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Regulation of TNF mediated antiapoptotic signaling in human neutrophils: role of δ‐PKC and ERK1/2
Author(s) -
Kilpatrick Laurie E.,
Sun Shuang,
Mackie DeMauri,
Baik Fred,
Li Haiying,
Korchak Helen M.
Publication year - 2006
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0406284
Subject(s) - mapk/erk pathway , p38 mitogen activated protein kinases , microbiology and biotechnology , signal transduction , biology , protein kinase c , tumor necrosis factor alpha , kinase , apoptosis , cancer research , immunology , biochemistry
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.