p21(Cip1) up-regulated during histone deacetylase inhibitor-induced CD4(+) T-cell anergy selectively associates with mitogen-activated protein kinases.

Histone deacetylase inhibitor n-butyrate induced proliferative unresponsiveness in antigen-stimulated murine CD4(+) T cells. T cells anergized by n-butyrate demonstrated reduced interleukin-2 (IL-2) secretion and decreased activating protein 1 (AP-1) activity upon restimulation. Mechanistic studies determined that the cyclin-dependent kinase (cdk) inhibitor p21(Cip1) was up-regulated in the anergic CD4(+) T cells. ...
p21(Cip1) is known to inhibit the cell cycle through its interaction with cdk, proliferating cell nuclear antigen (PCNA) or c-Jun N-terminal kinase (JNK). p21(Cip1) did not preferentially associate with PCNA or cdk in anergic T helper type 1 (Th1) cells. Instead, among the three interaction partners, p21(Cip1) was found to interact with phospho-JNK and phospho-c-jun selectively in the anergic CD4(+) T cells. The activity of c-jun and downstream transcription factor AP-1 were suppressed in the anergic Th1 cells. In contrast, p21(Cip1) and the two phospho-proteins were never detected concurrently in the control CD4(+) T cells. The n-butyrate-induced p21(Cip1)-mediated inhibition of JNK and c-jun represents a novel potential mechanism by which proliferative unresponsiveness was maintained in CD4(+) T cells.
Mesh Terms:
Animals, Butyrates, CD4-Positive T-Lymphocytes, Clonal Anergy, Cyclin-Dependent Kinase Inhibitor p21, Histone Deacetylase Inhibitors, Interleukin-2, JNK Mitogen-Activated Protein Kinases, Male, Mice, Mice, Inbred C57BL, Protein Binding, Proto-Oncogene Proteins c-jun, Transcription Factor AP-1, Up-Regulation
Immunology
Date: Apr. 01, 2010
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