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,

    1. Department of Structural & Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA, USA
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  • Robert T. Dauchy,

    1. Department of Structural & Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA, USA
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  • Sen Liu,

    1. Department of Structural & Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA, USA
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  • Qiuyang Zhang,

    1. Department of Structural & Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA, USA
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  • Lulu Mao,

    1. Department of Structural & Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA, USA
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  • Erin M. Dauchy,

    1. Department of Structural & Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA, USA
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  • David E. Blask,

    1. Department of Structural & Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA, USA
    2. Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University Health Sciences Center, New Orleans, LA, USA
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  • Steven M. Hill,

    1. Department of Structural & Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA, USA
    2. Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University Health Sciences Center, New Orleans, LA, USA
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  • Brian G. Rowan,

    1. Department of Structural & Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA, USA
    2. Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University Health Sciences Center, New Orleans, LA, USA
    3. Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
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  • George C. Brainard,

    1. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA
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  • John P. Hanifin,

    1. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA
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  • Kate S. Cecil,

    1. Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA
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  • Zhenggang Xiong,

    1. Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
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  • Leann Myers,

    1. Department of Biostatistics and Bioinformatics, School of Public Health and Tropical Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
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  • Zongbing You

    Corresponding author
    1. Tulane Cancer Center and Louisiana Cancer Research Consortium, Tulane University Health Sciences Center, New Orleans, LA, USA
    2. Tulane Center for Stem Cell Research and Regenerative Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
    3. Department of Orthopaedic Surgery, School of Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
    4. Tulane Center for Aging, Tulane University Health Sciences Center, New Orleans, LA, USA
    • Department of Structural & Cellular Biology, Tulane University Health Sciences Center, New Orleans, LA, USA
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Address reprint requests to Zongbing You, Department of Structural and Cellular Biology, Tulane University, 1430 Tulane Ave SL 49, New Orleans, LA 70112, USA.

E-mail: zyou@tulane.edu

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.

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