takeda|Maiko|M|', 'Tsujinaka|Hiroki|H|', 'Tanaka|Yasuhito|Y|', 'Takasawa|Shin|S|']
D000818:Animals D001323:Autoantibodies D001324:Autoantigens D004847:Epithelial Cells D005260:Female D005786:Gene Expression Regulation D006801:Humans D015850:Interleukin-6 D051847:Lithostathine D051381:Rats D050791:STAT Transcription Factors D018987:Salivary Ducts D015398:Signal Transduction D012859:Sjogren's Syndrome
Interleukin-6 Autoantibody Signal transducer and activator of transcription (STAT) Janus kinase (JAK) Regenerating gene (Reg) Sjögren’s syndrome