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Thyroid-Stimulating Hormone Induces Interleukin-6 Release from Human Adipocytes through Activation of the Nuclear Factor-B Pathway

Departments of Medicine and Biochemistry, Microbiology, and Immunology, University of Ottawa, Chronic Disease Program, Ottawa Health Research Institute, Ottawa, Canada K1Y 4E9

Address all correspondence and requests for reprints to: Dr. Alexander Sorisky, Ottawa Health Research Institute, 725 Parkdale Avenue, Ottawa Ontario, Canada K1Y 4E9. E-mail: asorisky{at}ohri.ca.

Our objective was to identify the signaling pathway activated by TSH that induces IL-6 secretion from human abdominal sc differentiated adipocytes. Human abdominal sc preadipocytes in culture were differentiated into adipocytes. IL-6 release stimulated by TSH was inhibited by 35% (P < 0.05) with SN50, an inhibitor of nuclear factor-B (NF-B) nuclear translocation, and 60% (P < 0.01) with sc-514, an inhibitor of inhibitory-B (IB) kinase (IKK)-β. Phosphorylation of IKKβ increased upon TSH treatment (10.3-fold, P < 0.01), and IB levels were reduced by 78% (P < 0.01). TSH activated NF-B (23-fold, P < 0.001), a process that was inhibited (60%, P < 0.01) by SN50. Inhibition of protein kinase A by H89 did not affect TSH-stimulated IKKβ phosphorylation or IB degradation. TSH-mediated NF-B activation and IL-6 induction also specifically occurred in Chinese hamster ovarian cells expressing the human TSH receptor, resulting in a 5.9-fold (P < 0.001) increase in IKKβ phosphorylation and a 9.5-fold increase in IL-6 mRNA expression. Our data demonstrate that the IKKβ/NF-B pathway is a novel TSH target that is required for TSH-induced IL-6 release from human adipocytes.