title: Interleukin-6 enhances glucose-stimulated insulin secretion from pancreatic beta-cells: potential involvement of the PLC-IP3-dependent pathway.
abstract: OBJECTIVE
  Interleukin-6 (IL-6) has a significant impact on glucose metabolism. However, the effects of IL-6 on insulin secretion from pancreatic β-cells are controversial. Therefore, we analyzed IL-6 effects on pancreatic β-cell functions both in vivo and in vitro.
  
  
  METHODS
  First, to examine the effects of IL-6 on in vivo insulin secretion, we expressed IL-6 in the livers of mice using the adenoviral gene transfer system. In addition, using both MIN-6 cells, a murine β-cell line, and pancreatic islets isolated from mice, we analyzed the in vitro effects of IL-6 pretreatment on insulin secretion. Furthermore, using pharmacological inhibitors and small interfering RNAs, we studied the intracellular signaling pathway through which IL-6 may affect insulin secretion from MIN-6 cells.
  
  
  RESULTS
  Hepatic IL-6 expression raised circulating IL-6 and improved glucose tolerance due to enhancement of glucose stimulated-insulin secretion (GSIS). In addition, in both isolated pancreatic islets and MIN-6 cells, 24-h pretreatment with IL-6 significantly enhanced GSIS. Furthermore, pretreatment of MIN-6 cells with phospholipase C (PLC) inhibitors with different mechanisms of action, U-73122 and neomycin, and knockdowns of the IL-6 receptor and PLC-β(1), but not with a protein kinase A inhibitor, H-89, inhibited IL-6-induced enhancement of GSIS. An inositol triphosphate (IP(3)) receptor antagonist, Xestospondin C, also abrogated the GSIS enhancement induced by IL-6.
  
  
  CONCLUSIONS
  The results obtained from both in vivo and in vitro experiments strongly suggest that IL-6 acts directly on pancreatic β-cells and enhances GSIS. The PLC-IP(3)-dependent pathway is likely to be involved in IL-6-mediated enhancements of GSIS.
authors.affiliation: Department of Metabolic Diseases, Center for Metabolic Diseases, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan.
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Junta
authors.initials: J
authors.lastname: Imai
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamada
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishigaki
authors.forename: Keizo
authors.initials: K
authors.lastname: Kaneko
authors.forename: Kenji
authors.initials: K
authors.lastname: Uno
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Ishihara
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Oka
authors.forename: Hideki
authors.initials: H
authors.lastname: Katagiri
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D004963:Estrenes / Q000494:pharmacology; D018014:Gene Transfer Techniques; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism* / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009355:Neomycin / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism*
chemical_list: D004963:Estrenes; D007328:Insulin; D015850:Interleukin-6; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D011500:Protein Synthesis Inhibitors; D011760:Pyrrolidinones; D034741:RNA, Small Interfering; D013449:Sulfonamides; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D015544:Inositol 1,4,5-Trisphosphate; D010738:Type C Phospholipases; D009355:Neomycin; D005947:Glucose; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide