title: Induction of anergy in Th1 cells associated with increased levels of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1.
abstract: Th1 cells exposed to Ag and the G(1) blocker n-butyrate in primary cultures lose their ability to proliferate in Ag-stimulated secondary cultures. The ability of n-butyrate to induce anergy in Ag-stimulated, but not resting, Th1 cells was shown here to be blocked by cycloheximide. Subsequent experiments to delineate the nature of the protein apparently required for n-butyrate-induced Th1 cell anergy focused on the role of cyclin-dependent kinase (cdk) inhibitors p21(Cip1) and p27(Kip1). Normally, entry into S phase by Th1 cells occurs around 24 h after Ag stimulation and corresponds with relatively low levels of both p21(Cip1) and p27(Kip1). However, unlike control Th1 cells, anergic Th1 cells contained high levels of both p21(Cip1) and p27(Kip1) when examined 24 h after Ag stimulation. The increase in p21(Cip1) observed in Ag-stimulated anergic Th1 cells appeared to be initiated in primary cultures. In contrast, the increase in p27(Kip1) observed in these anergic Th1 cells appears to represent a re-expression of the protein much earlier than control cells following Ag stimulation in secondary cultures. The anergic Th1 cells contained functionally active cdk inhibitors capable of inhibiting the activity of both endogenous and exogenous cdks. Consequently, it appears that n-butyrate-induced anergy in Th1 cells correlated with the up-regulation of p21(Cip1) and perhaps the downstream failure to maintain low levels of p27(Kip1). Increased levels of both p21(Cip1) and p27(Kip1) at the end of G(1) could prevent cdk-mediated entry into S phase, and thus help maintain the proliferative unresponsiveness found in the anergic Th1 cells.
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Jackson
authors.forename: A
authors.initials: A
authors.lastname: DeLoose
authors.forename: K M
authors.initials: KM
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D000941:Antigens / Q000494:pharmacology; D002087:Butyrates / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017635:Clonal Anergy / Q000187:drug effects / Q000276:immunology*; D002999:Clone Cells; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000378:metabolism*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D016193:G1 Phase / Q000187:drug effects / Q000276:immunology; D006433:Hemocyanins / Q000276:immunology / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D018417:Th1 Cells / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
chemical_list: D000941:Antigens; D002087:Butyrates; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D018984:Epitopes, T-Lymphocyte; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006433:Hemocyanins; D018844:Cyclin-Dependent Kinases; C032808:keyhole-limpet hemocyanin