title: 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.affiliation: Department of Structural & Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA, USA.
authors.forename: Dongxia
authors.initials: D
authors.lastname: Ge
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dauchy
authors.forename: Sen
authors.initials: S
authors.lastname: Liu
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Lulu
authors.initials: L
authors.lastname: Mao
authors.forename: Erin M
authors.initials: EM
authors.lastname: Dauchy
authors.forename: David E
authors.initials: DE
authors.lastname: Blask
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hill
authors.forename: Brian G
authors.initials: BG
authors.lastname: Rowan
authors.forename: George C
authors.initials: GC
authors.lastname: Brainard
authors.forename: John P
authors.initials: JP
authors.lastname: Hanifin
authors.forename: Kate S
authors.initials: KS
authors.lastname: Cecil
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Xiong
authors.forename: Leann
authors.initials: L
authors.lastname: Myers
authors.forename: Zongbing
authors.initials: Z
authors.lastname: You
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology*; D020381:Interleukin-17 / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology; D008550:Melatonin / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D007328:Insulin; D020381:Interleukin-17; D007334:Insulin-Like Growth Factor I; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D008550:Melatonin
keywords: glycogen synthase kinase 3β; inflammation; insulin; insulin-like growth factor 1; interleukin-17; melatonin; prostate cancer
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