Regulation of fas ligand expression during activation-induced cell death in T cells by p38 mitogen-activated protein kinase and c-Jun NH2-terminal kinase

J Exp Med. 2000 Mar 20;191(6):1017-30. doi: 10.1084/jem.191.6.1017.

Abstract

Activation-induced cell death (AICD) is a mechanism of peripheral T cell tolerance that depends upon an interaction between Fas and Fas ligand (FasL). Although c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) may be involved in apoptosis in various cell types, the mode of regulation of FasL expression during AICD in T cells by these two MAPKs is incompletely understood. To investigate the regulatory roles of these two MAPKs, we analyzed the kinetics of TCR-induced p38 MAPK and JNK activity and their regulation of FasL expression and AICD. We report that both JNK and p38 MAPK regulate AICD in T cells. Our data suggest a novel model of T cell AICD in which p38 MAPK acts early to initiate FasL expression and the Fas-mediated activation of caspases. Subsequently, caspases stimulate JNK to further upregulate FasL expression. Thus, p38 MAPK and downstream JNK converge to regulate FasL expression at different times after T cell receptor stimulation to elicit maximum AICD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / immunology*
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology*
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Line
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Fas Ligand Protein
  • Hybridomas
  • Imidazoles / pharmacology
  • JNK Mitogen-Activated Protein Kinases
  • Ligands
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Membrane Glycoproteins / biosynthesis*
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mitogen-Activated Protein Kinases / metabolism
  • Mitogen-Activated Protein Kinases / physiology*
  • Pyridines / pharmacology
  • T-Lymphocytes / cytology
  • T-Lymphocytes / enzymology*
  • T-Lymphocytes / immunology*
  • fas Receptor / metabolism*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Imidazoles
  • Ligands
  • Membrane Glycoproteins
  • Pyridines
  • fas Receptor
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Caspases
  • SB 203580