Insulin and IGF1 enhance IL‐17‐induced chemokine expression through a GSK3B‐dependent mechanism: a new target for melatonin's anti‐inflammatory action
- 31 July 2013
- journal article
- research article
- Published by Wiley in Journal of Pineal Research
- Vol. 55 (4), 377-387
- https://doi.org/10.1111/jpi.12084
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.Keywords
Funding Information
- National Institute of General Medical Sciences (8P20GM103518-09)
- National Cancer Institute (R01CA174714)
- Department of Defense
- National Institutes of Health (PC121647)
- Developmental Fund of Tulane Cancer Center
- Louisiana Cancer Research Consortium
This publication has 56 references indexed in Scilit:
- Obesity, type 2 diabetes, and cancer: the insulin and IGF connectionEndocrine-Related Cancer, 2012
- The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-αNature Medicine, 2012
- Chronic melatonin consumption prevents obesity‐related metabolic abnormalities and protects the heart against myocardial ischemia and reperfusion injury in a prediabetic model of diet‐induced obesityJournal of Pineal Research, 2010
- The proliferating role of insulin and insulin-like growth factors in cancerTrends in Endocrinology & Metabolism, 2010
- Enhanced production of IL-17A during zymosan-induced peritonitis in obese miceJournal of Leukocyte Biology, 2009
- Ubiquitin-mediated activation of TAK1 and IKKOncogene, 2007
- Functional MT1 and MT2 Melatonin Receptors in MammalsEndocrine, 2005
- IL-17 stimulates inflammatory responses via NF-κB and MAP kinase pathways in human colonic myofibroblastsAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2002
- Requirement for glycogen synthase kinase-3β in cell survival and NF-κB activationNature, 2000
- The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and RafBiochemical Journal, 1994