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In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment
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AbstractTwo 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 γ (IFN-γ) 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-γ and, to a lesser extent, IL-12 positively regulated the IL-12Rβ2 subunit but had no effect on IL-12Rβ1. On examining the effect of IL-12 on STAT4 and T-bet (2 key factors involved in IFN-γ 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-γ led to STAT1 activation, strong expression of T-bet, and IFN-γ expression. IL-12 therefore initiates a cascade of events in B cells, including STAT4 activation, IL-12Rβ2 up-regulation, IFN-γ production, and T-bet up-regulation, potentially leading to Th1-like differentiation. (Blood. 2003;102:4084-4089)
American Society of Hematology
Title: In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment
Description:
AbstractTwo 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 γ (IFN-γ) 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-γ and, to a lesser extent, IL-12 positively regulated the IL-12Rβ2 subunit but had no effect on IL-12Rβ1.
On examining the effect of IL-12 on STAT4 and T-bet (2 key factors involved in IFN-γ 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-γ led to STAT1 activation, strong expression of T-bet, and IFN-γ expression.
IL-12 therefore initiates a cascade of events in B cells, including STAT4 activation, IL-12Rβ2 up-regulation, IFN-γ production, and T-bet up-regulation, potentially leading to Th1-like differentiation.
(Blood.
2003;102:4084-4089).
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