Regulation of cyclooxygenase-2 expression by small GTPase Rac2 in bone marrow macrophages.
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 IkappaBalpha significantly and had less immunoreactive PU.1. We show that both NF-kappaB 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.
Azim
Anser C
AC
Department of Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, University of Illinois, Chicago, IL 60612, USA.
Cao
Hongmei
H
Gao
Xiaopei
X
Joo
Myungsoo
M
Malik
Asrar B
AB
van Breemen
Richard B
RB
Sadikot
Ruxana T
RT
Park
Gyeyoung
G
Christman
John W
JW
D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D020672:I-kappa B Proteins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation / Q000187:drug effects; D011453:Prostaglandins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D000097766:RAC2 GTP-Binding Protein; D000099232:Proto-Oncogene Protein Spi-1
D051546:Cyclooxygenase 2; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; D020559:Monomeric GTP-Binding Proteins; D000072000:NF-KappaB Inhibitor alpha; D011453:Prostaglandins; D011518:Proto-Oncogene Proteins; D051197:Toll-Like Receptor 4; D015534:Trans-Activators; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; D000099232:Proto-Oncogene Protein Spi-1; C000606205:Nfkbia protein, mouse