Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity

Lue, Hongqi; Thiele, Michael; Franz, Joakim; Dahl, Edgar; Speckgens, Stefanie; Leng, Lin; Fingerle‐Rowson, Günter; Bucala, Richard; Lüscher, Bernhard; Bernhagen, Jürgen

doi:10.1038/sj.onc.1210318

Cited by 319 publications

(320 citation statements)

References 50 publications

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“…Therefore, we investigated whether sCD74/MIF exhibited a different activation profile of classical MIF‐dependent kinases compared with MIF‐mediated activation of membrane CD74. As expected from previous work,56 we observed early as well as sustained protein kinase B (AKT) activation following MIF stimulation (0.5 hours: P <0.001, d =8.31; 10 hours: P =0.0485, d =1.18). This effect was significantly reduced in the presence of sCD74 (Figure 4A through 4D; whole blots of phosphorylated AKT, total AKT and tubulin are shown in Figure S9 and S10), suggesting that sCD74 inhibits MIF‐mediated AKT signaling (rMIF versus sCD74/rMIF, 0.5 hours: 198.7±8.40% versus 136.2±24.86%; P =0.0197, d =2.23; 10 hours: 157.5±30.91% versus 76.92±19.4; P =0.0422, d =1.32).…”

Section: Resultssupporting

confidence: 89%

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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BackgroundAlthough macrophage migration inhibitory factor (MIF) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD74, the function of the soluble CD74 receptor ectodomain (sCD74) and its interaction with circulating MIF have not been explored in cardiac disease.Methods and ResultsCardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co‐treatment with recombinant MIF and sCD74 induced cell death (P<0.001), which was mediated by receptor‐interacting serine/threonine‐protein kinase (RIP)1/RIP3‐dependent necroptosis (P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT‐qPCR technology revealed a 4‐fold upregulation of several interferon‐induced genes upon co‐treatment of myofibroblasts with sCD74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD74 as a modulator of MIF signaling by diminishing MIF‐mediated protein kinase B (AKT) activation (P=0.0197) and triggering p38 activation (P=0.0641). We obtained evidence that sCD74 inhibits MIF‐mediated survival pathway through the C‐X‐C chemokine receptor 4/AKT axis, enabling the induction of CD74‐dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD74/MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244).ConclusionsThese findings suggest that treatment of cardiac myofibroblasts with sCD74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD74/MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.

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Section: Resultssupporting

confidence: 89%

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soppert

Kraemer

Beckers

et al. 2018

JAHA

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“…Migration under such conditions was not only significantly decreased compared to the ''2 h'' treatment (P < 0.005), but there was also a tendency, which however did not reach statistical significance, that permanent exposure to rMIF led to a slight inhibitory effect compared to migration in the absence of rMIF. This could indicate that a baseline migration response is mediated by a low-efficiency constitutive-like release of MIF from the wtMEFs, consistent with earlier reports on autocrine effects of MIF [27][28][29].…”

Section: Short-term Treatment With Mif Promotes the Migration Ofsupporting

confidence: 90%

Macrophage migration inhibitory factor (MIF) promotes fibroblast migration in scratch‐wounded monolayers in vitro

Dewor

Steffens²,

Krohn³

et al. 2007

FEBS Letters

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MIF was recently redefined as an inflammatory cytokine, which functions as a critical mediator of diseases such as septic shock, rheumatoid arthritis, atherosclerosis, and cancer. MIF also regulates wound healing processes. Given that fibroblast migration is a central event in wound healing and that MIF was recently demonstrated to promote leukocyte migration through an interaction with G-protein-coupled receptors, we investigated the effect of MIF on fibroblast migration in wounded monolayers in vitro. Transient but not permanent exposure of primary mouse or human fibroblasts with MIF significantly promoted wound closure, a response that encompassed both a proliferative and a pro-migratory component. Importantly, MIF-induced fibroblast activation was accompanied by an induction of calcium signalling, whereas chronic exposure with MIF down-regulated the calcium transient, suggesting receptor desensitization as the underlying mechanism.

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“…2). HuMIF binding of CD74 is also known to activate Akt (43), which can then result in BAD phosphorylation leading to activation of antiapoptotic pathways (44).…”

Section: Resultsmentioning

confidence: 99%

Trichomonas vaginalis homolog of macrophage migration inhibitory factor induces prostate cell growth, invasiveness, and inflammatory responses

Twu¹,

Dessì

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

155

138

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Significance Prostate cancer is the most common nonskin cancer in America and the fifth most common cancer worldwide. Inflammation is implicated in the initiation and progression of prostate cancer; however, sources of inflammation remain unidentified. Trichomonas vaginalis is a prevalent parasite that infects prostate epithelium and is associated with an increase in aggressive prostate cancer. Here, we demonstrate that a secreted T. vaginalis protein homologous to human macrophage migration inhibitory factor elicits antibodies in infected individuals, increases prostate cell proliferation and invasiveness, and induces cellular pathways linked to inflammation. This study demonstrates that a specific parasite-derived protein can mimic its human homolog to increase inflammation and cell proliferation, which, in turn, may result in the promotion and progression of prostate cancer.

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Macrophage migration inhibitory factor (MIF) promotes cell survival by activation of the Akt pathway and role for CSN5/JAB1 in the control of autocrine MIF activity

Cited by 319 publications

References 50 publications

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Soluble CD74 Reroutes MIF/CXCR4/AKT‐Mediated Survival of Cardiac Myofibroblasts to Necroptosis

Macrophage migration inhibitory factor (MIF) promotes fibroblast migration in scratch‐wounded monolayers in vitro

Trichomonas vaginalis homolog of macrophage migration inhibitory factor induces prostate cell growth, invasiveness, and inflammatory responses

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