Structural and functional comparison of MIF ortholog from Plasmodium yoelii with MIF from its rodent host

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• 作者：Dingding Shao ; Xiang Zhong ; Yan-Feng Zhou ; Zhifu Han ; Yahui Lin ; Zhensheng Wang ; Lingyi Bu ; Lianhui Zhang ; Xiao-Dong Su ; Heng Wang
• 关键词：Macrophage migration inhibitory factor ; Malaria ; Tautomerase activity ; Crystal structure ; ERK1/2
• 刊名：Molecular Immunology
• 出版年：2010
• 出版时间：January 2010
• 年：2010
• 卷：47
• 期：4
• 页码：726-737
• 全文大小：1977 K

文摘

Host-derived macrophage migration inhibitory factor (MIF) has been implicated in the pathogenesis of malaria infection, especially in malarial anemia. Although two Plasmodium parasite-derived MIF orthologs, Plasmodium falciparum MIF and P. berghei MIF were identified recently, the crystal structure and the precise roles of Plasmodium-derived MIFs, particularly in combination with the host MIF, remain unknown. In this study, we identified another MIF ortholog from a rodent-specific P. yoelii (PyMIF). This molecule shares a conserved three-dimensional structure with murine MIF (MmMIF), but with a different substrate binding pattern and much lower tautomerase activity. It could activate host cells via several signaling pathways in vitro, and inhibiting macrophage apoptosis, also similarly to MmMIF. However, we found that PyMIF and MmMIF acted synergistically to activate the MAPK-ERK1/2 signaling pathway at very low concentration but acted antagonistically at higher concentration. Furthermore, we detected PyMIF in the sera of infected mice and found that injection of recombinant PyMIF (rPyMIF) during infection could up-regulate several pro-inflammatory cytokines in vivo and slightly delay the death of infected mice. These data suggest that PyMIF modulates host immune responses together with host MIF and has potential to prolong parasitemia or the chronicity of malaria infection.