Apoptotic Neutrophils Release Macrophage Migration Inhibitory Factor upon Stimulation with Tumor Necrosis Factor-α*
- 1 To whom correspondence should be addressed: Dept. of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland, Tel.: 41-31-632-3281; Fax: 41-31-632-4992; E-mail: shida.yousefi{at}pki.unibe.ch.
Abstract
Macrophage migration inhibitory factor (MIF) is an important cytokine involved in the regulation of innate immunity and present at increased levels during inflammatory responses. Here we demonstrate that mature blood and tissue neutrophils constitutively express MIF as a cytosolic protein not associated with azurophil granules. Functionally active MIF, but not proteases stored in azurophil granules, was released from apoptotic neutrophils following short term tumor necrosis factor (TNF)-α stimulation in a caspase-dependent manner and prior to any detectable phagocytosis by monocyte-derived macrophages. Moreover, TNF-α-mediated MIF release was blocked by glyburide and propenicide, both inhibitors of ATP-binding cassette-type transporters, suggesting that this transporter system is activated during neutrophil apoptosis. Taken together, apoptotic mature neutrophils release MIF upon short term TNF-α stimulation. Therefore, apoptosis may not always occur without the induction of pro-inflammatory mechanisms.
Footnotes
-
↵2 The abbreviations used are: MIF, macrophage migration inhibitory factor; Ab, antibody; mAb, monoclonal antibody; ABC, ATP-binding cassette; C5a, complement factor 5a; GM-CSF, granulocyte/macrophagecolony-stimulating factor; MBP, maltose-binding protein; MPO, myeloperoxidase; TNF, tumor necrosis factor; TNF-R, TNF receptor; IL, interleukin; Z, benzyloxycarbonyl; fmk, fluoromethyl ketone; ELISA, enzyme-linked immunosorbent assay; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
-
↵* This work was supported by Grants 31-68449.02 and 310000-112078 from the Swiss National Science Foundation (to S. Y.). 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.
-
- Received April 27, 2006.
- Revision received July 21, 2006.
