Role of MIF in Inflammation and Tumorigenesis

Bach, Jan-Philipp; Rinn, Birgit; Meyer, Bernhard; Dodel, Richard; Bacher, Michael

doi:10.1159/000155223

Cited by 113 publications

(105 citation statements)

References 116 publications

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“…MIF has since been shown to be constitutively expressed in numerous tissues and cell types (30) and have a variety of biological activities, including pivotal roles in the regulation of immune and inflammatory responses and promotion of tumorigenesis (31). Elevated levels of MIF have been observed in a number of disease states including cardiovascular disease (32), arthritis (33), diabetes (34), sepsis (35), and many cancer types (36,37).…”

Section: Discussionmentioning

confidence: 99%

Direct Modification of the Proinflammatory Cytokine Macrophage Migration Inhibitory Factor by Dietary Isothiocyanates

Brown

Blaikie

Smith

et al. 2009

Journal of Biological Chemistry

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Isothiocyanates are a class of phytochemicals with widely reported anti-cancer and anti-inflammatory activity. However, knowledge of their activity at a molecular level is limited. The objective of this study was to identify biological targets of phenethyl isothiocyanate (PEITC) using an affinity purification approach. An analogue of PEITC was synthesized to enable conjugation to a solid-phase resin. The pleiotropic cytokine macrophage migration inhibitory factor (MIF) was the major protein captured from cell lysates. Site-directed mutagenesis and mass spectrometry showed that PEITC covalently modified the N-terminal proline residue of MIF. This resulted in complete loss of catalytic tautomerase activity and disruption of protein conformation, as determined by impaired recognition by a monoclonal antibody directed to the region that receptors and interacting proteins bind to MIF. The conformational change was supported by in silico modeling. Monoclonal antibody binding to plasma MIF was disrupted in humans consuming watercress, a major dietary source of PEITC. The isothiocyanates have significant potential for development as MIF inhibitors, and this activity may contribute to the biological properties of these phytochemicals.Isothiocyanates are a class of phytochemicals with recognized anti-cancer activity. They can act in a chemopreventive capacity via inhibition of carcinogen-activating phase I enzymes (1) and induction of phase II detoxification enzymes (2). Isothiocyanates are also active in the post-initiation phase of tumorigenesis and are, therefore, proposed to have chemotherapeutic potential (3, 4). Isothiocyanate-mediated disruption of cancer progression is achieved by a variety of mechanisms including modulation of cell growth (5), inhibition of angiogenesis (6), suppression of metastasis (7), and induction of apoptosis (8, 9). Isothiocyanates can also modulate inflammatory pathways via inhibition of the transcription factor nuclear factor B (10).The electrophilic carbon residue in the isothiocyanate moiety (-NACAS) is capable of reacting with biological nucleophiles such as cysteine in proteins and the tripeptide glutathione (11,12). Binding of isothiocyanates to Kelch-like ECH-associated protein 1 (Keap1) (13), transient receptor potential channels (14), MEKK1 protein kinase (15), and tubulin (16) has been demonstrated to occur via covalent modification of cysteine. Reaction with amines to form stable thiourea derivatives can also occur. However, this is generally considered to be a less favorable reaction at physiological pH (11).To elucidate the major cellular targets of biologically active isothiocyanates, we have utilized an affinity-based target identification approach. An amine linker was added to phenethyl isothiocyanate (PEITC) 3 without compromising cytotoxicity, and the molecule was immobilized to a solid phase resin. The pleiotropic cytokine macrophage migration inhibitory factor (MIF) was identified as a major biological target of PEITC. Using mass spectrometry and site-directed mutagene...

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Section: Discussionmentioning

confidence: 99%

Direct Modification of the Proinflammatory Cytokine Macrophage Migration Inhibitory Factor by Dietary Isothiocyanates

Brown

Blaikie

Smith

et al. 2009

Journal of Biological Chemistry

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“…Despite its discovery in the mid-1960s as a T-cell-derived factor that modulated the motility of monocytes, macrophage migration inhibitory factor (MIF) has been shown to be involved in cancers [9][10][11][12][13]. Interestingly, both circulating and intracellular levels of MIF were elevated in patients with cancers, and the levels of MIF were closely correlated with tumor aggressiveness and metastatic potential, suggesting that MIF contributed to disease severity and survival [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Steroid receptor coactivator 3 regulates autophagy in breast cancer cells through macrophage migration inhibitory factor

et al. 2012

Cell Res

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SRC-3/AIB1 (steroid receptor coactivator 3/amplified in breast cancer 1) is an authentic oncogene that contributes to the development of drug resistance and poor disease-free survival in cancer patients. Autophagy is also an important cell death mechanism that has tumor suppressor function. In this study, we identified macrophage migration inhibitory factor (MIF) as a novel target gene of SRC-3 and demonstrated its importance in cell survival. Specifically, we showed that MIF is a strong suppressor of autophagic cell death. We further showed that suppression of MIF, in turn, induced autophagic cell death, enhanced chemosensitivity and inhibited tumorigenesis in a xenograft mouse tumorigenesis model. Our study demonstrated that regulation of MIF expression and suppression of autophagic cell death is a potent mechanism by which SRC-3 contributes to increased chemoresistance and tumorigenicity.

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“…It is, therefore, necessary to explore and investigate the tumorigenesis of gastric cancer and its novel therapy targets [6] . Macrophage migration inhibitory factor (MIF) is a multi-functional cytokine, which is associated with inflammation and tumorigenesis [7,8] . Recent studies have shown that MIF is related to the initiation and progression of gastric cancer, but its underlying mechanism is not very clear [9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Macrophage migration inhibitory factor regulatesproliferation of gastric cancer cellsvia the PI3K/Akt pathway

Li¹,

Xie²,

Lei³

et al. 2009

WJG

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AIM:To investigate the effects of macrophage migration inhibitory factor (MIF) on proliferation of human gastric cancer MGC-803 cells and expression of cyclin D1 and p27Kip1 in them, and further determine whether the effects are related to the PI3K/Akt signal transduction pathway. METHODS:Gastric cancer MGC-803 cells were cultured and then treated with 50 μg/L recombinant human MIF (rhMIF) with and without a PI3K inhibitor, LY294002 (25 μmol/L). MTT assay was used to detect the proliferation of MGC-803 cells. Cell cycle was detected by flow cytometry. Expression of cyclin D1 and p27Kip1 mRNA was by reverse transcription-polymerase chain reaction. Protein expression of phosphorylated Akt (p-Akt), Akt, cyclin D1 and p27Kip1 was examined by immunocytochemistry and Western blotting.RESULTS: rhMIF significantly stimulated the proliferation of MGC-803 cells and cell cycle progression from G1 phase to S phase in a concentration-and time-dependent manner. After the MGC-803 cells were treated with rhMIF for 24 h, the expression of cyclin D1 was significantly up-regulated compared with the cells not treated with rhMIF at both mRNA and protein levels (0.97 ± 0.02 vs 0.74 ± 0.01, P = 0.002; 0.98 ± 0.05 vs 0.69 ± 0.04, P = 0.003). The p27Kip1 was downregulated but only statistically significant at the protein level. rhMIF significantly increased the expression of p-Akt, which reached the peak at 30 min, but did not affect the expression of Akt. However, LY294002 inhibited all the effects of rhMIF. CONCLUSION:Macrophage MIF increases the proliferation of gastric cancer cells, induces the expression of cyclin D1 at the transcriptional level and inhibits the expression of p27Kip1 at the post-transcriptional level via the PI3K/Akt pathway.

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Role of MIF in Inflammation and Tumorigenesis

Cited by 113 publications

References 116 publications

Direct Modification of the Proinflammatory Cytokine Macrophage Migration Inhibitory Factor by Dietary Isothiocyanates

Direct Modification of the Proinflammatory Cytokine Macrophage Migration Inhibitory Factor by Dietary Isothiocyanates

Steroid receptor coactivator 3 regulates autophagy in breast cancer cells through macrophage migration inhibitory factor

Macrophage migration inhibitory factor regulatesproliferation of gastric cancer cellsvia the PI3K/Akt pathway

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