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(Journal of Leukocyte Biology. 2006;80:1512-1521.)
© 2006 by Society for Leukocyte Biology

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

Department of Pediatrics, University of Pennsylvania School of Medicine and the Joseph Stokes Jr. Research Institute, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

¹ Correspondence: Immunology Section, Room 1208A Abramson Research Center, Children’s Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA. E-mail: kilpatrick{at}email.chop.edu

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 (-PKC) is a critical regulator of TNFR-1 signaling. -PKC associates with TNFR-1 in response to TNF and is required for NFB activation and inhibition of caspase 3. The role of -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 -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 -PKC antagonist, V1.1-PKC-Tat peptide, inhibited TNF-mediated ERK1/2 activation, but not p38 MAPK. ERK1/2 inhibition did not alter recruitment of -PKC to TNFR-1, indicating -PKC is acting upstream of ERK1/2. In HL-60 cells differentiated to a neutrophilic phenotype, -PKC depletion by -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, -PKC is a positive regulator of ERK1/2 activation via TNFR-1 but has no role in p38 MAPK activation.

Key Words: sepsis • MAP kinases • caspase 3 • -PKC siRNA