A functional link between heme oxygenase-1 and tristetraprolin in the anti-inflammatory effects of nicotine

Nicotine stimulates the cholinergic anti-inflammatory pathway and prevents excessive inflammation by inhibiting the release of inflammatory cytokines from macrophages. We have previously reported that heme oxygenase-1 (HO-1) and tristetraprolin (UP) are induced by nicotine and mediate the anti-inflammatory function of nicotine in macrophages. However, it was not clear whether the two molecules are functionally linked. In this study, we sought to determine whether HO-1 associates with UP to mediate the anti-inflammatory effects of nicotine. Inhibition of HO-1 activity or HO-1 expression attenuated the effects of nicotine on STAT3 activation, UP induction, and TNF-alpha production in LPS-treated macrophages. Induction of HO-1 expression increased the level of UP in the absence of nicotine. In an LPS-induced endotoxemia model, HO-1 deficiency blocked the effects of nicotine on the STAT3 phosphorylation, UP induction, and LPS-induced TNF-alpha production in the liver. Downregulation of STAT3 by siRNA attenuated the effect of nicotine on UP expression and TNF-alpha production but did not affect the nicotine-mediated induction of HO-1. In UP knockout mice, nicotine treatment enhanced HO-1 expression and STAT3 activation but failed to inhibit LPS-induced TNF-alpha production. Our results suggest that HO-1 and UP are functionally linked in mediating the anti-inflammatory effects of nicotine; HO-1 is necessary for the induction of UP by nicotine. This novel nicotine-HO-1-UP signaling pathway provides new possibilities for the treatment of inflammatory diseases.(C) 2013 Elsevier Inc. All rights reserved.