Méndez-Samperio P, Ayala-Verdin H E, Trejo-Echeverria A
Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, IPN Carpio y Plan de Ayala, México, México.
Scand J Immunol. 1999 Jul;50(1):61-7.
Interferon (IFN)-gamma is a cytokine which plays a critical role in the host defence against human tuberculosis infection. There is evidence that interleukin (IL)-12 can exert a potent effect in stimulating the production of IFN-gamma, and it is well known that a costimulatory signal provided by CD40 may enhance IL-12 production by monocytes/macrophages. However, it is unclear whether CD40-CD40L stimulation is able to regulate the production of mycobacterial-induced IFN-gamma through an IL-12-dependent pathway. In this study, we investigated the capacity of the Bacille Calmette-Guérin (BCG) strain of Mycobacterium bovis to induce the production of interferon-gamma through IL-12 and/or CD40 costimulation from human cells. Our data demonstrate that anti-IL-12 antibodies markedly reduced the levels of IFN-gamma produced by the BCG-stimulated human cells, while exogenous recombinant (r)IL-12 up-regulated the production of IFN-gamma. In addition, the stimulatory effect of IL-12 on BCG-induced IFN-gamma secretion was specific, as it was significantly abolished in the presence of anti-IL-12 antibodies. We also observed that the presence of an anti-CD40L monoclonal antibody significantly inhibited the production of IL-12 and IFN-gamma by human cells activated with BCG. In contrast, an isotype control antibody showed no effect on cytokine production. Furthermore, the presence of a trimeric soluble CD40L agonist (CD40T) in cultures increased the production of IL-12 and IFN-gamma. Importantly, the stimulatory capacity of CD40T on BCG-induced IFN-gamma secretion was blocked by a monoclonal antibody against IL-12, indicating that the effect of CD40T on T cells was mediated through IL-12. Together, these studies are the first to demonstrate that BCG-induced IFN-gamma production by human cells appears to be mediated by IL-12 in a CD40-dependent manner and suggest that CD40-CD40L activation may be a critical mediator in regulating the immune response to stimulation with BCG.
干扰素（IFN）-γ是一种细胞因子，在宿主抵御人类结核感染中发挥关键作用。有证据表明，白细胞介素（IL）-12在刺激IFN-γ产生方面可发挥强大作用，并且众所周知，CD40提供的共刺激信号可增强单核细胞/巨噬细胞产生IL-12。然而，尚不清楚CD40-CD40L刺激是否能够通过依赖IL-12的途径调节分枝杆菌诱导的IFN-γ产生。在本研究中，我们调查了牛分枝杆菌卡介苗（BCG）菌株通过人细胞的IL-12和/或CD40共刺激诱导干扰素-γ产生的能力。我们的数据表明，抗IL-12抗体显著降低了BCG刺激的人细胞产生的IFN-γ水平，而外源性重组（r）IL-12上调了IFN-γ的产生。此外，IL-12对BCG诱导的IFN-γ分泌的刺激作用具有特异性，因为在存在抗IL-12抗体的情况下该作用被显著消除。我们还观察到，抗CD40L单克隆抗体的存在显著抑制了被BCG激活的人细胞产生IL-12和IFN-γ。相比之下，同型对照抗体对细胞因子产生没有影响。此外，培养物中三聚体可溶性CD40L激动剂（CD40T）的存在增加了IL-12和IFN-γ的产生。重要的是，CD40T对BCG诱导的IFN-γ分泌的刺激能力被抗IL-12单克隆抗体阻断，表明CD40T对T细胞的作用是通过IL-12介导的。总之，这些研究首次证明人细胞中BCG诱导的IFN-γ产生似乎是以CD40依赖的方式由IL-12介导的，并表明CD40-CD40L激活可能是调节对BCG刺激的免疫反应的关键介质。
