Carbon Monoxide Induces Heme Oxygenase-1 to Modulate STAT3 Activation in Endothelial Cells via S-Glutathionylation

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.

Lycopene inhibits NF-κB activation and adhesion molecule expression through Nrf2-mediated heme oxygenase-1 in endothelial cells

“…6A and B). Previous studies have shown that CO donors exert their effects via HO-1 induction in various systems (20,21). In the present study, as shown in Fig.…”

“…6B). Our previous data found that CO seems to be the major mediator of the anti-inflammatory effects of HO-1 (20,21). In this study, we found that pre-treatment of the ECs with 25 µM CO donor [tricarbonyldichlororuthenium (II) dimer] (TCDC) for 3 h inhibited TNFα-induced ICAM-1 expression ( Fig.…”

“…In our previous study, we reported that the Nrf2induced expression of HO-1 and the related signaling pathways exerted anti-inflammatory effects in ECs (19). Recently, we also demonstrated that HO-1 exerts anti-inflammatory effects by its derivative CO production (20,21). However, the detailed mechanisms responsible for the anti-inflammatory effects of lycopene in ECs have not yet been fully elucidated.…”

Protein Thiol Redox Signaling in Monocytes and Macrophages

“…Similarly, increased oxidation of AMPKa cysteine residues occurs in lung tissue from mice treated with a pharmacologic inhibitor of catalase, aminotriazole (ATZ), or in lungs from acatalasemic mice (239). In contrast, overexpression of catalase prevents (i) UV light-induced mitochondrial pyruvate dehydrogenase-S-glutathionylation in HeLa cells (91), (ii) p65 NF-jB-S-glutathionylation in an endothelial cell line exposed to two different carbon monoxide (CO) donors, tricarbonyl dichlororuthenium (II) dimer and methylene chloride, and (iii) STAT3-S-glutathionylation in bovine aorta endothelial cells exposed CO donors (226).…”

The Heme Metabolite Carbon Monoxide Facilitates KSHV Infection by Inhibiting TLR4 Signaling in Endothelial Cells

“…HO-1 is thought to contribute to cytoprotection and proliferation through the catabolism of heme, a pro-oxidant molecule that is cytotoxic in excess, into metabolites with anti-oxidant, pro-angiogenic, anti-apoptotic, and anti-inflammatory activities (Ryter and Tyrrell, 2000; Ryter et al, 2006; Ryter and Choi, 2009). Of particular relevance to the current study, the endogenous gasotransmitter CO participates in intracellular signaling pathways that culminate in anti-inflammatory, anti-coagulative and pro-survival outcomes (Liu et al, 2002; Pae et al, 2004; Otterbein et al, 2005; Nakahira et al, 2006; Ryter and Choi, 2009; Ruan et al, 2014; Yang et al, 2014; Xue and Habtezion, 2014; Riquelme et al, 2015). The discovery of compounds categorized as “carbon monoxide releasing molecules” (CORM) has allowed for further mechanistic insight into the role of CO in biological systems (Ryter and Choi, 2015).…”