Ca2+- and Protein Kinase C-dependent Signaling Pathway for Nuclear Factor-{kappa}B Activation, Inducible Nitric-oxide Synthase Expression, and Tumor Necrosis Factor-{alpha} Production in Lipopolysaccharide-stimulated Rat Peritoneal Macrophages.
Lipopolysaccharide (LPS)-activated macrophages are pivotal in innate immunity. With LPS treatment, extracellular signals are transduced into macrophages via Toll-like receptor 4 and induce inflammatory mediator production by activating signaling pathways, including the nuclear factor-kappaB (NF-kappaB) pathway and the mitogen-activated protein kinase ( MAPK) pathway. However, the mechanisms by which the intracellular free Ca(2+) concentration ([Ca(2+)](i)) increases and protein kinase C (PKC) is activated remain unclear. Therefore, we investigated the signaling pathway for Ca(2+)- and PKC-dependent NF-kappaB activation, inducible nitric-oxide synthase expression, and tumor necrosis factor-alpha (TNF-alpha) production in LPS-stimulated rat peritoneal macrophages. The results demonstrated that the LPS-induced transient [Ca(2+)](i) increase is due to Ca(2+) release and influx. Extracellular and intracellular Ca(2+) chelators inhibited phosphorylation of PKCalpha and PKCbeta. A PKCbeta-specific and a general PKC inhibitor blunted phosphorylation of serine in mitogen- activated/extracellular signal-regulated kinase kinase kinase (MEKK) 1. Moreover, a MEKK inhibitor reduced activation of inhibitorykappaB kinase and NF-kappaB. Upstream of the [Ca(2+)](i) increase, a protein-tyrosine kinase inhibitor reduced phosphorylation of phospholipase C (PLC) gamma. Furthermore, a PLC inhibitor eliminated the transient [Ca(2+)](i) increase and decreased the amount of activated PKC. Therefore, these results revealed the following roles of Ca(2+) and PKC in the signaling pathway for NF-kappaB activation in LPS-stimulated macrophages. After LPS treatment, protein-tyrosine kinase mediates PLCgamma1/2 phosphorylation, which is followed by a [Ca(2+)](i) increase. Several PKCs are activated, and PKCbeta regulates phosphorylation of serine in MEKK1. Moreover, MEKKs regulate inhibitory kappaB kinase activation. Sequentially, NF-kappaB is activated, and inducible nitric-oxide synthase and tumor necrosis factor-alpha production is promoted.[1]References
- Ca2+- and Protein Kinase C-dependent Signaling Pathway for Nuclear Factor-{kappa}B Activation, Inducible Nitric-oxide Synthase Expression, and Tumor Necrosis Factor-{alpha} Production in Lipopolysaccharide-stimulated Rat Peritoneal Macrophages. Zhou, X., Yang, W., Li, J. J. Biol. Chem. (2006) [Pubmed]
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