Regulation of TNF mediated antiapoptotic signaling in human neutrophils:: role of δ-PKC and ERK1/2

被引:76
作者
Kilpatrick, Laurie E.
Sun, Shuang
Mackie, DeMauri
Baik, Fred
Li, Haiying
Korchak, Helen M.
机构
[1] Childrens Hosp Philadelphia, Immunol Sect, Joseph Stokes Jr Res Inst, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA
关键词
sepsis; MAP kinases; caspase; 3; delta-PKC siRNA;
D O I
10.1189/jlb.0406284
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 NF kappa B 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, V1.1 delta-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 nentrophilic phenotype, delta-PKC depletion by delta-PKC siRNA resulted in inhibition of TNF mediated ERK1/2 activation but not p38 MAPK. Thus, ERKI/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.
引用
收藏
页码:1512 / 1521
页数:10
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