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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1248-1256. Prepublished online as a Blood First Edition Paper on October 3, 2006; DOI 10.1182/blood-2006-03-012898. This Article Full Text (PDF) All Versions of this Article: blood-2006-03-012898v1 109/3/1248    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Fessler, M. B. Articles by Worthen, G. S. Search for Related Content PubMed PubMed Citation Articles by Fessler, M. B. Articles by Worthen, G. S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 27, 2006 Accepted September 8, 2006 A dual role for RhoA in suppression and induction of cytokines in the human neutrophil Michael B. Fessler*, Patrick G. Arndt, Ingo Just, Jerry A. Nick, Kenneth C. Malcolm, and G. Scott Worthen Department of Medicine, National Jewish Medical and Research Center, Denver, CO Department of Medicine, University of Colorado Health Sciences Center, Denver, CO Department of Toxicology, Hannover Medical School, Hannover, Germany Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO * Corresponding author; email: fesslerm{at}niehs.nih.gov. Production of tumor necrosis factor- (TNF) by the neutrophil (PMN) is a pivotal event in innate immunity, but the signals regulating TNF induction in this primary cell are poorly understood. Herein, we use protein transduction to identify novel, opposing anti- and pro-cytokine-inducing roles for RhoA in the resting and lipopolysaccharide (LPS)-stimulated human PMN, respectively. In the resting cell, RhoA suppresses Cdc42 activation, IB degradation, nuclear factor-B (NF-B) activation, and induction of TNF and NF-B-dependent chemokines. Suppression of TNF induction by RhoA is Rho kinase (ROCK)-independent, but Cdc42-dependent, as TNF induction by C3 transferase is attenuated by inhibition of Cdc42, and constitutively active Cdc42 suffices to activate NF-B and induce TNF. By contrast, we also place RhoA downstream of p38 mitogen-activated protein kinase and Cdc42 in a novel LPS-activated pathway in which p38, Cdc42, and ROCK all promote TNF protein expression. The p65 subunit of NF-B co-precipitates with RhoA in a manner sensitive to RhoA activation state. Our findings suggest a new, two-faced role for RhoA as a checkpoint in innate immunity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. Daryadel, S. Yousefi, D. Troi, I. Schmid, J. Schmidt-Mende, C. Mordasini, C. A. Dahinden, A. Ziemiecki, and H.-U. Simon RhoH/TTF Negatively Regulates Leukotriene Production in Neutrophils J. Immunol., May 15, 2009; 182(10): 6527 - 6532. [Abstract] [Full Text] [PDF]

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