Insulin and IGF1 enhance IL‐17‐induced chemokine expression through a GSK3B‐dependent mechanism: a new target for melatonin's anti‐inflammatory action. Issue 4 (20th August 2013)

• Record Type: Journal Article
• Authors: Ge, Dongxia; Dauchy, Robert T.; Liu, Sen; Zhang, Qiuyang; Mao, Lulu; Dauchy, Erin M.; Blask, David E.; Hill, Steven M.; Rowan, Brian G.; Brainard, George C.; Hanifin, John P.; Cecil, Kate S.; Xiong, Zhenggang; Myers, Leann; You, Zongbing
• Is Part Of: Journal of pineal research. Volume 55:Issue 4(2013)
• Page Start: 377
• Page End: 387
• Publication Date: 2013-08-20
• Subjects: Pineal gland -- Periodicals; Pineal Gland -- Periodicals; Épiphyse (Glande); Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 612.492
• DOI: 10.1111/jpi.12084
• Languages: English
• ISSNs: 0742-3098

Abstract

<abstract abstract-type="main" id="jpi12084-abs-0001"> <title>Abstract</title> <p>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<sup>+/+</sup>, but not in Gsk3b<sup>−/−</sup> mouse embryonic fibroblast (MEF) cells. IL‐17 induced higher levels of Cxcl1 and Ccl20 in the Gsk3b<sup>−/−</sup> MEF cells, compared with the Gsk3b<sup>+/+</sup> 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<sup>+/+</sup>, but in not Gsk3b<sup>−/−</sup> 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.</p> </abstract>