Submitted on January 30, 2007
Accepted on June 8, 2007
Regulation of cyclooxygenase 2 expression by small GTPase Rac2 in bone marrow macrophages
Anser Chaudhry Azim1, Hongmei Cao2, Xiaopei Gao3, Myungsoo Joo4, Asrar B. Malik5, Richard B. Van Breemen6, Ruxana T Sadikot7, Gye-Young Park8, and John W. Christman9*
1 Pulmonary/Critical Care Medicine, University of Illinois at Chicago, Chicago, Illinois, United States
2 Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 60612, Illinois, United States
3 Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, United States; Department of Medicine, University of Illinois at Chicago, 840 S. Wood Street, Chicago, Illinois, 60612-7323, United States
4 Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee, United States
5 Department of Pharmacology, University of Illinois, College of Medicine, Chicago, Illinois, United States
6 Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, Chicago, Illinois, United States
7 Pulmonary Critical Care and Sleep Medicine, University of Illinois, Chicago, Illinois, United States
8 Pulmonary, Univ. of Illinois at Chicago, Chicago, Illinois, United States
9 Professor of Medicne and Pharmacology, Chief, Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois, Chicago, Illinois, United States
* To whom correspondence should be addressed. E-mail: jwc{at}uic.edu.
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. In spite of a compensatory increase in Rac1, BMDM from Rac2-/- null mice have less biologically active GTP-bound Rac in response to LPS stimulation. Signaling molecules (down stream of Rac2 and TLR4 receptor) like p42/44, p38, and pAKT were also affected in BMDM from Rac2-/- null mice macrophages. We also observed that BMDM from Rac2-/- null failed to degrade IkBα significantly, and had less immunoreactive PU.1. Here we show that both NF-κB 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.
