HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Published online before print October 24, 2006

This Article Full Text (Reprint (PDF)) All Versions of this Article: jlb.0806536v1 81/2/567    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cloutier, A. Articles by McDonald, P. P. Search for Related Content PubMed PubMed Citation Articles by Cloutier, A. Articles by McDonald, P. P.

© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0806536

Received for publication August 28, 2006.
Revised October 5, 2006.
Accepted for publication October 6, 2006.

Article

Differential involvement of NF-B and MAP kinase pathways in the generation of inflammatory cytokines by human neutrophils

Pulmonary Division, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada

^@ To whom correspondence should be addressed. E-mail: patrick.mcdonald{at}USherbrooke.ca.

	Abstract

The ability of human neutrophils to express a variety of genes encoding inflammatory mediators is well documented, and mounting evidence suggests that neutrophil-derived cytokines and chemokines contribute to the recruitment of discrete leukocyte populations at inflammatory sites. Despite this, our understanding of the signaling intermediates governing the generation of inflammatory cytokines by neutrophils remains fragmentary. Here, we report that inhibitors of the p38 MAPK and MEK pathways substantially diminish the release of (and in the case of p38 inhibitors, the gene expression of) several inflammatory cytokines in neutrophils stimulated with LPS or TNF. In addition, various NF-B inhibitors were found to profoundly impede the inducible gene expression and release of inflammatory cytokines in these cells. The MAPK inhibitors did not affect NF-B activation; instead, the transcriptional effects of the p38 MAPK inhibitor appear to involve transcriptional factor IID. Conversely, the NF-B inhibitors failed to affect the activation of MAPKs. Finally, the MAPK inhibitors were found to prevent the activation a key component of the translational machinery, S6 ribosomal protein, in keeping with their post-transcriptional impact on cytokine generation. To our knowledge, this constitutes the first demonstration that in neutrophils, the inducible expression of proinflammatory cytokines by physiological stimuli largely reflects the ability of the latter to activate NF-B and selected MAPK pathways. Our data also raise the possibility that NF-B or MAPK inhibitors could be useful in the treatment of inflammatory disorders in which neutrophils predominate.

Key Words: transcription factors • protein kinases • chemokines • neutrophils • inflammation

This article has been cited by other articles:

				M. H. Kogut, K. J. Genovese, Haiqi He, and P. Kaiser Flagellin and lipopolysaccharide up-regulation of IL-6 and CXCLi2 gene expression in chicken heterophils is mediated by ERK1/2-dependent activation of AP-1 and NF-{kappa}B signaling pathways Innate Immunity, August 1, 2008; 14(4): 213 - 222. [Abstract] [PDF]

				J. Luo, T. Tsuji, H. Yasuda, Y. Sun, Y. Fujigaki, and A. Hishida The molecular mechanisms of the attenuation of cisplatin-induced acute renal failure by N-acetylcysteine in rats Nephrol. Dial. Transplant., July 1, 2008; 23(7): 2198 - 2205. [Abstract] [Full Text] [PDF]

				T. M. Cunha, W. A. Verri Jr., I. R. Schivo, M. H. Napimoga, C. A. Parada, S. Poole, M. M. Teixeira, S. H. Ferreira, and F. Q. Cunha Crucial role of neutrophils in the development of mechanical inflammatory hypernociception J. Leukoc. Biol., April 1, 2008; 83(4): 824 - 832. [Abstract] [Full Text] [PDF]