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Insulin and IGF 1 enhance IL ‐17‐induced chemokine expression through a GSK 3B‐dependent mechanism: a new target for melatonin's anti‐inflammatory action
Author(s) -
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
Publication year - 2013
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12084
Subject(s) - ccl20 , melatonin , gsk3b , gsk 3 , endocrinology , chemistry , medicine , protein kinase b , chemokine , cxcl1 , inflammation , signal transduction , biology , biochemistry , chemokine receptor
Obesity is a chronic inflammation with increased serum levels of insulin, insulin‐like growth factor 1 ( IGF 1), and interleukin‐17 ( IL ‐17). The objective of this study was to test a hypothesis that insulin and IGF 1 enhance IL ‐17‐induced expression of inflammatory chemokines/cytokines through a glycogen synthase kinase 3β ( GSK 3B)‐dependent mechanism, which can be inhibited by melatonin. We found that insulin/ IGF 1 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 IGF 1 activated Akt to phosphorylate GSK 3B at serine 9, thus inhibiting GSK 3B activity. Melatonin inhibited Akt activation, thus decreasing P‐ GSK 3B at serine 9 (i.e., increasing GSK 3B 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 PC 3 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 IGF 1 in obesity.