title: Anergic T cells are defective in both jun NH2-terminal kinase and mitogen-activated protein kinase signaling pathways.
abstract: T helper type 1 cells (Th1) become anergic when stimulated through the antigen receptor in the absence of costimulation. They do not produce IL-2 or proliferate in response to subsequent stimulation. Previous studies have indicated that anergic T cells are defective in the trnsactivational activity of the transcription factor, AP-1, which is required for optimal IL-2 transcription. Using two murine Th1 cell clones, we demonstrate that anergic Th1 cells have defects in both jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) activities. These kinases have been shown to be important for the upregulation of AP-1 activity. Furthermore, our data show that ERK and JNK activities are restored when anergy is induced in the presence of the protein synthesis inhibitor cycloheximide, or when anergic T cells are allowed to proliferate in response to exogenous IL-2. These treatments have previously been shown to prevent or reverse the anergic state. Our results suggest that defects in both JNK and ERK may result in the decreased AP-1 activity and the reduced IL-2 transcription observed in anergic T cells.
authors.affiliation: Dupont Merck Pharmaceutical Company, Inflammatory Diseases Research, Wilmington, Delaware 19880-0400, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: DeSilva
authors.forename: W S
authors.initials: WS
authors.lastname: Feeser
authors.forename: E J
authors.initials: EJ
authors.lastname: Tancula
authors.forename: P A
authors.initials: PA
authors.lastname: Scherle
mesh_terms: D000818:Animals; D000906:Antibodies; D017252:CD3 Complex / Q000276:immunology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured; D017635:Clonal Anergy; D003513:Cycloheximide / Q000494:pharmacology; D009980:Influenza A virus / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D000906:Antibodies; D017252:CD3 Complex; D007376:Interleukin-2; D011518:Proto-Oncogene Proteins; D018808:Transcription Factor AP-1; D015759:Ionomycin; D003513:Cycloheximide; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate