Title

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

Authors

Dongxia Ge, Department of Structural and Cellular Biology, Tulane University Health Sciences Center
Robert T Dauchy, Department of Structural and Cellular Biology, Tulane University Health Sciences Center
Sen Liu, Department of Structural and Cellular Biology, Tulane University Health Sciences Center
Qiuyang Zhang, Department of Structural and Cellular Biology, Tulane University Health Sciences Center
Lulu Mao, Department of Structural and Cellular Biology, Tulane University Health Sciences Center
Erin M Dauchy, Department of Structural and Cellular Biology, Tulane University Health Sciences Center
David E Blask, Department of Structural and Cellular Biology, Tulane University Health Sciences Center; Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University Health Sciences Center
Steven M Hill, Department of Structural and Cellular Biology, Tulane University Health Sciences Center; Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University Health Sciences Center
Brian G Rowan, Department of Structural and Cellular Biology, Tulane University Health Sciences Center; Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University Health Sciences Center; Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University Health Sciences Center
George Brainard, Department of Neurology, Thomas Jefferson UniversityFollow
John P Hanifin, Department of Neurology, Thomas Jefferson University, Jefferson Medical CollegeFollow
Kate Cecil MS, Jefferson School of Population HealthFollow
Zhenggang Xiong, Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center
Leann Myers, Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University Health Sciences Center
Zongbing You, Department of Structural and Cellular Biology, Tulane University Health Sciences Center; Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University Health Sciences Center; Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University Health Sciences Center; Department of Orthopaedic Surgery, School of Medicine, Tulane University Health Sciences Center; Tulane Center for Aging, Tulane University Health Sciences Center

Document Type

Article

Publication Date

11-1-2013

Comments

This article has been peer reviewed. It was published in: Journal of Pineal Research.

Volume 55, Issue 4, November 2013, Pages 377-387.

The published version is available at DOI: 10.1111/jpi.12084

Copyright © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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.