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 IL1β levels. The aim of the present study is to explore whether IL1β could regulate hepatic SHBG production to account for low SHBG levels in these diseases. We provide evidence that daily IL1β 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 IL1β-induced down-regulation of SHBG promoter activity in luciferase reporter gene assays. Daily treatment with IL1β reduces hepatic nuclear factor (HNF)-4α mRNA and protein levels via the MEK-1/2 and JNK MAPK signaling pathways. Moreover, IL1β rapidly decreased HNF-4α mRNA and protein levels while increased phospho-c-Jun protein levels after the treatment. Finally, daily IL1β treatment of human SHBG transgenic mice reduced plasma SHBG and SHBG mRNA levels. Moreover, IL1β treatment also reduced HNF-4α mRNA and protein levels while increased hepatic phospho-c-Jun protein levels. Our results show that IL1β reduces hepatic SHBG production by decreasing HNF-4α via MEK-1/2 and JNK MAPK pathways. In addition, our findings suggest that IL1β could be involved the low plasma SHBG levels reported in chronic low-grade inflammatory diseases.
Diabetes and Metabolism Research Unit, Vall d’Hebron Institut de Recerca, Universitat Autònoma de Barcelona and Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (Instituto de Salud Carlos III), 08035 Barcelona, Spain.
Rafael
R
Simó
Anna
A
Barbosa-Desongles
Cristina
C
Hernandez
David M
DM
Selva
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D017930:Genes, Reporter; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012738:Sex Hormone-Binding Globulin / Q000096:biosynthesis* / Q000235:genetics; D013739:Testosterone / Q000097:blood; D018808:Transcription Factor AP-1 / Q000378:metabolism
C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D053583:Interleukin-1beta; D012738:Sex Hormone-Binding Globulin; D018808:Transcription Factor AP-1; D013739:Testosterone; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases