Role of TCR-induced extracellular signal-regulated kinase activation in the regulation of early IL-4 expression in naive CD4+ T cells.
Although extracellular signal-regulated kinase (Erk) activation influences IL-4 production in various experimental systems, its role during Th differentiation is unclear. In this study, we show that Erk plays a critical role in IL-4 expression during TCR-induced Th differentiation of naive CD4(+) T cells. Stimulation of CD4(+) T cells with a high affinity peptide resulted in sustained Erk activation and Th1 differentiation. However, reduction of Erk activity led to a dramatic increase in IL-4 production and Th2 generation. Analysis of RNA and nuclear proteins of CD4(+) T cells 48 h after stimulation revealed that this was due to early IL-4 expression. Interestingly, transient Erk activation resulted in altered AP-1 DNA binding activity and the induction of an AP-1 complex that was devoid of Fos protein and consisted of Jun-Jun dimers. These data show that in the presence of a strong TCR signal, IL-4 expression can be induced in naive CD4(+) T cells by altering the strength of Erk activation. In addition, these data suggest that TCR-induced Erk activation is involved in the regulation of IL-4 expression by altering the composition of the AP-1 complex and its subsequent DNA binding activity.
Jorritsma
Patricia J
PJ
Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Brogdon
Jennifer L
JL
Bottomly
Kim
K
D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D007399:Interphase / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000502:physiology; D008969:Molecular Sequence Data; D009036:Moths; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding / Q000276:immunology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000032:analysis / Q000302:isolation & purification / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
D003574:Cytochrome c Group; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D015847:Interleukin-4; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one