Involvement of Macrophage Migration Inhibitory Factor (MIF) in the Mechanism of Tumor Cell Growth

Takahashi, Norihiko; Nishihira, Jun; Sato, Yuji; Kondo, Masao; Ogawa, Hidehiko; Ohshima, Takahiro; Une, Yoshie; Todo, Satoru

doi:10.1007/bf03401765

Cited by 150 publications

(135 citation statements)

References 22 publications

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“…This is consistent with the action of exogenous MIF on MAPK/AP-1 activation (3,4,8,9,40,41), and MAPK-dependent control of cell growth and tumorigenesis (7,42,43). In NIH3T3 cells, MIF was required for ERK-induced cell proliferation (3,4,6).…”

Section: Discussionsupporting

confidence: 80%

Regulation of IL-1 and TNF Receptor Expression and Function by Endogenous Macrophage Migration Inhibitory Factor

Toh

Aeberli

Lacey

et al. 2006

The Journal of Immunology

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Macrophage migration inhibitory factor (MIF) has a key role in regulation of innate and adaptive immunity and is implicated in sepsis, tumorigenesis, and autoimmune disease. MIF deficiency or immunoneutralization leads to protection against fatal endotoxic, exotoxic, and infective shock, and anti-inflammatory effects in other experimental models of inflammatory disease. We report a novel regulatory role of MIF in type 1 IL-1R and p55 TNFR expression and function. Compared with wild-type cells, MIF-deficient cells were hyporesponsive to IL-1- and TNF-induced MAPK activity, AP-1 activity, and cellular proliferation, while NF-κB function was preserved. Hyporesponsiveness of MIF-deficient cells was associated with down-regulation of cytokine receptor expression, which was restored by reconstitution of either an upstream kinase of MAPK, MAPK/ERK kinase, or MIF. These data suggest that endogenous MIF is required for cytokine activation of MAPK/AP-1 and cytokine receptor expression. This autocrine regulatory pathway defines an important amplifying role of endogenous MIF in cytokine-mediated immune and inflammatory diseases and provides further molecular evidence for the critical role of MIF in cellular activation.

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Section: Discussionsupporting

confidence: 80%

Regulation of IL-1 and TNF Receptor Expression and Function by Endogenous Macrophage Migration Inhibitory Factor

Toh

Aeberli

Lacey

et al. 2006

The Journal of Immunology

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“…3 We found TSP-1 mRNA to be differentially expressed. TSP-1 mRNA expression in the iMIF cell line compared with the iRNA cell line was 88-fold higher by real-time PCR (Fig.…”

Section: Mrna and Protein Expression Of Tsp-1 Are Up-regulated In Imimentioning

confidence: 70%

“…A comparative gene expression analysis of the iMIF and iRNA cells identified TSP-1 as being significantly up-regulated in the iMIF cells. 3 TSP-1 protein expression correlated with mRNA expression and was secreted 2-fold higher in iMIF cell cultures compared with iRNA cell cultures. Additionally, iMIF tumors established 1 week slower than iRNA control tumors, and our data suggest that this is in part through blocking development of intratumoral vasculature.…”

Section: Discussionmentioning

confidence: 89%

Interference of Macrophage Migration Inhibitory Factor Expression in a Mouse Melanoma Inhibits Tumor Establishment by Up-Regulating Thrombospondin-1

Culp

Tsagozis²,

Burgio³

et al. 2007

Molecular Cancer Research

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Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with proinflammatory, proangiogenic, and protumorigenic properties. The molecular mechanisms underlying the role of MIF in tumorigenesis and angiogenesis are not well understood. To address these roles, an interfering MIF (iMIF) RNA was stably introduced into the B16-F10 mouse melanoma cell line, reducing MIF mRNA expression 1.6-fold and MIF protein expression 2.8-fold relative to control cells. When iMIF cells were subcutaneously injected into C57BL/6 mice, tumor establishment was significantly delayed and there was a marked absence of intratumoral vasculature in iMIF tumors relative to controls. A comparative gene expression analysis of iMIF and control melanoma cell lines revealed that thrombospondin-1 (TSP-1) mRNA expression was up-regulated 88-fold in the iMIF cells by real-time PCR. A 2-fold increase in TSP-1 protein levels was observed in iMIF cell culture supernatants. These results strongly suggest that the delayed tumor establishment and reduced vasculature in iMIF melanomas are linked to the up-regulation of the antiangiogenic TSP-1. They further define a novel function of MIF as a regulator of TSP-1 in a mouse melanoma model. (Mol Cancer Res 2007;5(12):1225 -31)

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“…Moreover, MIF expression has been described in a number of cancers in humans and in animal models of neoplasia (25)(26)(27). Transfection of murine colon carcinoma cells with an antisense MIF plasmid was associated with significant decreases in cell proliferation (28). Recently, MIF detection in human cholesteatomas was found to correlate strongly with levels of the antiapoptotic protein galectin and to reflect the biologic aggressiveness of these lesions (29).…”

Section: Discussionmentioning

confidence: 99%

Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis

Leech

Lacey

Xue

et al. 2003

Arthritis & Rheumatism

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Objective. To study the capacity of macrophage migration inhibitory factor (MIF) to regulate proliferation, apoptosis, and p53 in an animal model of rheumatoid arthritis (RA) and in fibroblast-like synoviocytes (FLS) from humans with RA.Methods. Antigen-induced arthritis (AIA) was induced in MIF -/-mice and littermate controls. FLS were obtained from patients with RA. Western blotting and immunohistochemistry were used to measure p53 in cells and tissues. Apoptosis was detected in cells by flow cytometry using TUNEL and annexin V/propidium iodide labeling. Apoptosis in tissue was detected using TUNEL. Proliferation was assessed in cultured cells and tissue by 3 H-thymidine incorporation and Ki-67 immunostaining, respectively.Results. MIF inhibited p53 expression in human RA FLS. Levels of p53 were correspondingly increased in MIF -/-mouse tissues and cells. Spontaneous and sodium nitroprusside-induced apoptosis were significantly increased in MIF -/-cells. In vitro exposure of FLS to MIF reduced apoptosis and significantly induced FLS proliferation. Synoviocyte proliferation in MIF -/-mice was correspondingly reduced. A decrease in the severity of AIA in MIF -/-mice was associated with an increase in p53 and apoptosis in synovium. Evidence of in situ proliferation was scant in this model, and no difference in in situ proliferation was detectable in MIF -/-mice compared with wild-type mice.Conclusion. These results indicate a role for MIF in the regulation of p53 expression and p53-mediated events in the inflamed synovium and support the hypothesis that MIF is of critical importance in the pathogenesis of RA.

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Involvement of Macrophage Migration Inhibitory Factor (MIF) in the Mechanism of Tumor Cell Growth

Cited by 150 publications

References 22 publications

Regulation of IL-1 and TNF Receptor Expression and Function by Endogenous Macrophage Migration Inhibitory Factor

Regulation of IL-1 and TNF Receptor Expression and Function by Endogenous Macrophage Migration Inhibitory Factor

Interference of Macrophage Migration Inhibitory Factor Expression in a Mouse Melanoma Inhibits Tumor Establishment by Up-Regulating Thrombospondin-1

Regulation of p53 by macrophage migration inhibitory factor in inflammatory arthritis

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