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Selective activation and functional significance of p38α mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils
Jerry A. Nick, … , Gary L. Johnson, G. Scott Worthen
Jerry A. Nick, … , Gary L. Johnson, G. Scott Worthen
Published March 15, 1999
Citation Information: J Clin Invest. 1999;103(6):851-858. https://doi.org/10.1172/JCI5257.
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Article

Selective activation and functional significance of p38α mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils

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Abstract

Activation of leukocytes by proinflammatory stimuli selectively initiates intracellular signal transduction via sequential phosphorylation of kinases. Lipopolysaccharide (LPS) stimulation of human neutrophils is known to result in activation of p38 mitogen-activated protein kinase (MAPk); however, the upstream activator(s) of p38 MAPk is unknown, and consequences of p38 MAPk activation remain largely undefined. We investigated the MAPk kinase (MKK) that activates p38 MAPk in response to LPS, the p38 MAPk isoforms that are activated as part of this pathway, and the functional responses affected by p38 MAPk activation. Although MKK3, MKK4, and MKK6 all activated p38 MAPk in experimental models, only MKK3 was found to activate recombinant p38 MAPk in LPS-treated neutrophils. Of p38 MAPk isoforms studied, only p38α and p38δ were detected in neutrophils. LPS stimulation selectively activated p38α. Specific inhibitors of p38α MAPk blocked LPS-induced adhesion, nuclear factor-kappa B (NF-κB) activation, and synthesis of tumor necrosis factor-α (TNF-α). Inhibition of p38α MAPk resulted in a transient decrease in TNF-α mRNA accumulation but persistent loss of TNF-α synthesis. These findings support a pathway by which LPS stimulation of neutrophils results in activation of MKK3, which in turn activates p38α MAPk, ultimately regulating adhesion, NF-κB activation, enhanced gene expression of TNF-α, and regulation of TNF-α synthesis.

Authors

Jerry A. Nick, Natalie J. Avdi, Scott K. Young, Lisa A. Lehman, Patrick P. McDonald, S. Courtney Frasch, Marcella A. Billstrom, Peter M Henson, Gary L. Johnson, G. Scott Worthen

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Figure 7

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Scheme depicting proposed intracellular signaling pathways and functiona...
Scheme depicting proposed intracellular signaling pathways and functional consequences in response to stimulation of human neutrophils with LPS. Binding of CD14 by LPS in the presence of LBP initiates a signal that passes though a transmembrane spanning protein and a series of yet unknown upstream signaling events, leading to activation of the MKK3–p38α MAPk cascade. The activator of MKK3 in this cell (MEKK-X) is not known. Activation of p38α MAPk then results in rapid responses such as adhesion and activation of NF-κB. Synthesis of the TNF-α peptide is also dependent on p38α MAPk activation, in part through activation of NF-κB, but primarily through regulation of translation. LBS, lipopolysaccharide-binding protein.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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