Enzymatically Inactive Macrophage Migration Inhibitory Factor Inhibits Monocyte Chemotaxis and Random Migration

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• 作者：Anne Hermanowski-Vosatka ; Steven S. Mundt ; Julia M. Ayala ; Shefali Goyal ; William A. Hanlon ; Robert M. Czerwinski ; Samuel D. Wright ; and Christian P. Whitman
• 刊名：Biochemistry
• 出版年：1999
• 出版时间：September 28, 1999
• 年：1999
• 卷：38
• 期：39
• 页码：12841 - 12849
• 全文大小：99K
• 年卷期：v.38,no.39(September 28, 1999)
• ISSN：1520-4995

文摘

Macrophage migration inhibitory factor (MIF) is a cytokine that was first described as aninhibitor of the random migration of monocytes and macrophages and has since been proposed to havea number of immune and catalytic functions. One of the functions assigned to MIF is that of a tautomerasethat interconverts the enol and keto forms of phenylpyruvate and (p-hydroxyphenyl)pyruvate and convertsD-dopachrome, a stereoisomer of naturally occurring L-dopachrome, to 5,6-dihydroxyindole-2-carboxylicacid. The physiological significance of the MIF enzymatic activity is unclear. The three-dimensionalstructure of MIF is strikingly similar to that of two microbial enzymes (4-oxalocrotonate tautomerase and5-carboxymethyl-2-hydroxymuconate isomerase) that otherwise share little sequence identity with MIF.MIF and these two enzymes have an invariant N-terminal proline that serves as a catalytic base. Here wereport a new biological function for MIF, as an inhibitor of monocyte chemoattractant protein 1- (MCP-1-) induced chemotaxis of human peripheral blood monocytes. We find that MIF inhibition of chemotaxisdoes not occur at the level of the CC chemokine receptor for MCP-1, CCR2, since MIF does not alter thebinding of ¹²⁵I-MCP-1 to monocytes. The role of MIF enzymatic activity in inhibition of monocytechemotaxis and random migration was studied with two MIF mutants in which the N-terminal prolinewas replaced with either a serine or a phenylalanine. Both mutants remain capable of inhibiting monocytechemotaxis and random migration despite significantly reduced or no phenylpyruvate tautomerase activity.These data suggest that this enzymatic activity of MIF does not play a role in its migration inhibitingproperties.