IL-2 induction by simian immunodeficiency virus involves MAP kinase signaling but is independent of calcineurin/NF-AT activity.
The major T cell growth factor interleukin-2 (IL-2) is secreted by activated T cells in response to antigenic stimulation. This requires signal transduction via the CD3/TCR complex and the CD28 coreceptor, leading to activation of mitogen-activated protein kinase (MAPK) and calcineurin/NF-AT signaling pathways. We observed that simian immunodeficiency virus derived from African green monkeys (SIVagm3) is a potent activator of IL-2 gene expression. IL-2 promoter studies in A3.01 T cells demonstrated that SIVagm3 induced an up to 38-fold increased transcriptional activation of the IL-2 promoter. Inhibition of MAPK signaling pathways using inhibitors of MEK, JNK or p38 abolished SIVagm3-induced IL-2 activation in a dose-dependent manner. In contrast, the immunosuppressive drug cyclosporin A (CyA), a classical IL-2 inhibitor that blocks calcineurin activity, had no effect. Consistent with this finding, the nuclear factor of activated T cells (NF-AT), which is activated by calcineurin, was not induced by SIVagm3. Analyzing further transcription factor binding sites located on the IL-2 promoter we found that SIVagm3 did mainly promote transcriptional activation of the CD28/AP-1 and NF-kappaB responsive elements. These DNA elements were also induced by the viral transactivator protein (Tat) and expression of Tat was sufficient to activate IL-2 induction in stimulated cells. Our results show that SIVagm3 is capable of stimulating IL-2 gene expression via molecular mechanisms different from those induced during classical T cell activation.
Muckenfuss
Heide
H
Department of Medical Biotechnology, Paul-Ehrlich-Institut, Paul-Ehrlich-Str. 51-59, D-63225 Langen, Germany.
Hamdorf
Matthias
M
Avots
Andris
A
Sanzenbacher
Ralf
R
Tschulena
Ulrich
U
Cichutek
Klaus
K
Flory
Egbert
E
D000818:Animals; D018106:CD28 Antigens / Q000235:genetics; D019703:Calcineurin / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D015696:Gene Products, tat / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015302:Simian Immunodeficiency Virus / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
D018106:CD28 Antigens; D015696:Gene Products, tat; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019703:Calcineurin