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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-kappaB (NF-kappaB) nuclear translocation, and 60% (P < 0.01) with sc-514, an inhibitor of inhibitory-kappaB (IkappaB) kinase (IKK)-beta. Phosphorylation of IKKbeta increased upon TSH treatment (10.3-fold, P < 0.01), and IkappaBalpha levels were reduced by 78% (P < 0.01). TSH activated NF-kappaB (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 IKKbeta phosphorylation or IkappaBalpha degradation. TSH-mediated NF-kappaB 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 IKKbeta phosphorylation and a 9.5-fold increase in IL-6 mRNA expression. Our data demonstrate that the IKKbeta/NF-kappaB pathway is a novel TSH target that is required for TSH-induced IL-6 release from human adipocytes.

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