Regulation of cyclooxygenase-2 expression by small GTPase Rac2 in bone marrow macrophages

1 Department of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, 2 Department of Medicinal Chemistry and Pharmacognosy, and 3 Department of Pharmacology, University of Illinois, Chicago; 4 Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois; and 5 Section of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville Tennessee Submitted 30 January 2007 ; accepted in final form 8 June 2007 Cyclooxygenase 2 (COX-2) is induced by microbial products, proinflammatory cytokines, growth factors, and oncogenes. The Rho family includes RhoA, Rac1, Rac2, Rac3, and Cdc42 and is involved in regulation of the actin cytoskeleton organization, cell growth, vesicular cell trafficking, and transcriptional regulation. Rac2 binds to NADPH oxidase protein complex, and Rac2 null neutrophils are known to have poor phagocytic activity. We examined whether Rac2, the predominant small GTPase in hematopoietic cells, influences COX-2 expression in bone marrow-derived macrophages (BMDM). We showed that BMDM from Rac2 –/– null mice have reduced COX-2 expression in response to treatment with endotoxin. Despite a compensatory increase in Rac1, BMDM from Rac2 –/– null mice have less biologically active GTP-bound Rac in response to LPS stimulation. Signaling molecules (downstream of Rac2 and Toll-like receptor 4) such as p42/44, p38, and pAKT were also affected in BMDM from Rac2 –/– null mouse macrophages. We also observed that BMDM from Rac2 –/– null failed to degrade I B significantly and had less immunoreactive PU.1. We show that both NF- B pathway and PU.1 are involved in normal macrophage function and play a role in macrophage COX-2 expression. In summary, these data indicate that Rac2 regulates COX-2 expression in BMDM. small guanosine triphosphatases; Rac1; Cdc42 Address for reprint requests and other correspondence: J. W. Christman, Section of Pulmonary, Critical Care, and Sleep Medicine, Univ. of Illinois at Chicago, 840 South Wood St., Chicago, IL 60612 (e-mail: jwc{at}uic.edu )