Inhibition of SRC tyrosine kinases suppresses activation of nuclear factor-kappa B, and serine and tyrosine phosphorylation of Ikappa B-alpha in lipopolysaccharide-stimulated RAW 264.7 macrophages.
Kang-JL; Lee-HW; Kim-HJ; Lee-HS; Castranova-V; Lim-CM; Koh-Y
J Toxicol Environ Health, A 2005 Oct; 68(19):1643-1662
Involvement of protein tyrosine kinases (PTK) in lipopolysaccharide (LPS)-induced nuclear factor-kappa B (NF-kappa B) activation has been demonstrated. Studies investigated the role of PTK and the underlying mechanisms by which PTK play a role in LPS induction of pathways leading to NF-kappa B activation in macrophages. Inhibitors of PTK-genistein, herbimycin A, or AG126-blocked LPS-induced NF-kappa B activation. Genistein also blocked pervanadate-induced NF-kappa B activation. Furthermore, Src TK selective inhibitors-damnacanthal or PP1-blocked LPS-induced NF-kappa B activation over a range of nanomolar concentrations. Genistein, damnacanthal, or PP1 blocked the LPS-induced serine phosphorylation, the degradation of I kappa B-alpha and the consequent translocation of the p65 subunit of NF-kappa B to the nucleus. In addition to serine phosphorylation of I kappa B-alpha, LPS-induced NF-kappa B activation also required tyrosine phosphorylation of I kappa B-alpha. These TK inhibitors blocked substantially LPS induction of tyrosine phosphorylation of I kappa B-alpha. Furthermore, cSrc and Lck were physically associated with I kappa B-alpha. These results suggest that the LPS-induced NF-kappa B pathways are dependent on both serine and tyrosine phosphorylation of I kappa B-alpha, and that Src TK, such as cSrc and Lck, are key components of the LPS signaling pathway through at least two different mechanisms associated with NF-kappa B activation.
Proteins; Lung-disorders; Injuries; Pulmonary-system-disorders; Respiratory-system-disorders
Dr. Jihee Lee Kang, Department of Physiology, College of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-ku, Seoul, 158-056, Korea
Journal of Toxicology and Environmental Health, Part A: Current Issues