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


ABSTRACT: 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 (TTP) 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 TTP 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, TTP induction, and TNF-? production in LPS-treated macrophages. Induction of HO-1 expression increased the level of TTP in the absence of nicotine. In an LPS-induced endotoxemia model, HO-1 deficiency blocked the effects of nicotine on the STAT3 phosphorylation, TTP induction, and LPS-induced TNF-? production in the liver. Downregulation of STAT3 by siRNA attenuated the effect of nicotine on TTP expression and TNF-? production but did not affect the nicotine-mediated induction of HO-1. In TTP knockout mice, nicotine treatment enhanced HO-1 expression and STAT3 activation but failed to inhibit LPS-induced TNF-? production. Our results suggest that HO-1 and TTP are functionally linked in mediating the anti-inflammatory effects of nicotine; HO-1 is necessary for the induction of TTP by nicotine. This novel nicotine-HO-1-TTP signaling pathway provides new possibilities for the treatment of inflammatory diseases.

SUBMITTER: Jamal Uddin M 

PROVIDER: S-EPMC4798239 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Jamal Uddin Md M   Joe Yeonsoo Y   Zheng Min M   Blackshear Perry J PJ   Ryter Stefan W SW   Park Jeong Woo JW   Chung Hun Taeg HT  

Free radical biology & medicine 20131002


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 (TTP) 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 TTP to med  ...[more]

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