Oxidants Inhibit ERK/MAPK and Prevent Its Ability to Delay Neutrophil Apoptosis Downstream of Mitochondrial Changes and at the Level of XIAP

Abstract

Normal spontaneous apoptosis in neutrophils is enhanced by “stress” stimuli such as tumor necrosis factor-α, Fas ligand, and oxidants, and this effect is inhibited by anti-apoptotic stimuli including granulocyte-macrophage colony-stimulating factor, lipopolysaccharide, and formylmethionine-leucine-phenylalanine. In this report we demonstrate that anti-apoptotic stimuli protect neutrophils from stress-induced apoptosis via activation of the ERK/MAPK pathway. The protection occurs downstream of mitochondrial alterations assessed as a decrease in membrane potential concomitant with enhanced cytochrome c release. ERK activation was shown to inhibit apoptosis by maintaining levels of XIAP, which is normally decreased in the presence of the pro-apoptotic/stress stimuli. This report also demonstrates that potent intra- and extracellular oxidants inhibit the protective effect of ERK. Oxidant-dependent inhibition of ERK was because of activation of p38 MAPK and activation of the protein phosphatases PP1 and PP2A. Our data suggest that ERK suppresses stress-induced apoptosis downstream of mitochondrial alterations by maintaining XIAP levels and that oxidants block this effect through activation of p38 and protein phosphatases. Normal spontaneous apoptosis in neutrophils is enhanced by “stress” stimuli such as tumor necrosis factor-α, Fas ligand, and oxidants, and this effect is inhibited by anti-apoptotic stimuli including granulocyte-macrophage colony-stimulating factor, lipopolysaccharide, and formylmethionine-leucine-phenylalanine. In this report we demonstrate that anti-apoptotic stimuli protect neutrophils from stress-induced apoptosis via activation of the ERK/MAPK pathway. The protection occurs downstream of mitochondrial alterations assessed as a decrease in membrane potential concomitant with enhanced cytochrome c release. ERK activation was shown to inhibit apoptosis by maintaining levels of XIAP, which is normally decreased in the presence of the pro-apoptotic/stress stimuli. This report also demonstrates that potent intra- and extracellular oxidants inhibit the protective effect of ERK. Oxidant-dependent inhibition of ERK was because of activation of p38 MAPK and activation of the protein phosphatases PP1 and PP2A. Our data suggest that ERK suppresses stress-induced apoptosis downstream of mitochondrial alterations by maintaining XIAP levels and that oxidants block this effect through activation of p38 and protein phosphatases. Apoptosis is an essential process for development, normal growth, and tissue homeostasis. Neutrophils are unique in their ability to undergo rapid spontaneous apoptosis once released from the bone marrow, resulting in their clearance from the circulation within a few hours. During in vitro culture, 80% will undergo apoptosis within 16–20 h (1Savill J.S. Wylie A.H. Henson J.E. Walport M.J. Henson P.M. Haslett C. J. Clin. Investig. 1989; 83: 865-875Crossref PubMed Scopus (1353) Google Scholar). Recently, we have suggested that repetitive engagement of cell surface β2 integrins within the vasculature, as well as during transvascular emigration of the cells during inflammation, may serve as a protective stimulus to prolong the life span of the cell (2Whitlock B.B. Gardai S. Fadok V. Bratton D. Henson P.M. J. Cell Biol. 2000; 151: 1305-1320Crossref PubMed Scopus (112) Google Scholar, 3Watson R.W.G. Rotstein O.D. Nathens A.B. Parodo J. Marshall J.C. J. Immunol. 1997; 158: 945-953PubMed Google Scholar). Cytokines, LPS, 1The abbreviations used are: LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinase; GM-CSF, granulocyte-macrophage colony-stimulating factors; fMLP, formyl-methionine-leucine-phenylalanine; TNFα, tumor necrosis factor-α; DPI, diphenyleneiodonium chloride; OTC, (–)-2-oxo-4-thiazolidine carboxylic acid; IAP, inhibitor of apoptosis; PI3K, phosphatidylinositol 3-kinase; CGD, chronic granulomatous disease; BSA, bovine serum albumin; MEK, MAPK/ERK kinase. and chemotactic factors also block the spontaneous apoptotic process in the neutrophil (2Whitlock B.B. Gardai S. Fadok V. Bratton D. Henson P.M. J. Cell Biol. 2000; 151: 1305-1320Crossref PubMed Scopus (112) Google Scholar). TNFα, Fas ligand, and a variety of oxidants, which are encountered within an inflammatory lesion (4Takeda Y. Watanabe H. Yonehara S. Yamashita T. Saito S. Sendo F. Int. Immunol. 1993; 5: 691-694Crossref PubMed Scopus (159) Google Scholar, 5Frasch S.C. Nick J.A. Fadok V.A. Bratton D.L. Worthen G.S. Henson P.M. J. Biol. Chem. 1998; 273: 8389-8397Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar, 6Liles W.C. Kiener P.A. Ledbetter J.A. Aruffoe A. Klebanoff S.J. J. Exp. Med. 1996; 184: 429-440Crossref PubMed Scopus (543) Google Scholar), are sometimes referred to as “stress” stimuli and can accelerate neutrophil apoptosis. Enhanced apoptosis during an inflammatory reaction may help prevent tissue damage as it promotes the surface exposure of phosphatidylserine and ultimately results in the removal of neutrophils from the blood or tissue by local phagocytes. The apoptotic process in neutrophils is delayed by at least three major pathways involving 1) PI3K/Akt, 2) the mitogen-activated protein kinase (MAPK) of the extracellular signal-regulated kinase (ERK) subgroup (7Sweeney J.F. Nguyen P.K. Omann G. Hinshaw D.B. J. Surg. Res. 1999; 81: 108-112Abstract Full Text PDF PubMed Scopus (17) Google Scholar), and 3) activation of NF-κB (8Ward C. Chilvers E.R. Lawson M.F. Pryde J.G. Fujihara S. Farrow S.N. Haslett C. Rossi A.G. J. Biol. Chem. 1999; 274: 4309-4318Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar). These pathways not only block spontaneous apoptosis but also prevent apoptosis induced by UV irradiation, TNFα, or Fas ligation (5Frasch S.C. Nick J.A. Fadok V.A. Bratton D.L. Worthen G.S. Henson P.M. J. Biol. Chem. 1998; 273: 8389-8397Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar, 9Tudan C. Jackson J.K. Blanis L. Pelech S.L. Burt H.M. J. Immunol. 2000; 165: 5798-5806Crossref PubMed Scopus (32) Google Scholar). Our previous investigations have determined that the combined presence of integrin activation (but not integrin clustering) and pro-apoptotic stress stimuli down-regulate or bypass these anti-apoptotic pathways resulting in markedly enhanced neutrophil apoptosis (2Whitlock B.B. Gardai S. Fadok V. Bratton D. Henson P.M. J. Cell Biol. 2000; 151: 1305-1320Crossref PubMed Scopus (112) Google Scholar). The three mitogen-activated protein kinases MAPK/ERK, c-Jun NH2-terminal kinase/stress-activated protein kinase, and p38 have been implicated in controlling neutrophil apoptosis through the regulation of downstream kinases and activation of transcription factors. ERK activation is by a variety of necessary growth factors including GM-CSF, LPS, and fMLP and is important for their ability to inhibit apoptosis (7Sweeney J.F. Nguyen P.K. Omann G. Hinshaw D.B. J. Surg. Res. 1999; 81: 108-112Abstract Full Text PDF PubMed Scopus (17) Google Scholar). ERK activation also inhibits apoptosis induced by stress stimuli such as oxidants, TNFα, UV light, as well as growth factor withdrawal (7Sweeney J.F. Nguyen P.K. Omann G. Hinshaw D.B. J. Surg. Res. 1999; 81: 108-112Abstract Full Text PDF PubMed Scopus (17) Google Scholar). In this report we demonstrate that ERK blocks spontaneous and stress-induced neutrophil apoptosis downstream of mitochondrial injury and release of cytochrome c, a process also noted in other cell types (10Erhardt P. Schremser E.J. Cooper G.M. Mol. Cell. Biol. 1999; 19: 5308-5315Crossref PubMed Scopus (267) Google Scholar). The inhibitor of apoptosis (IAP) family is a likely target for ERK-mediated protection. These proteins were initially identified in baculovirus and are highly conserved across species. They act directly on caspases, distal to mitochondrial perturbation (11Yang Y.L. Li X.M. Cell Res. 2000; 10: 169-177Crossref PubMed Scopus (253) Google Scholar). The IAP family consists of cIAP-1, cIAP-2, XIAP, neuronal apoptosis inhibitory protein, and survivin. Their baculoviral IAP repeat domains recruit and inhibit caspase activity, regulate cell cycle progression, and modulate receptor-mediated signal transduction (11Yang Y.L. Li X.M. Cell Res. 2000; 10: 169-177Crossref PubMed Scopus (253) Google Scholar, 12Roy N. Deveraux Q.L. Takahashi R. Salvesen G.S. Reed J.C. EMBO J. 1997; 16: 6914-6925Crossref PubMed Scopus (1140) Google Scholar). XIAP is a potent inhibitor of apoptosis that directly binds to and inhibits caspase 3, 7, and 9 and has recently been implicated in protecting T-cells, epithelial cells, and bone marrow macrophages from a variety of pro-apoptotic/stress stimuli including dexamethasone, cisplatin, etoposide, and Fas ligation (13Yang Y. Ashwell J.D. J. Clin. Immunol. 1999; 19: 337-349Crossref PubMed Scopus (19) Google Scholar, 14Asselin E. Mills G.B. Tsang B.K. Cancer Res. 2001; 61: 1862-1868PubMed Google Scholar, 15Lin H. Chen C. Chen B.D. Biochem. J. 2001; 353: 299-306Crossref PubMed Scopus (46) Google Scholar). XIAP contains a ring finger domain that becomes highly ubiquitinated upon the induction of apoptosis, in part due to auto-ubiquitination resulting in rapid degradation of the protein (16Yang Y. Fang S. Jensen J.P. Weissman A.M. Ashwell J.D. Science. 2000; 288: 874-877Crossref PubMed Scopus (873) Google Scholar). Ring mutants of XIAP display higher protein levels after exposure to apoptotic stimuli and in fact delay dexamethasone-induced apoptosis in T-cells (13Yang Y. Ashwell J.D. J. Clin. Immunol. 1999; 19: 337-349Crossref PubMed Scopus (19) Google Scholar). XIAP activity is also regulated by the SMAC/DIABLO protein, which binds the baculoviral IAP repeat 3 domain and disassociates XIAP from the caspases (17Liu Z. Sun C. Olejniczak E.T. Meadows R.P. Betz S.F. Oost T. Herrmann J. Wu J.C. Fesik S.W. Nature. 2000; 408: 1004-1008Crossref PubMed Scopus (548) Google Scholar). Oxidants, intra- and extracellular, have long been associated with the induction of apoptosis, due in part to their ability to modify protein activity and alter intracellular signaling (18Lieberthal W. Triaca V. Koh J.S. Pagano P.J. Levine J.S. Am. J. Physiol. 1998; 275: F691-F702PubMed Google Scholar, 19Chen Y.C. Lin-Shiau S.Y. Lin J.K. J. Cell. Physiol. 1998; 177: 324-333Crossref PubMed Scopus (432) Google Scholar). Oxidants may also activate the ubiquitination pathway, in particular ubiquitin-protein isopeptide ligase (20Chandra J. Samali A. Orrenius S. Free Radic. Biol. Med. 2000; 29: 323-333Crossref PubMed Scopus (1148) Google Scholar), resulting in the degradation of important anti-apoptotic molecules such as XIAP. Oxidants are also known activators of the MAPK family, particularly p38 and c-Jun NH2-terminal kinase (21Wang K. Gross A. Waksman G. Korsmeyer S.J. Mol. Cell. Biol. 1998; 18: 6083-6089Crossref PubMed Scopus (189) Google Scholar). The effect of p38 on apoptosis still remains undetermined; there are reports demonstrating that activation of p38 enhances apoptosis and that inhibiting p38 results in enhanced survival (22Underwood D.C. Osborn R.R. Bochnowicz S. Webb E.F. Rieman D.J. Lee J.C. Romanic A.M. Adams J.L. Hay Am. J. Physiol. 2000; PubMed Google other that p38 may in inhibiting apoptosis S. D. L. T. J. 16: PubMed Scopus Google Scholar). In neutrophils p38 is in apoptosis and has also been to spontaneous apoptosis (5Frasch S.C. Nick J.A. Fadok V.A. Bratton D.L. Worthen G.S. Henson P.M. J. Biol. Chem. 1998; 273: 8389-8397Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar, K. S. J. A. J. Immunol. 1999; Google Scholar). The effect of p38 activity on neutrophil apoptosis has not been but ability to ERK activity in epithelial cells and macrophages a for a pro-apoptotic effect E. J. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, Z. J. Science. PubMed Scopus Google Scholar, K. Worthen G.S. Gardai S. Fadok V.A. Bratton D.L. Henson P.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In this report we demonstrate that stress-induced apoptosis is associated with mitochondrial damage and or decreased of the potent anti-apoptotic XIAP. ERK activation inhibits stress-induced apoptosis by maintaining XIAP levels but not prevent the mitochondrial including decreased mitochondrial membrane potential and release of cytochrome of oxidants ERK activation through the of p38 and activation of protein phosphatases and and were from and were to to neutrophils by was from and from were used at a of were as to of was used at was used at a of was used at and were from was from and was used at a of was from and used at a of to apoptosis. The inhibitor was used at inhibitor diphenyleneiodonium was used at p38 inhibitor was used at and the protein and were used at and were from and were from Cell and were used at in c was from and used at neutrophils were from blood by a as C. Henson P.M. Am. J. Google Scholar). was with and cell of Apoptosis in neutrophils were at in with and in Neutrophils were to or were to or UV in the presence or of fMLP with the inhibitor p38 inhibitor or or protein and used a of stimuli. Apoptosis was assessed after h for UV and h for other stimuli. cells were and at for 3 and were with a were as apoptotic their and and least cells were in a The of was by of in by these within neutrophils were with at for in and by in to a of in the that occurs upon decreased mitochondrial membrane potential A. G. C. Biochem. Res. 1993; PubMed Scopus Google Scholar). The in to a decrease in the levels of in the c neutrophils were for with the inhibitor at which fMLP and were for h was to the for at after which cells were c was as in Hay N. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google with the c and a and cytochrome c cells were and were with on a at were at and was used as by S.J. S. J. Immunol. PubMed Scopus Google Scholar). neutrophils were with for in a to of of the or fMLP or of a at cells were on and by XIAP were at and were for h with stress stimuli or in the presence or of fMLP or the inhibitor cells were also for with the inhibitor with h cells were in of with and and for on were and for were on a and with were with were as in (5Frasch S.C. Nick J.A. Fadok V.A. Bratton D.L. Worthen G.S. Henson P.M. J. Biol. Chem. 1998; 273: 8389-8397Abstract Full Text Full Text PDF PubMed Scopus (272) Google and with to protein of and were at in with and to were or and were at for or for p38 cells were with fMLP for and and 3, and with or a with the stimuli. were on in of with the inhibitor and inhibitor for were at for at and were for and on a were with or were to (5Frasch S.C. Nick J.A. Fadok V.A. Bratton D.L. Worthen G.S. Henson P.M. J. Biol. Chem. 1998; 273: 8389-8397Abstract Full Text Full Text PDF PubMed Scopus (272) Google and with or at were that were with an and for ERK and from with the stimulus at were for ERK activity by an activity with of the cells were at and with with and and were at at for and were to protein of and for h at with were with and once with were in of protein, inhibitor and and for at with of the reaction was to three with and by and were from at least three was the The and were used for and ERK Apoptosis of have the of the ERK/MAPK in protecting cells from apoptosis. we that of the β2 integrin inhibits stress-induced neutrophil apoptosis via the ERK pathway, downstream of mitochondrial perturbation (2Whitlock B.B. Gardai S. Fadok V. Bratton D. Henson P.M. J. Cell Biol. 2000; 151: 1305-1320Crossref PubMed Scopus (112) Google Scholar, J. Li T. J. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar). the ERK inhibition of apoptosis but not mitochondrial we a by fMLP, a stimulus known to activate ERK and inhibit stress-induced apoptosis (5Frasch S.C. Nick J.A. Fadok V.A. Bratton D.L. Worthen G.S. Henson P.M. J. Biol. Chem. 1998; 273: 8389-8397Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar), and a variety of pro-apoptotic and to the effect of ERK on apoptosis and mitochondrial Neutrophils were with in the presence or of fMLP and the inhibitor for and apoptosis was assessed by demonstrates the decrease in mitochondrial membrane potential assessed by in a it is it and were for a decrease in a decrease in mitochondrial membrane in a decrease in with the of apoptosis. fMLP inhibited apoptosis it not prevent the decrease in of the inhibitor the protective effect of fMLP on apoptosis but not alter these cytochrome c was Neutrophils were with in the presence or of fMLP, and were and cells for cytochrome cells cytochrome c is released the resulting in an in cytochrome c in the with to a decrease in cytochrome c mitochondrial as well as decreased of fMLP inhibited apoptosis, of cytochrome c and of membrane was still with apoptosis but not alter cytochrome c release of apoptosis and injury to the were with and as the ERK fMLP or GM-CSF, inhibited apoptosis but not mitochondrial not ERK the in XIAP by for ERK regulation is XIAP of the IAP XIAP blocks apoptosis by to caspase 3, and and inhibiting their the of XIAP in neutrophil apoptosis and the ability of ERK to regulate activity, the levels of XIAP in neutrophils to pro-apoptotic/stress stimuli was Neutrophils were with TNFα, or the for with pro-apoptotic stimuli a decrease in XIAP levels with cells the of XIAP was because of the inhibitor was to with the inhibitor a decrease in XIAP These data the that pro-apoptotic stimuli the degradation of XIAP, and this may to their ability to apoptosis. demonstrates that ERK activation XIAP levels in the presence of a stress Neutrophils were with fMLP and to for fMLP XIAP with the inhibitor XIAP levels to from cells with pro-apoptotic stimuli and Oxidants the of ERK to previous the of β2 integrin engagement in neutrophil apoptosis in the a stress and activation of the β2 integrin were anti-apoptotic (2Whitlock B.B. Gardai S. Fadok V. Bratton D. Henson P.M. J. Cell Biol. 2000; 151: 1305-1320Crossref PubMed Scopus (112) Google Scholar). β2 integrin and by integrin the and ERK pathways and inhibited stress-induced apoptosis through the ERK pathway. β2 integrin activation the and enhanced stress-induced apoptosis. The major integrin and with activation was the intracellular oxidants by β2 integrin activation with enhanced fMLP or oxidants the protective effect of ERK, neutrophils were with or the β2 for by the ERK fMLP and the stress UV Apoptosis was assessed at The ability of fMLP to inhibit apoptosis was in the presence of the stimuli to that with the inhibitor This effect was not unique for fMLP and UV as oxidants also the ability of to inhibit apoptosis p38 the of are potent of signaling and have been suggested to apoptosis through the activation of inhibition of was due to neutrophils were with the p38 inhibitor to exposure by fMLP and UV with the p38 inhibitor a ability of fMLP to inhibit apoptosis in the presence of oxidants that the extracellular oxidants and with the β2 p38 as as and this for also to p38 at with activation at p38 was neutrophils were with the inhibitor or to with the or These were to block p38 that and p38 in an The ability of oxidants to ERK is shown in with for to fMLP ERK as as 3 and to inhibit for to the p38 inhibitor the ability of oxidants to inhibit ERK of ERK the inhibition of ERK by was to due to cells were with or to the of and this was by fMLP for with the ERK in the presence of oxidants and p38 activity by β2 integrin activation ERK, neutrophils were with the inhibitor or the p38 inhibitor to with the β2 with the ERK activity In the presence of and of in ERK These data that the in signaling β2 integrin and with activation is due to and p38 integrin Oxidants p38 inhibited the ERK pathway, neutrophils were with the p38 inhibitor to of the extracellular This was by with fMLP and for with to fMLP inhibited at and and 3 with the p38 inhibitor to fMLP induction of of reports J. Li T. J. Mol. Cell. Biol. 2001; PubMed Scopus Google that activity can inhibited by the potent phosphatases PP1 and PP2A. a for these cells were with the inhibitor to with and the ability of fMLP to inhibit UV apoptosis was assessed with the inhibitor the ability of fMLP to protect neutrophils from apoptosis in the presence of The data in the inhibition of protein phosphatases ERK activity in the presence of potent These data that oxidants inhibit and ERK, via a p38 effect on phosphatases PP1 PP2A. is a signaling of ERK-mediated inhibition of neutrophil apoptosis and the effect oxidants have on this pathway. released from the bone marrow and the circulation neutrophils undergo spontaneous apoptosis. stress stimuli this including Fas TNFα, UV irradiation, or spontaneous and apoptosis are inhibited by PI3K/Akt, which to block at the of mitochondrial and activation of caspases Hay N. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar), through This to act downstream of the at the of caspase inhibition (10Erhardt P. Schremser E.J. Cooper G.M. Mol. Cell. Biol. 1999; 19: 5308-5315Crossref PubMed Scopus (267) Google Scholar, J.S. S. Mol. Biol. Cell. PubMed Scopus (46) Google Scholar). demonstrate that stress-induced apoptosis was by a variety of stimuli including growth factors for or in mitochondrial damage still The likely for these were of the IAP we for of the IAP family, including and only XIAP levels were upon of an apoptotic stimulus not also on XIAP as a likely due in part to ability to and inhibit the activity of caspases 3, and The of XIAP to to spontaneous apoptosis, and after h of in there was a decrease in the levels of XIAP not this a stress-induced and spontaneous apoptosis is not may that during spontaneous apoptosis XIAP is regulated by degradation but may also regulated via with (17Liu Z. Sun C. Olejniczak E.T. Meadows R.P. Betz S.F. Oost T. Herrmann J. Wu J.C. Fesik S.W. Nature. 2000; 408: 1004-1008Crossref PubMed Scopus (548) Google Scholar). activation of ERK by fMLP XIAP levels in the presence of stress and of the inhibitor this protection. These data suggest that XIAP levels are regulated through a degradation and (11Yang Y.L. Li X.M. Cell Res. 2000; 10: 169-177Crossref PubMed Scopus (253) Google Scholar). ERK may help XIAP levels in of by inhibiting the ubiquitination pathway, likely through or it may XIAP via activation of transcription factors such as H. Chen C. Li Chen B.D. Exp. Cell Res. PubMed Scopus Google Scholar, L. Nature. 2001; PubMed Scopus Google Scholar). In inhibition of apoptosis by enhanced XIAP transcription has been associated with ERK activation in cells and cells H. Chen C. Li Chen B.D. Exp. Cell Res. PubMed Scopus Google Scholar, Z. H. D. S. E. J. Clin. Investig. 2001; PubMed Scopus Google Scholar). the with which ERK activation to within that of the regulation is at the of ubiquitination resulting in In a previous report we that of the integrin spontaneous and neutrophil apoptosis through activation of the and ERK during integrin activation ERK was and stress-induced apoptosis was due in part to activation and on activation S. B.B. C. D. Fadok V. Bratton D. Henson P.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). These the that oxidants by integrin activation also block the ERK pathway, the cells to stress-induced apoptosis. In the β2 integrin activation induced and the ability of fMLP to inhibit UV and apoptosis. of inhibition of fMLP protection was with of oxidants such as or In the or oxidants ERK of ERK activity and the this has on neutrophil apoptosis may have important in chronic granulomatous and during inflammatory are to oxidants through the pathway, and with normal neutrophils from have levels of spontaneous and stress-induced apoptosis not shown and Y. K. A. K. A. H. T. N. 1997; PubMed Google Scholar). This may in part to ERK and XIAP The effect may during an inflammatory reaction levels are These higher levels may inhibit ERK and to the rapid degradation of XIAP and enhanced apoptosis. This may important for the neutrophils can and tissue p38 MAPK is a known downstream target of oxidants (21Wang K. Gross A. Waksman G. Korsmeyer S.J. Mol. Cell. Biol. 1998; 18: 6083-6089Crossref PubMed Scopus (189) Google Scholar), and reports have suggested that it may have a effect on ERK Z. J. Science. PubMed Scopus Google Scholar, K. Worthen G.S. Gardai S. Fadok V.A. Bratton D.L. Henson P.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, H. Blanis L. Pelech S. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). p38 was in the presence of oxidants or the β2 integrin was of p38 with the inhibition of ERK and ability to inhibit apoptosis. that the p38 effect family kinases because of the family ERK activity in the presence of oxidants not The oxidants were shown to activate the family kinases and likely for pathways to of p38 not of ERK activation by p38 a effect on the MAPK or on In p38 inhibition was shown to prevent of it as the likely K. Worthen G.S. Gardai S. Fadok V.A. Bratton D.L. Henson P.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J.S. S. Mol. Biol. Cell. PubMed Scopus (46) Google Scholar). of have suggested that MAPK is by activation of phosphatases and in this likely PP1 J. Li T. J. Mol. Cell. Biol. 2001; PubMed Scopus Google Scholar, T. S. H. K. Y. A. R. S. 1998; PubMed Scopus Google Scholar). In of this the and the of ERK not alter p38 activation not activation of phosphatases is The data potential the of and pro-apoptotic in neutrophils and suggest a potential these stimuli the presence of pro-apoptotic stress such as oxidants may the anti-apoptotic in the stimuli and are likely in inflammatory and may to to the removal of neutrophils during the of the