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c-Jun N-terminal kinase but not mitogen-activated protein kinase is sensitive to cAMP inhibition in T lymphocytes
1Graduate Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, Republic of China.
Abstract:
The molecular mechanism underlying the cAMP inhibition of nuclear activation events in T lymphocytes is unknown. Recently, the activation of fibroblasts and muscle cells are shown to be antagonized by cAMP through the inhibition of mitogen-activated protein (MAP) kinases signaling pathway. Whether a similar antagonism may account for the late inhibitory effect of cAMP in T cell was examined. Surprisingly, extracellular signal regulated kinase 2 (ERK1, ERK2, and ERK3) of MAP kinase were poorly inhibited by cAMP. High concentration of cAMP also only weakly antagonized Raf-1 in T cells. The resistance of ERK and Raf-1 to cAMP clearly distinguishes T cells from fibroblasts. In contrast, another MAP kinase homologue c-Jun N-terminal kinase (JNK) was inhibited by cAMP in good correlation with that of IL-2 suppression. Moreover, JNK was antagonized by a delayed kinetics which is characteristic of cAMP inhibition. Despite that both ERK and JNK are essential for T cell activation, selective inhibition by cAMP further supports the specific role of JNK in T cell activation.
Insights
Cyclic AMP (cAMP) inhibits T cell activation by selectively targeting c-Jun N-terminal kinase (JNK) but not extracellular signal-regulated kinases (ERK). This selective inhibition highlights JNK's specific role in T cell nuclear events.
Area of Science:
- Immunology
- Molecular Biology
- Cell Signaling
Background:
- The mechanism by which cyclic AMP (cAMP) inhibits T lymphocyte activation is not fully understood.
- cAMP antagonizes fibroblast and muscle cell activation by inhibiting mitogen-activated protein (MAP) kinases.
- Investigating if a similar mechanism applies to T cells could elucidate cAMP's inhibitory effects.
Purpose of the Study:
- To examine if cAMP inhibits T cell activation through MAP kinase pathways.
- To determine the specific MAP kinases involved in cAMP-mediated T cell inhibition.
- To compare cAMP's effect on MAP kinases in T cells versus other cell types.
Main Methods:
- Assessing the inhibition of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) by cAMP in T cells.
- Evaluating the antagonism of Raf-1 by cAMP.
- Correlating JNK inhibition with interleukin-2 (IL-2) suppression kinetics.
Main Results:
- ERK and Raf-1 showed resistance to cAMP inhibition in T cells, unlike in fibroblasts.
- cAMP effectively inhibited JNK in T cells, correlating with IL-2 suppression.
- JNK inhibition by cAMP followed a delayed kinetic pattern characteristic of cAMP's inhibitory effects.
Conclusions:
- T cells exhibit distinct resistance of ERK and Raf-1 to cAMP compared to fibroblasts.
- Selective inhibition of JNK, but not ERK, by cAMP in T cells suggests a specific role for JNK.
- These findings support JNK as a key mediator of cAMP-induced T cell activation inhibition.