Reciprocal effects of IFN-beta and IL-12 on STAT4 activation and cytokine induction in T cells.
IL-12 is an immunoregulatory cytokine, which promotes Th1 cell differentiation and is a major inducer of IFN-gamma. IFN-beta, a Type I IFN used in the treatment of multiple sclerosis, has been shown to significantly increase the expression of the anti-inflammatory cytokine IL-10, a major suppressor of Th1 cytokines. The beneficial immunomodulatory effects of IFN-beta may in part be a result of its ability to suppress IL-12. However, IL-12 and IFN-beta signal via the STAT4 pathway. Our aim was to investigate the relationship between IL-12 and IFN-beta by observing the effect of prior exposure to IL-12 or IFN-beta on the ability of T cells to subsequently respond to the other cytokine. We report that IFN-beta increases IL-12-induced STAT4 phosphorylation and up-regulates IL-12 receptor beta1 and beta2 expression. However, despite this up-regulation, IFN-beta suppressed IL-12-induced IFN-gamma expression. Our results suggest that this may be a result of the parallel induction of IL-10 by IFN-beta.
Fahey
Angela J
AJ
Divisions of Clinical Neurology , University of Nottingham, Nottingham NG7 2UH, UK.
Robins
R Adrian
RA
Constantinescu
Cris S
CS
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000378:metabolism / Q000494:pharmacology; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000494:pharmacology; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000494:pharmacology; D010766:Phosphorylation; D053707:Receptors, Interleukin-12 / Q000378:metabolism*; D011994:Recombinant Proteins; D050797:STAT4 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction
D007370:Interferon Type I; D053707:Receptors, Interleukin-12; D011994:Recombinant Proteins; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma