title: Insulin stimulates interleukin-6 expression and release in LS14 human adipocytes through multiple signaling pathways.
abstract: IL-6 is an important cytokine that regulates both immune and metabolic functions. Within adipose tissue, preadipocytes produce significant amounts of IL-6, but little is known about the factors or mechanisms that regulate IL-6 production in these cells. Using LS14, a newly developed human adipocyte cell line, our objective was to determine the mechanisms by which insulin stimulates IL-6 production and release in preadipocytes. Insulin increased IL-6 gene expression and secretion in a time- and dose-dependent manner. Insulin decreased cyclic AMP (cAMP) but increased cyclic GMP (cGMP) levels, and IL-6 expression/release was stimulated by a cGMP analog. The stimulatory effect of insulin and cGMP was abrogated by a specific inhibitor of protein kinase G (cyclic GMP-dependent protein kinase). Both insulin and cGMP rapidly induced phosphorylation of cAMP response element binding protein. Insulin also activated the MAPK signaling pathway, and its blockade prevented the insulin-stimulated increases in IL-6 cell content and release, but not IL-6 gene expression. Although inhibition of the proteosome increased IL-6 cell content and release, proteosome activity was unaffected by insulin. These data suggest that the stimulatory effects of insulin on IL-6 release involve several interrelated components: transcription, intracellular releasable pool, and secretion, which are differentially regulated and, thus, determine the size of the releasable pool of IL-6. Insulin-induced IL-6 gene expression is mediated by cGMP/cyclic GMP-dependent protein kinase/cAMP response element binding protein, whereas MAPK is involved in the insulin-stimulated IL-6 synthesis/release.
authors.affiliation: Department of cancer and Cell Biology, University of Cincinnati School of Medicine, Cincinnati, Ohio 45267-0521, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: LaPensee
authors.forename: Eric R
authors.initials: ER
authors.lastname: Hugo
authors.forename: Nira
authors.initials: N
authors.lastname: Ben-Jonathan
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism / Q000494:pharmacology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008954:Models, Biological; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D013997:Time Factors
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D007328:Insulin; D015850:Interleukin-6; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000242:Cyclic AMP; D017869:Cyclic GMP-Dependent Protein Kinases; D046988:Proteasome Endopeptidase Complex; D006152:Cyclic GMP; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide