巨噬细胞移动抑制因子在炎症及肿瘤生成过程中的作用(2)
最新研究报道，在单核细胞，巨噬细胞中发现高尔基体蛋白p115和MIF都有表达，且在细胞质中p115能够调节MIF的分泌。在炎症刺激下，单核细胞中p115 能从高尔基体上移位到细胞质其他部位，游离的p115 可与细胞质中的MIF因子结合，可将MIF 转运到细胞膜上与其特异的CD74，CD44受体结合；也可刺激MIF 的分泌，使得上清液中的p115和MIF含量增加。p115 的这种位置变化可以产生一系列的级联反应，从而引起细胞内的信号传导。在前列腺癌中免疫共沉淀结果也显示高尔基体上的蛋白p115的羧基末端与MIF相连[21]，这表明前列腺癌细胞中p115 和MIF相关。Bucala[22]提出MIF的调节是受体为基础的信号转导通路, 可与靶细胞表面受体相互作用，CD74 是细胞膜上MIF的高亲和力结合蛋白, 分布在细胞质和胞膜上, 但是MIF不能与胞质中的CD74结合, 只能与胞膜及膜外区域的CD74受体结合，且CD74 是一种II 型跨膜蛋白, 可启动向ERK /MAPK 激酶传导依赖的M IF信号, 有研究报道MIF能短暂也可持续地激活ERK信号通路, 与细胞增殖, 分化相关[23]。MIF结合到CD74-CD44复合体, 导致CD74-ICD释放, 通过Sky和Akt激活NF-B, 促进B细胞DNA合成, 进入S期, 细胞分裂, Bcl-XL 和Bcl-2转录增加, 细胞存活。何兴祥等[24]实验表明靶向MIF的siRNA可以促进大肠癌细胞的凋亡, 可能的机制是MIF siRNA抑制MIF的表达, 导致CD74 的表达下降, Caspases8和Caspases3表达增加诱导凋亡增加。易永芬等[25]研究指出胃癌及肝癌中P115和MIF的表达呈正相关, P115在肿瘤中表达的增加影响MIF的表达和分泌, 改变其在细胞内空间位置, 使得MIF能够与细胞膜及胞外的CD74受体结合,活化MAPK途径, 导致肿瘤的发生。
, http://www.100md.com
综上所述，MIF在炎症性疾病、自身免疫性疾病及肿瘤的发生发展过程中起重要作用，有望成为疾病早期诊断预测疾病进展和治疗预后的生物靶标。一些小分子MIF抑制剂已被合成并进入临床试验阶段。
参考文献
[1]El-Turk F, Cascella M, Lashuel HA ,et al.The conformational flexibility of the carboxy terminal residues 105-114 is a key modulator of the catalytic activity and stability of macrophage migration inhibitory factor[J]. Biochemistry ,2008,47: 10740–10756.
[2]Winner M, Meier J, Mitchell R A, et al. A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells[J]. Cancer Res., 2008,68:7253–7257.
, 百拇医药
[3]Shi X, Leng L, Bucala R, et al. CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex[J]. Immunity 2006, 25: 595–606.
[4]Bernhagen J, Krohn R, Weber C, et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment[J]. Nat Med 2007, 13: 587–596.
[5]Lue H, Kapurniotu A, Bernhagen J, 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 Signal, 2006, 18:688–703.
, http://www.100md.com
[6]Roger T, Chanson AL, Knaup-Reymond M,Calandra T: Macrophage migration inhibitory factor promotes innate immune responses by suppressing glucocorticoid-induced expression of mitogen-activated protein kinase phosphatase-1[J]. Eur J Immunol,2005, 35: 3405–3413.
[7]Bucala R, Donnelly SC: Macrophage migration inhibitory factor: a probable link between inflammation and cancer[J]. Immunity, 2007, 26: 281–285.
[8]Attila Paszt,Szabolcs A,Katalin Eder, et al. Effects of glucocorticoid agonist and antagonist on the pathogenesis of L-arginine-induced acute pancreatitis in rat[J]. Pancreas, 2008 ,36(4):369-76.
, 百拇医药
[9]Hasan O, Rozita H, Sepideh H , et al. Urine macrophage migration inhibitory factor in children with urinary tract infection: a possible predictor of acute pyelonephritis[J]. Pediatr Nephrol ,2009,24:105-111
[10]Santos LL, Dacumos A,Yamana J, et al. Reduced arthritis in MIF deficient mice is associated with reduced T cell activation: down-regulation of ERK MAP kinase phosphorylation[J].Clinical and Experimental Immunology ,2008, 152: 372-380, http://www.100md.com(石柳亿 赵国海)
, http://www.100md.com
综上所述，MIF在炎症性疾病、自身免疫性疾病及肿瘤的发生发展过程中起重要作用，有望成为疾病早期诊断预测疾病进展和治疗预后的生物靶标。一些小分子MIF抑制剂已被合成并进入临床试验阶段。
参考文献
[1]El-Turk F, Cascella M, Lashuel HA ,et al.The conformational flexibility of the carboxy terminal residues 105-114 is a key modulator of the catalytic activity and stability of macrophage migration inhibitory factor[J]. Biochemistry ,2008,47: 10740–10756.
[2]Winner M, Meier J, Mitchell R A, et al. A novel, macrophage migration inhibitory factor suicide substrate inhibits motility and growth of lung cancer cells[J]. Cancer Res., 2008,68:7253–7257.
, 百拇医药
[3]Shi X, Leng L, Bucala R, et al. CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex[J]. Immunity 2006, 25: 595–606.
[4]Bernhagen J, Krohn R, Weber C, et al. MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment[J]. Nat Med 2007, 13: 587–596.
[5]Lue H, Kapurniotu A, Bernhagen J, 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 Signal, 2006, 18:688–703.
, http://www.100md.com
[6]Roger T, Chanson AL, Knaup-Reymond M,Calandra T: Macrophage migration inhibitory factor promotes innate immune responses by suppressing glucocorticoid-induced expression of mitogen-activated protein kinase phosphatase-1[J]. Eur J Immunol,2005, 35: 3405–3413.
[7]Bucala R, Donnelly SC: Macrophage migration inhibitory factor: a probable link between inflammation and cancer[J]. Immunity, 2007, 26: 281–285.
[8]Attila Paszt,Szabolcs A,Katalin Eder, et al. Effects of glucocorticoid agonist and antagonist on the pathogenesis of L-arginine-induced acute pancreatitis in rat[J]. Pancreas, 2008 ,36(4):369-76.
, 百拇医药
[9]Hasan O, Rozita H, Sepideh H , et al. Urine macrophage migration inhibitory factor in children with urinary tract infection: a possible predictor of acute pyelonephritis[J]. Pediatr Nephrol ,2009,24:105-111
[10]Santos LL, Dacumos A,Yamana J, et al. Reduced arthritis in MIF deficient mice is associated with reduced T cell activation: down-regulation of ERK MAP kinase phosphorylation[J].Clinical and Experimental Immunology ,2008, 152: 372-380, http://www.100md.com(石柳亿 赵国海)