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

Abstract

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 IntroductionHepcidin, a circulating peptide hormone synthesized by the liver, functions as a master regulator of iron homeostasis. 1-3 Elevated levels of hepcidin can block the release of iron from macrophages, impair intestinal iron absorption, and cause hypoferremia, leading to iron deficiency anemia. [4][5][6][7] Hepcidin plays a major role in the anemia of inflammation observed in patients with a variety of disorders, including infection, arthritis, inflammatory bowel disease, trauma, cancer, and organ failure. 1,8 IL-6 is the principal regulator of hepcidin expression associated with the anemia of inflammation. 8 In humans, IL-6 can increase hepcidin levels and decrease serum iron levels. IL-6 treatment also induces hepcidin expression in vivo and in primary hepatocytes and hepatoma cell lines. The critical role of IL-6 in hepcidin expression is illustrated by experiments showing that anti-IL-6 Abs block hepcidin mRNA expression in vivo and in hepatocytes stimulated by lipopolysaccharide (LPS). 9 Furthermore, IL-6-deficient mice display impaired hepcidin induction and do not display low serum iron in response to pro-inflammatory stimuli. 9 These observations suggest a relationship between IL-6 and the expression of hepcidin in inflammation.IL-6 plays a central role in the regulation of the acute-phase response (APR) in hepatocytes. 10 After exposure to pro-inflammatory stimuli, IL-6 is released and binds to a complex of the IL-6 receptor-␣ and gp130. 11 The IL-6 ligand-receptor interaction results in the activation of JAKs, which in turn activate STAT-3 by tyrosine (Y705) phosphorylation. Phosphorylated STAT-3 subsequently translocates into the nucleus, where it regulates the transcription of target genes including hepcidin. 12 The transcriptional activity of STAT-3 is regulated by serine (S727) phosphorylation. Additional factors appear to regulate hepcidin expression, because IL-6-knockout mice maintain some hepcidin responsiveness to LPS. For example, IL-1 has been shown to stimulate hepcidin expression in both mouse hepatocytes and human Huh...

Genetics, Genetic Testing, and Management of Hemochromatosis: 15 Years Since Hepcidin

“…The cyclic adenosine monophosphate (cAMP) response element binding protein 3-like 3, CREB3L3 (also known as CREBH), an endoplasmic reticulum (ER) stress-associated liver-specific transcription factor 34 , up-regulates hepcidin transcription in response to exogenous and endogenous ER stressors leading to iron retention in vivo 30 (Figure 1). Hepcidin induction by CREB3L3 has been then confirmed by other studies in similar settings [35][36][37][38] . Because ER stress has been involved in a number of pathophysiological states, including inflammatory response, nutrient disorders and viral infection, it is anticipated that ER stress-driven hepcidin stimulation may cause systemic or intrahepatic iron retention in a variety of iron-unrelated disorders and thereby contribute to the pathogenesis of the underlying disease, including metabolic disorders associated with insulin resistance and activated gluconeogenesis (such as diabetes, obesity and non-alcoholic fatty liver disease, NADFD) [39][40][41][42] .…”

Transcriptional regulation of apolipoprotein A-IV by the transcription factor CREBH

“…It has been shown that CREBH is activated by ER stress and regulates the expression of hepcidin and proinfl ammatory and acute phase response genes, linking ER stress to infl ammation and iron metabolism ( 6,17,50 ). However, subsequent studies by other investigators failed to demonstrate the activation of CREBH processing by ER stress ( 10,11 ).…”

Carbon monoxide-releasing molecules reverse leptin resistance induced by endoplasmic reticulum stress

“…We cannot exclude the possibility that other uncharacterized mechanisms contribute to CO-dependent reversal of leptin resistance, and this warrants further investigation. Recently, we (24) reported that CORM-2 treatment decreased the STAT3 phosphorylation induced by IL-6 in the hepatoma cell line HepG2. We are now reporting that CORM-2 treatment increased the STAT3 phophorylation induced by leptin in a neuronal cell line (SK-N-AS).…”