IL1β Down-regulation of Sex Hormone-Binding Globulin Production by Decreasing HNF-4α Via MEK-1/2 and JNK MAPK Pathways

Patients suffering from low-grade chronic inflammatory diseases, such as rheumatoid arthritis, osteoarthritis, diabetes, and obesity, have low plasma sex hormone-binding globulin (SHBG) levels. These diseases are characterized among other features by high plasma IL1 beta levels. The aim of the present study is to explore whether IL1 beta could regulate hepatic SHBG production to account for low SHBG levels in these diseases. We provide evidence that daily IL1 beta treatment reduces SHBG production in HepG2 cells by the down-regulation of HNF-4A via the MAPK kinase (MEK)-1/2 and c-Jun N-terminal kinase (JNK) MAPK signaling pathways through the activation c-Jun transcription factors. The human SHBG promoter sequence contains two putative activator protein 1 (AP1) binding sites recognized by c-Jun transcription factors, but they are not necessary for the IL1 beta-induced down-regulation of SHBG promoter activity in luciferase reporter gene assays. Daily treatment with IL1 beta reduces hepatic nuclear factor (HNF)-4 alpha mRNA and protein levels via the MEK-1/2 and JNK MAPK signaling pathways. Moreover, IL1 beta rapidly decreased HNF-4 alpha mRNA and protein levels while increased phospho-c-Jun protein levels after the treatment. Finally, daily IL1 beta treatment of human SHBG transgenic mice reduced plasma SHBG and SHBG mRNA levels. Moreover, IL1 beta treatment also reduced HNF-4 alpha mRNA and protein levels while increased hepatic phospho-c-Jun protein levels. Our results show that IL1 beta reduces hepatic SHBG production by decreasing HNF-4 alpha via MEK-1/2 and JNK MAPK pathways. In addition, our findings suggest that IL1 beta could be involved the low plasma SHBG levels reported in chronic low-grade inflammatory diseases. (Molecular Endocrinology 26: 1917-1927, 2012)