title: Regulation of TNF mediated antiapoptotic signaling in human neutrophils: role of delta-PKC and ERK1/2.
abstract: TNF is implicated in the suppression of neutrophil apoptosis during sepsis. Multiple signaling pathways are involved in TNF-mediated antiapoptotic signaling; a role for the MAP kinases (MAPK), ERK1/2, and p38 MAPK has been suggested. Antiapoptotic signaling is mediated principally through TNF receptor-1 (TNFR-1), and the PKC isotype-delta (delta-PKC) is a critical regulator of TNFR-1 signaling. delta-PKC associates with TNFR-1 in response to TNF and is required for NFkappaB activation and inhibition of caspase 3. The role of delta-PKC in TNF-mediated activation of MAPK is not known. The purpose of this study was to determine whether the MAPK, ERK1/2, and p38 MAPK are involved in TNF antiapoptotic signaling and whether delta-PKC is a key regulator of MAPK activation by TNF. In human neutrophils, TNF activated both p38 MAPK and ERK1/2 principally via TNFR-1. The MEK1/2 inhibitors PD098059 and U0126, but not the p38 MAPK inhibitor SB203580, decreased TNF antiapoptotic signaling as measured by caspase 3 activity. A specific delta-PKC antagonist, V1.1delta-PKC-Tat peptide, inhibited TNF-mediated ERK1/2 activation, but not p38 MAPK. ERK1/2 inhibition did not alter recruitment of delta-PKC to TNFR-1, indicating delta-PKC is acting upstream of ERK1/2. In HL-60 cells differentiated to a neutrophilic phenotype, delta-PKC depletion by delta-PKC siRNA resulted in inhibition of TNF mediated ERK1/2 activation but not p38 MAPK. Thus, ERK1/2, but not p38 MAPK, is an essential component of TNF-mediated antiapoptotic signaling. In human neutrophils, delta-PKC is a positive regulator of ERK1/2 activation via TNFR-1 but has no role in p38 MAPK activation.
authors.affiliation: Department of Pediatrics, University of Pennsylvania School of Medicine and the Joseph Stokes Jr. Research Institute, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. kilpatrick@email.chop.edu
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Kilpatrick
authors.forename: Shuang
authors.initials: S
authors.lastname: Sun
authors.forename: Demauri
authors.initials: D
authors.lastname: Mackie
authors.forename: Fred
authors.initials: F
authors.lastname: Baik
authors.forename: Haiying
authors.initials: H
authors.lastname: Li
authors.forename: Helen M
authors.initials: HM
authors.lastname: Korchak
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D053148:Caspase 3 / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D018922:HL-60 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology* / Q000276:immunology; D051745:Protein Kinase C-delta / Q000276:immunology* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000276:immunology / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D011494:Protein Kinases; D051745:Protein Kinase C-delta; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3