A Role for Protein Phosphatase-2A in p38 Mitogen-activated Protein Kinase-mediated Regulation of the c-Jun NH2-terminal Kinase Pathway in Human Neutrophils

• Published in: The Journal of biological chemistry Vol. 277; no. 43; pp. 40687 - 40696
• Main Authors: Avdi, Natalie J., Malcolm, Kenneth C., Nick, Jerry A., Worthen, G. Scott
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 25-10-2002
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M204455200

Human neutrophil accumulation in inflammatory foci is essential for the effective control of microbial infections. Although
exposure of neutrophils to cytokines such as tumor necrosis factor-α (TNFα), generated at sites of inflammation, leads to
activation of MAPK pathways, mechanisms responsible for the fine regulation of specific MAPK modules remain unknown. We have
previously demonstrated activation of a TNFα-mediated JNK pathway module, leading to apoptosis in adherent human neutrophils
(Avdi, N. J., Nick, J. A., Whitlock, B. B., Billstrom, M. A., Henson, P. M., Johnson, G. L., and Worthen, G. S. (2001) J. Biol. Chem. 276, 2189–2199). Herein, evidence is presented linking regulation of the JNK pathway to p38 MAPK and the Ser/Thr protein phosphatase-2A
(PP2A). Inhibition of p38 MAPK by SB 203580 and M 39 resulted in significant augmentation of TNFα-induced JNK and MKK4 (but
not MKK7 or MEKK1) activation, whereas prior exposure to a p38-activating agent (platelet-activating factor) diminished the
TNFα-induced JNK response. TNFα-induced apoptosis was also greatly enhanced upon p38 inhibition. Studies with a reconstituted
cell-free system indicated the absence of a direct inhibitory effect of p38 MAPK on the JNK module. Neutrophil exposure to
the Ser/Thr phosphatase inhibitors okadaic acid and calyculin A induced JNK activation. Increased phosphatase activity following
TNFα stimulation was shown to be PP2A-associated and p38-dependent. Furthermore, PP2A-induced dephosphorylation of MKK4 resulted
in its inactivation. Thus, in neutrophils, p38 MAPK, through a PP2A-mediated mechanism, regulates the JNK pathway, thus determining
the extent and nature of subsequent responses such as apoptosis.