Upregulation of hepcidin by interleukin-1β in human hepatoma cell lines

Inamura, Junki; Ikuta, Katsuya; Jimbo, Junko; Shindo, Motohiro; Sato, Kazuya; Torimoto, Yoshihiro; Kohgo, Yutaka

doi:10.1016/j.hepres.2005.08.005

Cited by 36 publications

(23 citation statements)

References 45 publications

(61 reference statements)

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“…TNF-a and IL-1h levels may be also elevated in myeloma (17 -19) and both have been implicated in regulating hepcidin expression (11,20,21). Thus, we also measured these cytokines in the sera of our patients.…”

Section: Resultsmentioning

confidence: 99%

Involvement of Hepcidin in the Anemia of Multiple Myeloma

Sharma

Nemeth

Chen

et al. 2008

Clinical Cancer Research

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Purpose: Hepcidin is a liver-produced peptide implicated in the anemia of inflammation. Because interleukin (IL)-6 is a potent inducer of hepcidin expression and its levels are elevated in multiple myeloma, we studied the role of hepcidin in the anemia of multiple myeloma. Experimental Design: Urinary hepcidin and serum levels of IL-6, ferritin, C-reactive protein, tumor necrosis factor-a, and IL-1h were studied in newly diagnosed myeloma patients. In vitro hepcidin induction assay was assessed by real-time PCR assay. Results: Pretreatment urinary hepcidin levels in 44 patients with stage III multiple myeloma were 3-fold greater than normal controls. In the subset of multiple myeloma patients without renal insufficiency (n = 27), a marked inverse correlation was seen between hemoglobin at diagnosis and urinary hepcidin level (P = 0.014) strongly supporting a causal relationship between up-regulated hepcidin expression and anemia. The urinary hepcidin also significantly (P < 0.05) correlated with serum ferritin and C-reactive protein, whereas its correlation with serum IL-6 levels was of borderline significance (P = 0.06). Sera from 14 multiple myeloma patients, with known elevated urinary hepcidin, significantly induced hepcidin mRNA in the Hep3B cells, whereas normal sera had no effect. For 10 patients, the ability of anti-IL-6 and anti-IL-6 receptor antibodies to prevent the serum-induced hepcidin RNA was tested. In 6 of these patients, hepcidin induction was abrogated by the anti-IL-6 antibodies, but in the other 4 patients, the neutralizing antibodies had no effect. Conclusions: These results indicate hepcidin is up-regulated in multiple myeloma patients by both IL-6-dependent and IL-6-independent mechanisms and may play a role in the anemia of multiple myeloma.

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Section: Resultsmentioning

confidence: 99%

Involvement of Hepcidin in the Anemia of Multiple Myeloma

Sharma

Nemeth

Chen

et al. 2008

Clinical Cancer Research

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“…However, the hepcidin responsiveness to LPSs was maintained to some extent in IL-6-knockout mice [33], indicating that the LPS-induced expression of other inflammatory cytokines is responsible for the upregulation of hepcidin expression. Although IL-1 has been shown to play a role in the upregulation of hepcidin expression [12,13], other inflammatory cytokines might be involved in hepcidin synthesis. Suda et al [23] demonstrated that the stimulation of human monocytes and dendritic cells with LPS or fixed Staphylococcus aureus increased the production of OSM, suggesting that OSM could be upregulated in inflammatory conditions.…”

Section: Discussionmentioning

confidence: 99%

“…In response to iron loading, hepatocytes produce hepcidin to maintain iron homeostasis [8,9]; lack of hepcidin leads to the development of hereditary hemochromatosis that is characterized by excessive absorption of dietary iron and pathological increase in body iron stores [10,11]. Hepatic expression of hepcidin is also upregulated by inflammatory cytokines, including interleukin-6 (IL-6) [9,12] and IL-1 [12,13]. In vitro studies have demonstrated that hepcidin exerts antimicrobial effects on various bacteria [1,2].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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Overproduction of hepcidin by interleukin-6 (IL-6) is considered to be the main factor responsible for the development of anemia in inflammatory conditions. Since oncostatin M (OSM), a member of the IL-6 family, plays an important role in immune and inflammatory responses, we assessed the effect of OSM on hepcidin expression, as well as that of leukemia inhibitory factor (LIF), another member of the IL-6 family. We found that hepcidin expression was markedly induced by OSM and LIF in a time- and dose-dependent manner in hepatoma cell lines, and this expression was induced independent of IL-6/IL-6 receptor signaling. Luciferase assay revealed that OSM and LIF stimulated a -1.3-kb hepcidin promoter. This effect was markedly reduced when the signal transducer and activator of transcription (STAT) site of the promoter was mutated, and was almost completely abolished in the presence of AG-490, a Janus kinase (JAK) inhibitor. Hence, the JAK/STAT pathway plays a major role in OSM- and LIF-induced activation of the hepcidin promoter. In conclusion, we demonstrated that OSM and LIF can induce hepcidin expression mainly through the JAK/STAT pathways. Further studies are warranted to evaluate the clinical significance of OSM and LIF in the development of anemia in various inflammatory diseases.

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“…Stimuli such as hypoxia, erythropoiesis, iron levels, and inflammation control the expression of this gene. During anaemia related to chronic disease, gene expression is increased [11]. Several studies have demonstrated the influence of the serum hepcidin concentration on the pathogenesis of diseases such as juvenile hereditary haemochromatosis, in which a polymorphism present in the HAMP gene promotes hepcidin synthesis deficiency with iron accumulation in the tissues [12,13,14].…”

Section: Introductionmentioning

confidence: 99%

Hepcidin: Homeostasis and Diseases Related to Iron Metabolism

et al. 2017

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Iron is an essential metal for cell survival that is regulated by the peptide hormone hepcidin. However, its influence on certain diseases is directly related to iron metabolism or secondary to underlying diseases. Genetic alterations influence the serum hepcidin concentration, which can lead to an iron overload in tissues, as observed in haemochromatosis, in which serum hepcidin or defective hepcidin synthesis is observed. Another genetic imbalance of iron is iron-refractory anaemia, in which serum concentrations of hepcidin are increased, precluding the flow and efflux of extra- and intracellular iron. During the pathogenesis of certain diseases, the resulting oxidative stress, as well as the increase in inflammatory cytokines, influences the transcription of the HAMP gene to generate a secondary anaemia due to the increase in the serum concentration of hepcidin. To date, there is no available drug to inhibit or enhance hepcidin transcription, mostly due to the cytotoxicity described in the in vitro models. The proposed therapeutic targets are still in the early stages of clinical trials. Some candidates are promising, such as heparin derivatives and minihepcidins. This review describes the main pathways of systemic and genetic regulation of hepcidin, as well as its influence on the disorders related to iron metabolism.

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Upregulation of hepcidin by interleukin-1β in human hepatoma cell lines

Cited by 36 publications

References 45 publications

Involvement of Hepcidin in the Anemia of Multiple Myeloma

Involvement of Hepcidin in the Anemia of Multiple Myeloma

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

Hepcidin: Homeostasis and Diseases Related to Iron Metabolism

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