IL-1 receptor-associated kinase and low molecular weight GTPase RhoA signal molecules are required for bacterial lipopolysaccharide-induced cytokine gene transcription.
Proinflammatory cytokines such as IL-1, TNF, IL-6, and IL-8 are produced by leukocytes in response to bacteria or bacterial components. A great deal has been learned during the past few years about the synthesis and release of proinflammatory cytokines by leukocytes; however, relatively little is known about the intracellular events that lead to leukocyte proinflammatory cytokine gene transcription. This study examined the signal transduction pathway of IL-8 induction by bacterial LPS. Stimulation of monocytes with LPS rapidly activated RhoA, and pretreatment of monocytes with a RhoA inhibitor, C3 transferase exoenzyme, effectively blocked LPS-induced IL-8 gene expression. Overexpression of dominant negative RhoA (T19N) or IL-1R-associated kinase completely inhibited LPS-stimulated reporter gene expression. Induction of IL-8 was also inhibited by dominant negative IkappaB kinase and myeloid differentiation protein (MyD88). These results indicate that RhoA and IL-1R-associated kinase are novel signal transducers for LPS-induced Toll-like receptor 4-mediated proinflammatory cytokine synthesis in human monocytes.
Chen
Ling-Yu
LY
Department of Molecular and Experimental Medicine and Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Zuraw
Bruce L
BL
Liu
Fu-Tong
FT
Huang
Shuang
S
Pan
Zhixing K
ZK
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D029721:Drosophila Proteins; D004789:Enzyme Activation / Q000276:immunology; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D008970:Molecular Weight; D009000:Monocytes / Q000201:enzymology / Q000276:immunology; D053594:Myeloid Differentiation Factor 88; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014158:Transcription, Genetic / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D029721:Drosophila Proteins; D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D020742:rhoA GTP-Binding Protein