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.