Resistin up-regulates COX-2 expression via TAK1-IKK-NF-kappaB signaling pathway.

ABSTRACT

The hormone resistin, which was originally shown to induce insulin resistance, has been implicated in the regulation of inflammatory processes, but the molecular mechanism underlying such regulation has not been clearly defined. The goal of our study was to determine whether the expression of COX-2 can be induced by resistin and what the potential signaling pathway involved in this process is. Compared with controls, resistin significantly upregulated COX-2 expression in RAW264.7 macrophage cells. Administration of anti-resistin antibody could significantly reduce this effect. Induction of COX-2 by resistin was also markedly reduced in the presence of either dominant negative mutant IkappaBalpha or PDTC, a pharmacological inhibitor of NF-kappaB. On the other hand, NF-kappaB subunit p65 was upregulated by resistin. Moreover, we found that transforming growth factor-beta-activated kinase 1 (TAK1), a mitogen-activated protein kinase kinase kinase (MAPKKK), could be activated in response to resistin. These results suggest that resistin enhances COX-2 expression in mouse macrophage cells in a TAK1-IKK-NF-kappaB-dependent manner and therefore plays a critical role in inflammatory processes.