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J. Biol. Chem., Vol. 281, Issue 40, 29641-29651, October 6, 2006

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Human Macrophage Migration Inhibitory Factor

A PROVEN IMMUNOMODULATORY CYTOKINE?^*

Alex Kudrin, Martin Scott, Steven Martin, Chun-wa Chung, Rachelle Donn^¶||, Andrew McMaster^||, Stuart Ellison^||, David Ray^¶, Keith Ray¹, and Michael Binks

From the Department of Disease Biology, Rheumatology, and Inflammation and Discovery Research, GlaxoSmithKline, Stevenage SG1 2NY, United Kingdom, and ^¶Centre for Molecular Medicine, ^||Arthritis Research Campaign Epidemiology Unit, University of Manchester, Stopford Bldg., Oxford Rd., Manchester M13 9PT, United Kingdom

Macrophage migration inhibitory factor (MIF) is a pro-inflammatory mediator with the ability to induce various immunomodulatory responses and override glucocorticoid-driven immunosuppression. Some of these functions have been linked to the unusual enzymatic properties of the protein, namely tautomerase and oxidoreductase activities. However, there are conflicting reports regarding the functional role of these enzymatic properties in normal physiological homeostasis and disease progression. Therefore, we have produced a highly pure, virtually endotoxin-free recombinant MIF preparation and fully characterized this using a variety of biochemical and biophysical approaches. The recombinant protein, with demonstrable enzymatic activity, was then used to systematically examine the biological activity of MIF. Surprisingly, treatment with MIF alone failed to induce cytokine expression, with the exception of IL-8. However, co-treatment of lipopolysaccharide (LPS) in conjunction with MIF produced synergistic secretion of tumor necrosis factor-, interleukin (IL)-1, and IL-8 compared with LPS alone. The potentiating effect of MIF was seen at physiologically relevant concentrations. These data suggest that MIF has no conventional cytokine activity but, rather, acts to modulate and amplify the response to LPS.

Received for publication, February 6, 2006 , and in revised form, August 2, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data.

¹ To whom correspondence should be addressed: Dept. of Disease Biology, GlaxoSmithKline, Stevenage SG1 2NY, UK. Tel.: 44-1438-764917; E-mail: keith.p.ray{at}gsk.com.

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