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.
Selma Dagtas
Ayse
A
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA. aselmad@yahoo.com
Gilbert
Kathleen M
KM
D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D017635:Clonal Anergy / Q000187:drug effects* / Q000276:immunology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D007376:Interleukin-2 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology
D002087:Butyrates; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D007376:Interleukin-2; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases