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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.
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PHAGOCYTES
Dual role for RhoA in suppression and induction of cytokines in the human neutrophil
Michael B. Fessler1,2,
Patrick G. Arndt2,
Ingo Just3,
Jerry A. Nick1,2,
Kenneth C. Malcolm4, and
G. Scott Worthen1,2
1 Department of Medicine, National Jewish Medical and Research Center, Denver, CO;
2 Department of Medicine, University of Colorado School of Medicine, Denver;
3 Department of Toxicology, Hannover Medical School, Hannover, Germany;
4 Division of Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO
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, I B 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, because 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 coprecipitates with RhoA in a manner sensitive to the RhoA activation state. Our findings suggest a new, 2-faced role for RhoA as a checkpoint in innate immunity.
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