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J. Biol. Chem., Vol. 279, Issue 12, 10883-10891, March 19, 2004

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Lipopolysaccharide-induced c-Jun NH₂-terminal Kinase Activation in Human Neutrophils

ROLE OF PHOSPHATIDYLINOSITOL 3-KINASE AND Syk-MEDIATED PATHWAYS^*

Patrick G. Arndt, Naohito Suzuki¶, Natalie J. Avdi¶, Kenneth C. Malcolm¶||, and G. Scott Worthen¶||

From the ^¶Department of Medicine and ^||Division of Cell Biology, National Jewish Medical and Research Center and the Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Colorado School of Medicine, Denver, Colorado 80206

Polymorphonuclear leukocytes (neutrophils) respond to lipopolysaccharide (LPS) through the up-regulation of several pro-inflammatory mediators. We have recently shown that LPS-stimulated neutrophils express monocyte chemoattractant protein 1 (MCP-1), an AP-1-dependent gene, suggesting that LPS activates the c-Jun N-terminal kinase (JNK) pathway in neutrophils. Previously, we have shown the activation of p38 MAPK, but not JNK, in suspended neutrophils stimulated with LPS but have recently shown activation of JNK by TNF- in an adherent neutrophil system. We show here that exposure to LPS activates JNK in non-suspended neutrophils and that LPS-induced MCP-1 expression, but not tumor necrosis factor- (TNF-) or interleukin-8 (IL-8), is dependent on JNK activation. In addition, LPS stimulation of non-suspended neutrophils activates Syk and phosphatidylinositol 3-kinase (PI3K). Inhibition of Syk with piceatannol or PI3K with wortmannin inhibited LPS-induced JNK activation and decreased MCP-1 expression after exposure to LPS, suggesting that both Syk and PI3K reside in a signaling pathway leading to LPS-induced JNK activation in neutrophils. This Syk- and PI3K-dependent pathway leading to JNK activation after LPS exposure in non-suspended neutrophils is specific for JNK, because inhibition of neither Syk nor PI3K decreased p38 activation after LPS stimulation. Furthermore we show that PI3K inhibition decreased LPS-induced Syk activation suggesting that PI3K resides upstream of Syk in this pathway. Finally, we show that Syk associates with Toll-like receptor 4 (TLR4) upon LPS stimulation further implicating Syk in the LPS-induced signaling pathway in neutrophils. Overall our data suggests that LPS induces JNK activation only in non-suspended neutrophils, which proceeds through Syk- and PI3K-dependent pathways, and that JNK activation is important for LPS-induced MCP-1 expression but not for TNF- or IL-8 expression.

Received for publication, September 5, 2003 , and in revised form, December 22, 2003.

^* This work was supported by National Institutes of Health Grants HL67179 (to P. G. A.) and HL61407 (to G. S. W.). 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.

To whom correspondence should be addressed: National Jewish Medical and Research Center, 1400 Jackson St., D403, Denver, CO 80206. Tel.: 303-398-1640; Fax: 303-272-2319; E-mail: Patrick.Arndt{at}UCHSC.edu.

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