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J. Biol. Chem., Vol. 281, Issue 42, 31337-31347, October 20, 2006

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Ca²⁺- and Protein Kinase C-dependent Signaling Pathway for Nuclear Factor-B Activation, Inducible Nitric-oxide Synthase Expression, and Tumor Necrosis Factor- Production in Lipopolysaccharide-stimulated Rat Peritoneal Macrophages^*

From the Department of Biophysics in the School of Physics, Key Laboratory of Bioactive Materials of Education Ministry, Nankai University, Tianjin 300071, Peoples Republic of China

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-B (NF-B) pathway and the mitogen-activated protein kinase (MAPK) pathway. However, the mechanisms by which the intracellular free Ca²⁺ concentration ([Ca²⁺]_i) increases and protein kinase C (PKC) is activated remain unclear. Therefore, we investigated the signaling pathway for Ca²⁺- and PKC-dependent NF-B activation, inducible nitric-oxide synthase expression, and tumor necrosis factor- (TNF-) production in LPS-stimulated rat peritoneal macrophages. The results demonstrated that the LPS-induced transient [Ca²⁺]_i increase is due to Ca²⁺ release and influx. Extracellular and intracellular Ca²⁺ chelators inhibited phosphorylation of PKC and PKC. A PKC-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 inhibitoryB kinase and NF-B. Upstream of the [Ca²⁺]_i increase, a protein-tyrosine kinase inhibitor reduced phosphorylation of phospholipase C (PLC) . Furthermore, a PLC inhibitor eliminated the transient [Ca²⁺]_i increase and decreased the amount of activated PKC. Therefore, these results revealed the following roles of Ca²⁺ and PKC in the signaling pathway for NF-B activation in LPS-stimulated macrophages. After LPS treatment, protein-tyrosine kinase mediates PLC1/2 phosphorylation, which is followed by a [Ca²⁺]_i increase. Several PKCs are activated, and PKC regulates phosphorylation of serine in MEKK1. Moreover, MEKKs regulate inhibitory B kinase activation. Sequentially, NF-B is activated, and inducible nitric-oxide synthase and tumor necrosis factor- production is promoted.

Received for publication, March 23, 2006 , and in revised form, August 21, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 86-22-23501005; Fax: 86-22-23501594; E-mail: yangwenx{at}nankai.edu.cn.

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