Pretreatment with CO-releasing molecules suppresses hepcidin expression during inflammation and endoplasmic reticulum stress through inhibition of the STAT3 and CREBH pathways.

The circulating peptide hormone hepcidin maintains systemic iron homeostasis. Hepcidin production increases during inflammation and as a result of endoplasmic reticulum (ER) stress. Elevated hepcidin levels decrease dietary iron absorption and promote iron sequestration in reticuloendothelial macrophages. Furthermore, increased plasma hepcidin levels cause hypoferremia and the anemia associated with chronic diseases. The signal transduction pathways that regulate hepcidin during inflammation and ER stress include the IL-6-dependent STAT-3 pathway and the unfolded protein response-associated cyclic AMP response element-binding protein-H (CREBH) pathway, respectively. We show that carbon monoxide (CO) suppresses hepcidin expression elicited by IL-6- and ER-stress agents by inhibiting STAT-3 phosphorylation and CREBH maturation, respectively. The inhibitory effect of CO on IL-6-inducible hepcidin expression is dependent on the suppressor of cytokine signaling-3 (SOCS-3) protein. Induction of ER stress in mice resulted in increased hepatic and serum hepcidin. CO administration inhibited ER-stress-induced hepcidin expression in vivo. Furthermore, ER stress caused iron accumulation in splenic macrophages, which could be prevented by CO. Our findings suggest novel anti-inflammatory therapeutic applications for CO, as well as therapeutic targets for the amelioration of anemia in the hypoferremic condition associated with chronic inflammatory and metabolic diseases.