Insulin and IGF1 enhance IL-17-induced chemokine expression through a GSK3B-dependent mechanism: a new target for melatonin's anti-inflammatory action.

Abstract

Obesity is a chronic inflammation with increased serum levels of insulin, insulin-like growth factor 1 (IGF1), and interleukin-17 (IL-17). The objective of this study was to test a hypothesis that insulin and IGF1 enhance IL-17-induced expression of inflammatory chemokines/cytokines through a glycogen synthase kinase 3β (GSK3B)-dependent mechanism, which can be inhibited by melatonin. We found that insulin/IGF1 and lithium chloride enhanced IL-17-induced expression of C-X-C motif ligand 1 (Cxcl1) and C-C motif ligand 20 (Ccl20) in the Gsk3b(+/+) , but not in Gsk3b(-/-) mouse embryonic fibroblast (MEF) cells. IL-17 induced higher levels of Cxcl1 and Ccl20 in the Gsk3b(-/-) MEF cells, compared with the Gsk3b(+/+) MEF cells. Insulin and IGF1 activated Akt to phosphorylate GSK3B at serine 9, thus inhibiting GSK3B activity. Melatonin inhibited Akt activation, thus decreasing P-GSK3B at serine 9 (i.e., increasing GSK3B activity) and subsequently inhibiting expression of Cxcl1 and Ccl20 that was induced either by IL-17 alone or by a combination of insulin and IL-17. Melatonin's inhibitory effects were only observed in the Gsk3b(+/+) , but in not Gsk3b(-/-) MEF cells. Melatonin also inhibited expression of Cxcl1, Ccl20, and Il-6 that was induced by a combination of insulin and IL-17 in the mouse prostatic tissues. Further, nighttime human blood, which contained high physiologic levels of melatonin, decreased expression of Cxcl1, Ccl20, and Il-6 in the PC3 human prostate cancer xenograft tumors. Our data support our hypothesis and suggest that melatonin may be used to dampen IL-17-mediated inflammation that is enhanced by the increased levels of insulin and IGF1 in obesity.

• Authors: Dongxia Ge, Robert T Dauchy, Sen Liu, Qiuyang Zhang, Lulu Mao, Erin M Dauchy, David E Blask, Steven M Hill, Brian G Rowan, George C Brainard, John P Hanifin, Kate S Cecil, Zhenggang Xiong, Leann Myers, Zongbing You
• Journal: Journal of pineal research (J Pineal Res) Vol. 55 Issue 4 Pg. 377-87 (Nov 2013) ISSN: 1600-079X [Electronic] England
• PMID: 24033914 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Insulin
• Interleukin-17
• Insulin-Like Growth Factor I
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Glycogen Synthase Kinase 3
• Lithium Chloride
• Melatonin

Topics

• Animals
• Blotting, Western
• Cell Line, Tumor
• Glycogen Synthase Kinase 3 (genetics, metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Insulin (metabolism, pharmacology)
• Insulin-Like Growth Factor I (metabolism, pharmacology)
• Interleukin-17 (metabolism)
• Lithium Chloride (pharmacology)
• Melatonin (metabolism, pharmacology)
• Mice
• Mice, Knockout
• Phosphorylation (drug effects)
• Reverse Transcriptase Polymerase Chain Reaction
• Signal Transduction