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p38 mitogen-activated protein kinase is involved in Fas ligand expression
S C Hsu1, M A Gavrilin, M H Tsai
1Graduate Institute of Microbiology, National Taiwan University School of Medicine, Taipei 10018, Taiwan, R.O.C.
Abstract:
p38 mitogen-activated protein kinase (MAPK) is activated by T cell receptor engagement. Here we showed that T cell receptor activated p38alpha but not p38delta. Inhibition of p38alpha by the specific inhibitor SB 203580 prevented activation-induced cell death in T cells. SB 203580 had no effect on Fas-initiated apoptosis. Instead, SB 203580 preferentially inhibited activation-induced Fas ligand (FasL) expression. The inhibition on FasL expression by SB 203580 was correlated with the suppression on the FasL promoter activation. Overexpression of active MAPK kinase 3b, the activator of p38 MAPK, led to activation of FasL promoter and induction of FasL transcripts in T cells. Stress stimulation of T cells by anisomycin also induced FasL expression in a p38 MAPK-dependent manner. The induction of FasL expression in nonlymphoid cells such as 293T also required activation of p38 MAPK. Our results suggest that p38 MAPK is essential for FasL expression.
Insights
p38 mitogen-activated protein kinase (MAPK) activation is crucial for T cell receptor-induced cell death by regulating Fas ligand (FasL) expression. This study highlights p38 MAPK
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- T cell receptor (TCR) engagement activates p38 mitogen-activated protein kinase (MAPK) signaling pathways.
- p38 MAPK isoforms, specifically p38alpha and p38delta, are differentially regulated upon TCR activation.
- Activation-induced cell death (AICD) is a critical process in T cell homeostasis.
Purpose of the Study:
- To investigate the role of p38 MAPK in TCR-induced T cell death.
- To determine the specific p38 MAPK isoform involved in AICD.
- To elucidate the mechanism by which p38 MAPK influences AICD, focusing on Fas ligand (FasL) expression.
Main Methods:
- Utilized the specific p38alpha inhibitor SB 203580 to block p38 MAPK activity.
- Assessed T cell viability and apoptosis following TCR stimulation.
- Quantified Fas ligand (FasL) expression at both the transcript and promoter activation levels.
- Overexpressed MAPK kinase 3b (MKK3b) to activate p38 MAPK.
- Induced T cell stress using anisomycin.
Main Results:
- TCR engagement activated p38alpha but not p38delta.
- Inhibition of p38alpha by SB 203580 prevented AICD, without affecting Fas-initiated apoptosis.
- SB 203580 significantly inhibited activation-induced FasL expression and FasL promoter activation.
- Overexpression of active MKK3b and anisomycin-induced stress activated FasL promoter and transcripts in a p38 MAPK-dependent manner.
- p38 MAPK-dependent FasL induction was also observed in non-lymphoid 293T cells.
Conclusions:
- p38alpha MAPK is essential for TCR-induced FasL expression.
- p38 MAPK signaling is a key regulator of activation-induced cell death in T cells through the modulation of FasL.
- The findings identify p38 MAPK as a critical mediator in T cell apoptosis pathways.