巨噬细胞迁移抑制因子分子机制研究进展
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摘要
巨噬细胞迁移抑制因子(macrophage migration inhibitory factor,MIF)是一类多效性的前炎症细胞因子,能够促进其他多种前炎症因子的分泌或表达。其基因在大多数哺乳动物基因组中具有90%的同源性。MIF启动子区含有能够与多种转录因子结合的DNA结合位点,同时含有与其表达水平相关的多态性位点。MIF发挥其生物学功能,一方面可以通过非受体介导的内吞作用,实现MIF与c-Jun激活结构域结合蛋白-1(JAB1)的相互作用;另一方面,受体依赖型的MIF能够激活包括PI3K/AKT、MAPK和G蛋白偶联受体相关的信号传导途径等。此外,MIF还能够通过直接或间接方式调节肿瘤抑制基因p53的功能。MIF已经被证实参与调解炎症、肿瘤生成和纤维化等生物学过程。从MIF表达、相关受体、涉及的信号通路与生物学过程等方面,对其分子功能的研究进展进行了总结,并对MIF相关的分子机理进行了综述,旨在为MIF相关疾病的诊断和治疗提供线索。
Macrophage migration inhibitory factor( MIF) is one of the pleiotropic pro-inflammatory cytokines that promotes the secretion or expression of many other pro-inflammatory cytokines. At gene level it has 90% homology in the most of the mammalian genomes. The promoter region of MIF contains DNA-binding sites which could bind to a variety of transcription factors,as well as polymorphic sites associated with the expression level of MIF. MIF exerts its biological function by receptordependent or independent ways. In the receptor-independent approach,MIF is in taken by non-receptor-mediated endocytosis and interacts with c-Jun activation domain binding protein-1( JAB1). During the receptor-dependent pathway,MIF interacts with its receptors and further activates signaling pathways including PI3 K/AKT,MAPK and G protein-coupled receptors related signal cascades. Moreover,MIF can also directly or indirectly regulate the function of tumor suppressor gene p53. Due to its strong biological function,MIF has been confirmed to participate in the mediation of biological processes such as inflammation,tumorigenesis and fibrosis. This article summarized the research progress in molecular function of MIF expression,related receptors,involved signal pathways and biological processes,and reviewed the related molecular mechanisms,with the hope of providing clues for the diagnose and treatment of MIF-related diseases.
Macrophage migration inhibitory factor( MIF) is one of the pleiotropic pro-inflammatory cytokines that promotes the secretion or expression of many other pro-inflammatory cytokines. At gene level it has 90% homology in the most of the mammalian genomes. The promoter region of MIF contains DNA-binding sites which could bind to a variety of transcription factors,as well as polymorphic sites associated with the expression level of MIF. MIF exerts its biological function by receptordependent or independent ways. In the receptor-independent approach,MIF is in taken by non-receptor-mediated endocytosis and interacts with c-Jun activation domain binding protein-1( JAB1). During the receptor-dependent pathway,MIF interacts with its receptors and further activates signaling pathways including PI3 K/AKT,MAPK and G protein-coupled receptors related signal cascades. Moreover,MIF can also directly or indirectly regulate the function of tumor suppressor gene p53. Due to its strong biological function,MIF has been confirmed to participate in the mediation of biological processes such as inflammation,tumorigenesis and fibrosis. This article summarized the research progress in molecular function of MIF expression,related receptors,involved signal pathways and biological processes,and reviewed the related molecular mechanisms,with the hope of providing clues for the diagnose and treatment of MIF-related diseases.
引文
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[37]Onodera S,Nishihira J,Koyama Y,et al..Macrophage migration inhibitory factor up-regulates the expression of interleukin-8 messenger RNA in synovial fibroblasts of rheumatoid arthritis patients:Common transcriptional regulatory mechanism between interleukin-8 and interleukin-1β[J].Arth.Rheum.,2004,50:1437-1447.
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[40]Koga K,Kenessey A,Powell S R,et al..Macrophage migration inhibitory factor provides cardioprotection during ischemia/reperfusion by reducing oxidative stress[J].Antioxid.Redox Sign.,2011,14:1191.
[41]Funamizu N,Hu C,Lacy C,et al..Macrophage migration inhibitory factor induces epithelial to mesenchymal transition,enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma[J].Int.J.Cancer,2013,132:785-794.
[42]Ma H,Wang J,Thomas D P,et al..Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart[J].Circulation,2010,122:282.
[43]Babu SN,Chetal G,Kumar S.Macrophage migration inhibitory factor:a potential marker for cancer diagnosis and therapy[J].Asian Pacific J.Cancer Prev.,2012,13:1737-1744.
[44]Rockey D C,Bell P D,Hill J A.Fibrosis——a common pathway to organ injury and failure[J].New Eng.J.Med.,2015,372:1138-1149.
[45]Ueha S,Shand F,Matsushima K.Cellular and molecular mechanisms of chronic inflammation-associated organ fibrosis[J].Front.Immunol.,2012,3:71.
[46]Sabine T,Jürgen B,Heidi N.Arrest functions of the MIF ligand/receptor axes in atherogenesis[J].Front.Immunol.,2013,4:115.
[47]Binsky I,Haran M,Starlets D,et al..IL-8 secreted in a macrophage migration-inhibitory factor-and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival[J].Proc.Natl.Acad.Sci.USA,2007,104:13408-13413.
[48]Dickerhof N,Schindler L,Bernhagen J,et al..Macrophage migration inhibitory factor(MIF)is rendered enzymatically inactive by myeloperoxidase-derived oxidants but retains its immunomodulatory function[J].Free Rad.Biol.Med.,2015,89:498-511.
[49]Weiser W Y,Temple P A,Witekgiannotti J S,et al..Molecular cloning of a c DNA encoding a human macrophage migration inhibitory factor[J].Proc.Natl.Acad.Sci.USA,1989,86:7522-7526.
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[51]Thiele M,Kerschbaumer R J,Tam F W,et al..Selective targeting of a disease-related conformational isoform of macrophage migration inhibitory factor ameliorates inflammatory conditions[J].J.Immunol.,2015,195:2343-2352.
[52]Kassaar O,Pereira M M,Xu S,et al..Macrophage migration inhibitory factor is subjected to glucose modification and oxidation in Alzheimer's disease[J].Sci.Rep.,2017,7:42874.
[53]Brown K K,Blaikie F H,Smith R A,et al..Direct modification of the proinflammatory cytokine macrophage migration inhibitory factor by dietary isothiocyanates[J].J.Biol.Chem.,2009,284:32425-32433.
[54]Ouertatani-Sakouhi H,El-Turk F,Fauvet B,et al..A new class of isothiocyanate-based irreversible inhibitors of macrophage migration inhibitory factor[J].Biochemistry,2009,48:9858-9870.
[55]Dickerhof N,Magon N J,Tyndall J D,et al..Potent inhibition of macrophage migration inhibitory factor(MIF)by myeloperoxidase-dependent oxidation of epicatechins[J].Biochem.J.,2014,462:303-314.
[56]Watarai H,Nozawa R,Tokunaga A,et al..Posttranslational modification of the glycosylation inhibiting factor(GIF)gene product generates bioactive GIF[J].Proc.Natl.Acad.Sci.USA,2000,97:13251-13256.
[57]Nguyen M T,Beck J,Lue H,et al..A 16-residue peptide fragment of macrophage migration inhibitory factor,MIF-(50-65),exhibits redox activity and has MIF-like biological functions[J].J.Biol.Chem.,2003,278:33654-33671.
[58]Luedike P,Hendgen-Cotta U B,Sobierajski J,et al..Cardioprotection through S-nitros(yl)ation of macrophage migration inhibitory factor[J].Circulation,2012,125:1880-1889.
[59]Pohl J,Hendgen-Cotta U R,Rammos C,et al..Targeted intracellular accumulation of macrophage migration inhibitory factor in the reperfused heart mediates cardioprotection[J].Thromb.Haemost.,2016,116:200-212.
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[2]Ghoochani A,Schwarz M A,Yakubov E,et al..MIF-CD74signaling impedes microglial M1 polarization and facilitates brain tumorigenesis[J].Oncogene,2016,35(48):6246-6261.
[3]Calandra T,Roger T.Macrophage migration inhibitory factor:A regulator of innate immunity[J].Nat.Rev.Immunol.,2003,3:791-800.
[4]Roger T,Lugrin J,Ding X C,et al..Epigenetic Control of MIF Expression[M].World Scientific,2012,121-137.
[5]Sun H W,Bernhagen J,Bucala R,et al...Crystal structure at2.6-A resolution of human macrophage migration inhibitory factor[J].Proc.Natl.Acad.Sci.USA,1996,93:5191-5196.
[6]Trivedi-Parmar V C,Jorgensen W L.Advances and insights for small molecule inhibition of macrophage migration inhibitory factor[J].J.Med.Chem.,2018,doi:10.1021/acs.jmedchem.8b00589.
[7]Chen Y C,Zhang X W,Niu X H,et al..Macrophage migration inhibitory factor is a direct target of HBP1-mediated transcriptional repression that is overexpressed in prostate cancer[J].Oncogene,2010,29:3067-3078.
[8]Nobre C C,de Araújo J M,Fernandes T A,et al..Macrophage migration inhibitory factor(MIF):Biological activities and relation with cancer[J].Pathol.Oncol.Res.,2016,23:1-10.
[9]Beswick E J,Reyes V E.CD74 in antigen presentation,inflammation,and cancers of the gastrointestinal tract[J].World J.Gastroenterol.,2009,15:2855-2861.
[10]Gilyarom N,Radomir L,Sever L,et al..CD74 is a novel transcription regulator[J].Proc.Natl.Acad.Sci.USA,2017,114:562.
[11]Su H,Na N,Zhang X,et al..The biological function and significance of CD74 in immune diseases[J].Inflam.Res.,2017,66:1-8.
[12]Buanne P,Di Carlo E,Caputi L,et al..Crucial pathophysiological role of CXCR2 in experimental ulcerative colitis in mice[J].J.Leukocyte Biol.,2007,82:1239-1246.
[13]Alampour-Rajabi S,El Bounkari O,Rot A,et al..MIF interacts with CXCR7 to promote receptor internalization,ERK1/2and ZAP-70 signaling,and lymphocyte chemotaxis[J].FASEB J.Offic.Pub.Feder.Am.Soc.Exper.Biol.,2015,29:497-511.
[14]Chatterjee M,Rath D,Gawaz M.Role of chemokine receptors CXCR4 and CXCR7 for platelet function[J].Biochem.Soc.Transac.,2015,43:720-726.
[15]Zernecke A,Bernhagen J,Weber C.Macrophage migration inhibitory factor in cardiovascular disease[J].Circulation,2008,117:1594-602.
[16]Kim E K,Choi E J.Compromised MAPK signaling in human diseases:An update[J].Arch.Toxicol.,2015,89:867-882.
[17]Xie L,Qiao X,Wu Y,et al..beta-Arrestin1 mediates the endocytosis and functions of macrophage migration inhibitory factor[J].PLo S ONE,2011,6:e16428.
[18]Lindner R.Invariant chain complexes and clusters as platforms for MIF signaling[J].Cells,2017,6(1):6.
[19]De Luca A,Maiello M R,D'Alessio A,et al..The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways:role in cancer pathogenesis and implications for therapeutic approaches[J].Expert Opin.Therap.Targets,2012,16(S2):17-27.
[20]Mendoza M C,Er E E,Blenis J.The Ras-ERK and PI3Km TOR pathways:Cross-talk and compensation[J].Trends Biochem.Sci.,2011,36:320-328.
[21]Hers I,Vincent E E,Tavare J M.Akt signalling in health and disease[J].Cell.Sign.,2011,23:1515-1527.
[22]Gore Y,Starlets D,Maharshak N,et al..Macrophage migration inhibitory factor induces B cell survival by activation of a CD74-CD44 receptor complex[J].J.Biol.Chem.,2008,283:2784-2792.
[23]Lue H,Thiele M,Franz J,et al..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[J].Oncogene,2007,26:5046-5059.
[24]Khoo K H,Verma C S,Lane D P.Drugging the p53 pathway:Understanding the route to clinical efficacy[J].Nat.Rev.Drug Discov.,2014,13:217-236.
[25]Jung H,Seong H A,Ha H.Critical role of cysteine residue 81of macrophage migration inhibitory factor(MIF)in MIFinduced inhibition of p53 activity[J].J.Biol.Chem.,2008,283:20383-20396.
[26]Nobre C C,de Araujo J M,Fernandes T A,et al..Macrophage migration inhibitory factor(MIF):Biological activities and relation with cancer[J].Pathol.Oncol.Res.,2017,23:235-244.
[27]Abraham A G,O'Neill E.PI3K/Akt-mediated regulation of p53 in cancer[J].Biochem.Soc.Transac.,2014,42:798-803.
[28]Costa A F,Gomes S Z,Lorenzon-Ojea A R,et al..Macrophage migration inhibitory factor induces phosphorylation of Mdm2 mediated by phosphatidylinositol 3-kinase/Akt kinase:Role of this pathway in decidual cell survival[J].Placenta,2016,41:27-38.
[29]Pan Y,Yang H,Claret F X.Emerging roles of Jab1/CSN5 in DNA damage response,DNA repair,and cancer[J].Cancer Biol.Ther.,2014,15:256-262.
[30]Shackleford T J,Claret F X.JAB1/CSN5:a new player in cell cycle control and cancer[J].Cell Division,2010,5:26.
[31]Lue H,Kapurniotu A,Fingerle-Rowson G,et al..Rapid and transient activation of the ERK MAPK signalling pathway by macrophage migration inhibitory factor(MIF)and dependence on JAB1/CSN5 and Src kinase activity[J].Cell Sign.,2006,18:688-703.
[32]Vorst E P C V D,D9ring Y,Weber C.Chemokines and their receptors in Atherosclerosis[J].J.Mol.Med.,2015,93:963-971.
[33]Dayawansa N H,Gao X M,White D A,et al..Role of MIF in myocardial ischaemia and infarction:Insight from recent clinical and experimental findings[J].Clin.Sci.,2014,127:149.
[34]Schindler L,Dickerhof N,Hampton M B,et al..Post-translational regulation of macrophage migration inhibitory factor:Basis for functional fine-tuning[J].Redox Biol.,2017,15:135.
[35]Killick K E,Ni Cheallaigh C,O'Farrelly C,et al..Receptormediated recognition of mycobacterial pathogens[J].Cell.Microbiol.,2013,15:1484-1495.
[36]Kasama T,Ohtsuka K,Sato M.Macrophage migration inhibitory factor:A multifunctional cytokine in rheumatic diseases[J].Arthritis,2011,2010:106202.
[37]Onodera S,Nishihira J,Koyama Y,et al..Macrophage migration inhibitory factor up-regulates the expression of interleukin-8 messenger RNA in synovial fibroblasts of rheumatoid arthritis patients:Common transcriptional regulatory mechanism between interleukin-8 and interleukin-1β[J].Arth.Rheum.,2004,50:1437-1447.
[38]Amin M A,Haas C S,Zhu K,et al..Migration inhibitory factor up-regulates vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 via Src,PI3 kinase,and NFkappa B[J].Blood,2006,107:2252-2261.
[39]White D A,Fang L,Chan W,et al..Pro-inflammatory action of MIF in acute myocardial infarction via activation of peripheral blood mononuclear cells[J].PLo S ONE,2013,8:e76206.
[40]Koga K,Kenessey A,Powell S R,et al..Macrophage migration inhibitory factor provides cardioprotection during ischemia/reperfusion by reducing oxidative stress[J].Antioxid.Redox Sign.,2011,14:1191.
[41]Funamizu N,Hu C,Lacy C,et al..Macrophage migration inhibitory factor induces epithelial to mesenchymal transition,enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma[J].Int.J.Cancer,2013,132:785-794.
[42]Ma H,Wang J,Thomas D P,et al..Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart[J].Circulation,2010,122:282.
[43]Babu SN,Chetal G,Kumar S.Macrophage migration inhibitory factor:a potential marker for cancer diagnosis and therapy[J].Asian Pacific J.Cancer Prev.,2012,13:1737-1744.
[44]Rockey D C,Bell P D,Hill J A.Fibrosis——a common pathway to organ injury and failure[J].New Eng.J.Med.,2015,372:1138-1149.
[45]Ueha S,Shand F,Matsushima K.Cellular and molecular mechanisms of chronic inflammation-associated organ fibrosis[J].Front.Immunol.,2012,3:71.
[46]Sabine T,Jürgen B,Heidi N.Arrest functions of the MIF ligand/receptor axes in atherogenesis[J].Front.Immunol.,2013,4:115.
[47]Binsky I,Haran M,Starlets D,et al..IL-8 secreted in a macrophage migration-inhibitory factor-and CD74-dependent manner regulates B cell chronic lymphocytic leukemia survival[J].Proc.Natl.Acad.Sci.USA,2007,104:13408-13413.
[48]Dickerhof N,Schindler L,Bernhagen J,et al..Macrophage migration inhibitory factor(MIF)is rendered enzymatically inactive by myeloperoxidase-derived oxidants but retains its immunomodulatory function[J].Free Rad.Biol.Med.,2015,89:498-511.
[49]Weiser W Y,Temple P A,Witekgiannotti J S,et al..Molecular cloning of a c DNA encoding a human macrophage migration inhibitory factor[J].Proc.Natl.Acad.Sci.USA,1989,86:7522-7526.
[50]Bernhagen J,Calandra T,Mitchell R A,et al..MIF is a pituitary-derived cytokine that potentiates lethal endotoxaemia[J].Nature,1993,365:756-759.
[51]Thiele M,Kerschbaumer R J,Tam F W,et al..Selective targeting of a disease-related conformational isoform of macrophage migration inhibitory factor ameliorates inflammatory conditions[J].J.Immunol.,2015,195:2343-2352.
[52]Kassaar O,Pereira M M,Xu S,et al..Macrophage migration inhibitory factor is subjected to glucose modification and oxidation in Alzheimer's disease[J].Sci.Rep.,2017,7:42874.
[53]Brown K K,Blaikie F H,Smith R A,et al..Direct modification of the proinflammatory cytokine macrophage migration inhibitory factor by dietary isothiocyanates[J].J.Biol.Chem.,2009,284:32425-32433.
[54]Ouertatani-Sakouhi H,El-Turk F,Fauvet B,et al..A new class of isothiocyanate-based irreversible inhibitors of macrophage migration inhibitory factor[J].Biochemistry,2009,48:9858-9870.
[55]Dickerhof N,Magon N J,Tyndall J D,et al..Potent inhibition of macrophage migration inhibitory factor(MIF)by myeloperoxidase-dependent oxidation of epicatechins[J].Biochem.J.,2014,462:303-314.
[56]Watarai H,Nozawa R,Tokunaga A,et al..Posttranslational modification of the glycosylation inhibiting factor(GIF)gene product generates bioactive GIF[J].Proc.Natl.Acad.Sci.USA,2000,97:13251-13256.
[57]Nguyen M T,Beck J,Lue H,et al..A 16-residue peptide fragment of macrophage migration inhibitory factor,MIF-(50-65),exhibits redox activity and has MIF-like biological functions[J].J.Biol.Chem.,2003,278:33654-33671.
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