Tumor Necrosis Factor-α Activation of the c-Jun N-terminal Kinase Pathway in Human Neutrophils
The intensity and duration of an inflammatory response depends on the balance of factors that favor perpetuation versus resolution. At sites of inflammation, neutrophils adherent to other cells or matrix components are exposed to tumor necrosis factor-α (TNFα). Although TNFα has been implicated i...
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Veröffentlicht in: | The Journal of biological chemistry 2001-01, Vol.276 (3), p.2189 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | The intensity and duration of an inflammatory response depends on the balance of factors that favor perpetuation versus resolution. At sites of inflammation, neutrophils adherent to other cells or matrix components are exposed to tumor necrosis
factor-α (TNFα). Although TNFα has been implicated in induction of pro-inflammatory responses, it may also inhibit the intensity
of neutrophilic inflammation by promoting apoptosis. Since TNFα is not only an important activator of the stress-induced pathways
leading to p38 MAPk and c-Jun N-terminal kinase (JNK) but also a potent effector of apoptosis, we investigated the effects
of TNFα on the JNK pathway in adherent human neutrophils and the potential involvement of this pathway in neutrophil apoptosis.
Stimulation with TNFα was found to result in β 2 integrin-mediated activation of the cytoplasmic tyrosine kinases Pyk2 and Syk, and activation of a three-part MAPk module
composed of MEKK1, MKK7, and/or MKK4 and JNK1. JNK activation was attenuated by blocking antibodies to β 2 integrins, the tyrosine kinase inhibitors, genistein, and tyrphostin A9, a Pyk2-specific inhibitor, and piceatannol, a Syk-specific
inhibitor. Exposure of adherent neutrophils to TNFα led to the rapid onset of apoptosis that was demonstrated by augmented
annexin V binding and caspase-3 cleavage. TNF뱉induced increases in annexin V binding to neutrophils were attenuated by blocking
antibodies to β 2 integrins, and the caspase-3 cleavage was attenuated by tyrphostin A9. Hence, exposure of adherent neutrophils to TNFα leads
to utilization of the JNK-signaling pathways that may contribute to diverse functional responses including induction of apoptosis
and subsequent resolution of the inflammatory response. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M007527200 |