Regulation of TNF mediated antiapoptotic signaling in human neutrophils: role of δ-PKC and ERK1/2
- 1 December 2006
- journal article
- Published by Oxford University Press (OUP) in Journal of Leukocyte Biology
- Vol. 80 (6), 1512-1521
- https://doi.org/10.1189/jlb.0406284
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 (δ-PKC) is a critical regulator of TNFR-1 signaling. δ-PKC associates with TNFR-1 in response to TNF and is required for NFκB activation and inhibition of caspase 3. The role of δ-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 δ-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 δ-PKC antagonist, V1.1δ-PKC-Tat peptide, inhibited TNF-mediated ERK1/2 activation, but not p38 MAPK. ERK1/2 inhibition did not alter recruitment of δ-PKC to TNFR-1, indicating δ-PKC is acting upstream of ERK1/2. In HL-60 cells differentiated to a neutrophilic phenotype, δ-PKC depletion by δ-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, δ-PKC is a positive regulator of ERK1/2 activation via TNFR-1 but has no role in p38 MAPK activation.Keywords
Funding Information
- National Institutes of Health, Bethesda, MD (GM 64552, AI 24840)
This publication has 69 references indexed in Scilit:
- PKC-δ-dependent pathways contribute to PDGF-stimulated ERK1/2 activation in vascular smooth muscleAmerican Journal of Physiology-Cell Physiology, 2005
- PKC-δ and CaMKII-δ2 mediate ATP-dependent activation of ERK1/2 in vascular smooth muscleAmerican Journal of Physiology-Cell Physiology, 2004
- The survival effect of TNF‐α in human neutrophils is mediated via NF‐κB‐dependent IL‐8 releaseEuropean Journal of Immunology, 2004
- Genetic Deletion of the Tumor Necrosis Factor Receptor p60 or p80 Abrogates Ligand-mediated Activation of Nuclear Factor-κB and of Mitogen-activated Protein Kinases in MacrophagesJournal of Biological Chemistry, 2001
- TNFα Elicits Association of PI 3-Kinase with the p60TNFR and Activation of PI 3-Kinase in Adherent NeutrophilsBiochemical and Biophysical Research Communications, 2001
- Neutrophil β2-Integrin Upregulation Is Blocked by a p38 MAP Kinase InhibitorBiochemical and Biophysical Research Communications, 2000
- Tyrosine Phosphorylation of p38 but Not Extracellular Signal-Regulated Kinase in Normal Human Neutrophils Stimulated by Tumor Necrosis Factor: Comparative Study with Granulocyte-Macrophage Colony-Stimulating FactorBiochemical and Biophysical Research Communications, 1997
- Molecular cloning and expression of a receptor for human tumor necrosis factorCell, 1990
- Molecular cloning and expression of the human 55 kd tumor necrosis factor receptorCell, 1990
- Neutrophil activation on biological surfaces. Massive secretion of hydrogen peroxide in response to products of macrophages and lymphocytes.JCI Insight, 1987