Abstract
Involvement of protein tyrosine kinases (PTK) in lipopolysaccharide (LPS)-induced nuclear factor-kappa B (NF- 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- B activation in macrophages. Inhibitors of PTK - genistein, herbimycin A, or AG126 - blocked LPS-induced NF- B activation. Genistein also blocked pervanadate-induced NF- B activation. Furthennore, Src TK selective inhibitors - damnacanthal or PP1 - blocked LPS-induced NF- B activation over a range of nanomolar concentrations. Genistein, damnacanthal, or PP1 blocked the LPS-induced serine phosphorylation, the degradation of I B- , and the consequent translocation of the p65 subunit of NF- B to the nucleus. In addition to serine phosphorylation of I B- , LPS-induced NF- B activation also required tyrosine phosphorylation of I B- . These TK inhibitors blocked substantially LPS induction of tyrosine phosphorylation of I B- . Furthermore, cSrc and Lck were physically associated with I B- . These results suggest that the LPS-induced NF- B pathways are dependent on both serine and tyrosine phosphorylation of I B- , 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- B activation. Copyright
Original language | English |
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Pages (from-to) | 1643-1662 |
Number of pages | 20 |
Journal | Journal of Toxicology and Environmental Health - Part A |
Volume | 68 |
Issue number | 19 |
DOIs | |
State | Published - 8 Oct 2005 |
Bibliographical note
Funding Information:Received 29 October 2004; accepted 15 February 2005. This work was supported by grant R04-2002-000-00023-0 from the Basic Research Program of the Korea Science and Engineering Foundation. Address correspondence to Dr. Jihee Lee Kang, Department of Physiology, College of Medicine, Ewha Womans University, 911-1 Mok-6-dong, Yangcheon-ku, Seoul, 158-056, Korea. E-mail: [email protected]