In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment.
Two functionally distinct subsets of B cells that produce Th1- and Th2-like patterns of cytokines have recently been identified. Interleukin-12 (IL-12) is a critical immunoregulatory cytokine that promotes Th1 differentiation through activation of signal transducer and activator of transcription 4 (STAT4). IL-12 has been reported to induce interferon gamma (IFN-gamma) production in B cells, but the relevant signaling pathways are poorly documented. Here, in human primary B cells, we found a functional IL-12 receptor (IL-12R) that internalizes following IL-12 binding. IFN-gamma and, to a lesser extent, IL-12 positively regulated the IL-12Rbeta2 subunit but had no effect on IL-12Rbeta1. On examining the effect of IL-12 on STAT4 and T-bet (2 key factors involved in IFN-gamma promoter activation), we found that IL-12 induced the phosphorylation and nuclear translocation of STAT4. IL-12-dependent constitutive STAT4 activation was also observed in the Epstein-Barr virus (EBV)-transformed B-cell line RPMI 8866 that spontaneously produces IL-12. T-bet expression has been shown to be dependent on STAT1. IL-12 had no direct effect on STAT1 activation or T-bet expression in primary B cells. In contrast, IL-12-induced IFN-gamma led to STAT1 activation, strong expression of T-bet, and IFN-gamma expression. IL-12 therefore initiates a cascade of events in B cells, including STAT4 activation, IL-12Rbeta2 up-regulation, IFN-gamma production, and T-bet up-regulation, potentially leading to Th1-like differentiation.
Durali
Deniz
D
INSERM E-109, Faculté de Médecine Paris XI, 63 rue Gabriel Péri, Le Kremlin-Bicêtre Cedex, 94276 France.
de Goër de Herve
Marie-Ghislaine
MG
Giron-Michel
Julien
J
Azzarone
Bruno
B
Delfraissy
Jean-François
JF
Taoufik
Yassine
Y
D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000502:physiology*; D018123:Receptors, Interleukin / Q000032:analysis / Q000235:genetics; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; D015398:Signal Transduction; D020825:T-Box Domain Proteins; D018417:Th1 Cells; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494090:STAT4 protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D018664:Interleukin-12; D007371:Interferon-gamma