Integration of TCR and IL-4 signals through STAT6 and the regulation of IL-4 gene expression.
Signals generated by both antigen and cytokines binding to CD4(+) T cells synergize to promote helper T cell subset differentiation. For Th2 cell commitment neither IL-4 nor T cell receptor (TCR) stimulation are sufficient to drive differentiation. Th2 differentiation requires IL-4-receptor mediated signal transducers and activators of transcription 6 (STAT6) activation, but the possibility that IL-4 can directly enhance IL-4 production by T cells has remained unclear. In this report, IL-4 is shown to increase anti-CD3 or ionomycin induced IL-4 mRNA in differentiated murine Th2 cells. Anti-CD3 or ionomycin also enhances IL-4 induction of STAT6 activation, assayed by gel shift analysis of nuclear lysates. Surprisingly, cyclosporin A (CsA) also enhances STAT6 induction. Both ionomycin and CsA also enhance IL-4-induced transcriptional activity of a STAT6-linked promoter-reporter construct. In vitro calcineurin activity reduces STAT6 interactions with DNA, and CsA or FK506 can block this effect of calcineurin. These results indicate that IL-4 and TCR-generated calcium signals interact to maximize IL-4 gene expression and STAT6 activity. Calcineurin-mediated serine dephosphorylation of STAT6 and STAT6 serine phosphorylation may counter-regulate transcriptional activity of STAT6.
Immunology Research Division, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. csweber@siaf.unizh.ch
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Schmidt-Weber
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Rao
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Lichtman
D000818:Animals; D020013:Calcium Signaling; D005786:Gene Expression Regulation; D015847:Interleukin-4 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020239:Receptor Cross-Talk; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D050800:STAT6 Transcription Factor; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism*
D011948:Receptors, Antigen, T-Cell; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4