Oncostatin M and leukemia inhibitory factor increase hepcidin expression in hepatoma cell lines

Kanda, Junya; Uchiyama, Tomoki; Tomosugi, Naohisa; Higuchi, M.; Uchiyama, Takashi; Kawabata, Hiroshi

doi:10.1007/s12185-009-0443-x

Cited by 26 publications

(16 citation statements)

References 44 publications

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“…Pro-inflammatory properties of OSM were reported in the skin, adipose tissue, lung, heart and liver [32], [33], [34], [35], [36]. In contrast, other studies demonstrated anti-inflammatory effects of OSM, e.g.…”

Section: Discussionmentioning

confidence: 95%

Oncostatin M Mediates STAT3-Dependent Intestinal Epithelial Restitution via Increased Cell Proliferation, Decreased Apoptosis and Upregulation of SERPIN Family Members

et al. 2014

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ObjectiveOncostatin M (OSM) is produced by activated T cells, monocytes, and dendritic cells and signals through two distinct receptor complexes consisting of gp130 and LIFR (I) or OSMR-β and gp130 (II), respectively. Aim of this study was to analyze the role of OSM in intestinal epithelial cells (IEC) and intestinal inflammation.MethodsOSM expression and OSM receptor distribution was analyzed by PCR and immunohistochemistry experiments, signal transduction by immunoblotting. Gene expression studies were performed by microarray analysis and RT-PCR. Apoptosis was measured by caspases-3/7 activity. IEC migration and proliferation was studied in wounding and water soluble tetrazolium assays.ResultsThe IEC lines Caco-2, DLD-1, SW480, HCT116 and HT-29 express mRNA for the OSM receptor subunits gp130 and OSMR-β, while only HCT116, HT-29 and DLD-1 cells express LIFR mRNA. OSM binding to its receptor complex activates STAT1, STAT3, ERK-1/2, SAPK/JNK-1/2, and Akt. Microarray analysis revealed 79 genes that were significantly up-regulated (adj.-p≤0.05) by OSM in IEC. Most up-regulated genes belong to the functional categories “immunity and defense” (p = 2.1×10−7), “apoptosis” (p = 3.7×10−4) and “JAK/STAT cascade” (p = 3.4×10−6). Members of the SERPIN gene family were among the most strongly up-regulated genes. OSM significantly increased STAT3- and MEK1-dependent IEC cell proliferation (p<0.05) and wound healing (p = 3.9×10−5). OSM protein expression was increased in colonic biopsies of patients with active inflammatory bowel disease (IBD).ConclusionsOSM promotes STAT3-dependent intestinal epithelial cell proliferation and wound healing in vitro. Considering the increased OSM expression in colonic biopsy specimens of patients with active IBD, OSM upregulation may modulate a barrier-protective host response in intestinal inflammation. Further in vivo studies are warranted to elucidate the exact role of OSM in intestinal inflammation and the potential of OSM as a drug target in IBD.

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Section: Discussionmentioning

confidence: 95%

Oncostatin M Mediates STAT3-Dependent Intestinal Epithelial Restitution via Increased Cell Proliferation, Decreased Apoptosis and Upregulation of SERPIN Family Members

et al. 2014

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“…OSM is known as an alternate cytokine that is able to regulate hepcidin gene expression 24,25 and LIF can regulate hepcidin expression. 24 In the anemia of multiple myeloma, increased levels of BMP-2 stimulate hepcidin expression. 26 Therefore, we also investigated whether CO could down-regulate hepcidin expression elicited by these inflammatory mediators.…”

Section: Co Inhibits Hepcidin Expression By Il-6 and Er-stress Inducersmentioning

confidence: 99%

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

Shin

Chung

Joe

et al. 2012

Blood

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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...

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“…Published work has shown that OSM regulates LDLR in liver cells [90] suggesting a role in cholesterol metabolism. More recent studies have identified hepcidin as a target for regulation by OSM [91, 92] resulting in decreased serum iron levels and implicating OSM in disorders involving anaemia.…”

Section: Effects On Hepatocytes and Livermentioning

confidence: 99%

The Enigmatic Cytokine Oncostatin M and Roles in Disease

2013

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Oncostatin M is a secreted cytokine involved in homeostasis and in diseases involving chronic inflammation. It is a member of the gp130 family of cytokines that have pleiotropic functions in differentiation, cell proliferation, and hematopoetic, immunologic, and inflammatory networks. However, Oncostatin M also has activities novel to mediators of this cytokine family and others and may have fundamental roles in mechanisms of inflammation in pathology. Studies have explored Oncostatin M functions in cancer, bone metabolism, liver regeneration, and conditions with chronic inflammation including rheumatoid arthritis, lung and skin inflammatory disease, atherosclerosis, and cardiovascular disease. This paper will review Oncostatin M biology in a historical fashion and focus on its unique activities, in vitro and in vivo, that differentiate it from other cytokines and inspire further study or consideration in therapeutic approaches.

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Oncostatin M and leukemia inhibitory factor increase hepcidin expression in hepatoma cell lines

Cited by 26 publications

References 44 publications

Oncostatin M Mediates STAT3-Dependent Intestinal Epithelial Restitution via Increased Cell Proliferation, Decreased Apoptosis and Upregulation of SERPIN Family Members

Oncostatin M Mediates STAT3-Dependent Intestinal Epithelial Restitution via Increased Cell Proliferation, Decreased Apoptosis and Upregulation of SERPIN Family Members

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

The Enigmatic Cytokine Oncostatin M and Roles in Disease

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