Distinct role of spleen tyrosine kinase in the early phosphorylation of inhibitor of kappaB alpha via activation of the phosphoinositide-3-kinase and Akt pathways.
Nuclear factor (NF)-kappaB activation is a critical step in the triggering of inflammatory responses by macrophages. Although numerous investigations have been reported, the precise regulatory mechanisms controlling inflammatory responses mediated by NF-kappaB remain unclear. In this study, we investigated the early signaling events responsible for modulating NF-kappaB activation using various parameters, such as the expression of pro-inflammatory genes and the phosphorylation levels of inhibitor of kappaB alpha (IkappaB alpha) and its upstream kinases. Lipopolysaccharide (LPS) treatment biphasically induced activation of IkappaB alpha phosphorylation at 5 and 30 min, which induced subsequent pro-inflammatory gene expression that was maximized at 45 and 90 min. Of the intracellular signals tested, a series of signaling cascades composed of spleen tyrosine kinase (Syk), phosphoinositide-3-kinase (PI3K), and Akt (protein kinase B) were involved in regulating early phosphorylation of IkappaB alpha, according to biochemical and pharmacological analyses. Therefore, our data suggests that Syk-mediated activation of intracellular signaling in response to LPS may play an important role in LPS-induced inflammatory signaling events. Thus, Syk may be a potential target for the development of potent anti-inflammatory drugs.
Lee
Yong Gyu
YG
School of Bioscience and Biotechnology and the Institute of Bioscience and Biotechnology, Kangwon National University, 192-1 Hyoja-2-Dong, Chuncheon 200-701, South Korea.
Chain
Benjamin M
BM
Cho
Jae Youl
JY
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D020672:I-kappa B Proteins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology; D000072377:Syk Kinase; D014162:Transfection; D019061:src-Family Kinases
D000081247:CSK Tyrosine-Protein Kinase; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D013267:Stilbenes; D000072377:Syk Kinase; D019061:src-Family Kinases; C000606205:Nfkbia protein, mouse; C041525:3,3',4,5'-tetrahydroxystilbene; C000606897:Syk protein, mouse