Inhibition of transcription factor Stat1 activity in mononuclear cell cultures and T cells by the cyclic AMP signaling pathway.
Activation of T cells results in a cascade of gene activation and subsequent proliferation and differentiation into effector phenotypes. The regulation of transcription factors belonging to the signal transducer and activator of transcription (STAT) family was analyzed in PHA-activated mononuclear cells and in purified T cells activated by cross-linking cell surface CD3. Cell activation resulted in a delayed induction of STAT DNA-binding activity, which was sustained for several days, was composed predominantly of Stat1 and Stat3, and was blocked by cycloheximide and actinomycin D. Increased Stat1 and Stat3 mRNA and protein levels were detected, respectively 4 and 24 h after activation. Stimulation of the cAMP signal transduction pathway, which skews cytokine production toward a Th2 pattern, resulted in the preferential suppression of Stat1 activity. cAMP inhibited the induction of expression of IL-2 receptor components, but did not inhibit IL-4 receptor alpha-chain and CD69 expression or the induction of activator protein 1 transcription factors. cAMP signaling inhibited Stat1 at several different levels, including suppression of DNA binding and down-regulation of Stat1 protein and mRNA levels. Our results demonstrate the regulation of STAT activity by a signaling pathway that regulates the T cell functional phenotype and is distinct from the cytokine-activated Janus kinase-STAT signaling pathway.
Ivashkiv
L B
LB
Department of Medicine, Hospital for Special Surgery, Comell University Graduate School of Medical Sciences, New York, NY 10021, USA.
Schmitt
E M
EM
Castro
A
A
D001483:Base Sequence; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D003513:Cycloheximide / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015290:Second Messenger Systems / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015533:Transcriptional Activation
D016207:Cytokines; D004268:DNA-Binding Proteins; D010835:Phytohemagglutinins; D011500:Protein Synthesis Inhibitors; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D003609:Dactinomycin; D003513:Cycloheximide; D000242:Cyclic AMP