Abstract
IL-6/STAT3 pathway is involved in a variety of biological responses, including cell proliferation, differentiation, apoptosis, and inflammation. In our present study, we found that CO releasing molecules (CORMs) suppress IL-6-induced STAT3 phosphorylation, nuclear translocation and transactivity in endothelial cells (ECs). CO is a byproduct of heme degradation mediated by heme oxygenase (HO-1). However, CORMs can induce HO-1 expression and then inhibit STAT3 phosphorylation. CO has been found to increase a low level ROS and which may induce protein glutathionylation. We hypothesized that CORMs increases protein glutathionylation and inhibits STAT3 activation. We found that CORMs increase the intracellular GSSG level and induce the glutathionylation of multiple proteins including STAT3. GSSG can inhibit STAT3 phosphorylation and increase STAT3 glutathionylation whereas the antioxidant enzyme catalase can suppress the glutathionylation. Furthermore, catalase blocks the inhibition of STAT3 phosphorylation by CORMs treatment. The inhibition of glutathione synthesis by BSO was also found to attenuate STAT3 glutathionylation and its inhibition of STAT3 phosphorylation. We further found that HO-1 increases STAT3 glutathionylation and that HO-1 siRNA attenuates CORM-induced STAT3 glutathionylation. Hence, the inhibition of STAT3 activation is likely to occur via a CO-mediated increase in the GSSG level, which augments protein glutathionylation, and CO-induced HO-1 expression, which may enhance and maintain its effects in IL-6-treated ECs.
Highlights
IL-6 is a key proinflammatory cytokine involved in a wide spectrum of diseases, including atherosclerosis, osteoporosis, arthritis, diabetes and certain cancers [1]
The carbon monoxide (CO) releasing molecules (CORMs) have been shown to function by reproducing the biological effects of CO which derive from HO activity [10]
We pretreated endothelial cells (ECs) with chalcone or 15d-PGJ2, two electrophilic chemicals, and found that this attenuated the subsequent IL-6-induced phosphorylation of STAT3 [6,35]. These inhibitory effects may come from electrophilic activity which may directly react with the thiol group in STAT3 or modulate the intracellular GSH level
Summary
IL-6 is a key proinflammatory cytokine involved in a wide spectrum of diseases, including atherosclerosis, osteoporosis, arthritis, diabetes and certain cancers [1]. IL-6 signaling has been extensively studied and is known to be mediated through a tyrosine kinase mechanism involving the JAK/STAT pathway [1]. STAT3 is a member of a family of functionally related STAT proteins (signal transducers and activators of transcription) and plays a key role in a variety of biological activities, including cell growth and differentiation, inflammation and immune responses [2]. Tyrosine phosphorylation of STAT3 results in the homo- or heterodimerization of this protein and its subsequent translocation into the nucleus where these dimeric complexes bind to target response elements, including interferon response elements (IREs) and serum-inducible elements (SIEs), and activate gene expression [3]. Recent studies have demonstrated that HO-1 functions as part of the cytoprotective mechanisms that underlie antioxidant activities [8] and shows potential as a novel therapeutic target for cardiovascular diseases [9]. The detailed mechanisms underlying CO induced cytoprotective effects remain unclear
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