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PNAS 101 (18): 7076-7081

Copyright © 2004 by the National Academy of Sciences.

Medical Sciences

Neutrophils alter the inflammatory milieu by signal-dependent translation of constitutive messenger RNAs

Stephan W. Lindemann * {dagger}, Christian C. Yost * {ddagger}, Melvin M. Denis *, Thomas M. McIntyre * § ¶, Andrew S. Weyrich * §, and Guy A. Zimmerman * § ||

*Program in Human Molecular Biology and Genetics and Departments of §Internal Medicine, Pathology, and {ddagger}Pediatrics, University of Utah, 15 North, 20230 East, Building 533, Room 4220, Salt Lake City, UT 84112

Communicated by Raymond L. White, University of California at San Francisco, Emeryville, CA, March 22, 2004

Received for publication January 25, 2004.

Abstract: The mechanisms by which neutrophils, key effector cells of the innate immune system, express new gene products in inflammation are largely uncharacterized. We found that they rapidly translate constitutive mRNAs when activated, a previously unrecognized response. One of the proteins synthesized without a requirement for transcription is the soluble IL-6 receptor {alpha}, which translocates to endothelial cells and induces a temporal switch to mononuclear leukocyte recruitment. Its synthesis is regulated by a specialized translational control pathway that is inhibited by rapamycin, a bacterial macrolide with therapeutic efficacy in transplantation, inflammatory syndromes, and neoplasia. Signal-dependent translation in activated neutrophils may be a critical mechanism for alteration of the inflammatory milieu and a therapeutic target.

Abbreviations: PMNs, polymorphonuclear leukocytes; mTOR, mammalian target of rapamycin; IL-6R{alpha}, IL-6 receptor {alpha} subunit; PAF, platelet-activating factor; HUVEC, human umbilical vein endothelial cell; LPS, lipopolysaccharide; fMLP, N-formylmethionylleucylphenylalanine; EC, endothelial cells.

{dagger} Present address: Department of Medicine II, Johannes Gutenberg University, 55101 Mainz, Germany.

|| To whom correspondence should be addressed. E-mail: guy.zimmerman{at}hmbg.utah.edu.

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