D'Andrea A, Aste-Amezaga M, Valiante N M, Ma X, Kubin M, Trinchieri G
The Wistar Institute of Anatomy and Biology, Philadelphia, PA 19104.
J Exp Med. 1993 Sep 1;178(3):1041-8. doi: 10.1084/jem.178.3.1041.
Natural killer cell stimulatory factor or interleukin 12 (NKSF/IL-12) is a heterodimeric cytokine produced by monocytes/macrophages, B cells, and possibly other accessory cell types primarily in response to bacteria or bacterial products. NKSF/IL-12 mediates pleiomorphic biological activity on T and NK cells and, alone or in synergy with other inducers, is a powerful stimulator of interferon gamma (IFN-gamma) production. IL-10 is a potent inhibitor of monocyte-macrophage activation, that inhibits production of tumor necrosis factor alpha (TNF-alpha), IL-1 and also IFN-gamma from lymphocytes acting at the level of accessory cells. Because TNF-alpha and IL-1 are not efficient inducers of IFN-gamma, the mechanism by which IL-10 inhibits IFN-gamma production is not clear. In this paper, we show that IL-10 is a potent inhibitor of NKSF/IL-12 production from human peripheral blood mononuclear cells activated with Staphylococcus aureus or lipopolysaccharide (LPS). Both the production of the free NKSF/IL-12 p40 chain and the biologically active p70 heterodimer are blocked by IL-10. NKSF/IL-12 p40 chain mRNA accumulation is strongly induced by S. aureus or LPS and downregulated by IL-10, whereas the p35 mRNA is constitutively expressed and only minimally regulated by S. aureus, LPS, or IL-10. Although IL-10 is able to block the production of NKSF/IL-12, a powerful inducer of IFN-gamma both in vitro and in vivo, the mechanism of inhibition of IFN-gamma by IL-10 cannot be explained only on the basis of inhibition of NKSF/IL-12 because IL-10 can partially inhibit IFN-gamma production induced by NKSF/IL-12, and also, the IFN-gamma production in response to various stimuli in the presence of neutralizing antibodies to NKSF/IL-12. Our findings that antibodies against NKSF/IL-12, TNF-alpha, or IL-1 beta can significantly inhibit IFN-gamma production in response to various stimuli and that NKSF/IL-12 and IL-1 beta can overcome the IL-10-mediated inhibition of IFN-gamma, suggest that IL-10 inhibition of IFN-gamma production is primarily due to its blocking production from accessory cells of the IFN-gamma-inducer NKSF/IL-12, as well as the costimulating molecule IL-1 beta.
自然杀伤细胞刺激因子或白细胞介素12（NKSF/IL-12）是一种异二聚体细胞因子，主要由单核细胞/巨噬细胞、B细胞以及可能的其他辅助细胞类型产生，主要是对细菌或细菌产物作出反应。NKSF/IL-12对T细胞和NK细胞介导多形性生物活性，并且单独或与其他诱导剂协同作用时，是干扰素γ（IFN-γ）产生的强大刺激剂。IL-10是单核细胞-巨噬细胞激活的有效抑制剂，它抑制肿瘤坏死因子α（TNF-α）、IL-1以及来自作用于辅助细胞水平的淋巴细胞的IFN-γ的产生。由于TNF-α和IL-1不是IFN-γ的有效诱导剂，IL-10抑制IFN-γ产生的机制尚不清楚。在本文中，我们表明IL-10是用金黄色葡萄球菌或脂多糖（LPS）激活的人外周血单个核细胞产生NKSF/IL-12的有效抑制剂。游离的NKSF/IL-12 p40链和具有生物活性的p70异二聚体的产生均被IL-10阻断。金黄色葡萄球菌或LPS强烈诱导NKSF/IL-12 p40链mRNA的积累，而IL-10使其下调，而p35 mRNA组成性表达，仅受金黄色葡萄球菌、LPS或IL-10的最小调节。尽管IL-10能够阻断NKSF/IL-12的产生，NKSF/IL-12在体外和体内都是IFN-γ的强大诱导剂，但不能仅基于对NKSF/IL-12的抑制来解释IL-10对IFN-γ的抑制机制，因为IL-10可以部分抑制由NKSF/IL-12诱导的IFN-γ产生，而且，在存在针对NKSF/IL-12的中和抗体的情况下，对各种刺激作出反应时的IFN-γ产生。我们的研究结果表明，针对NKSF/IL-12、TNF-α或IL-1β的抗体可以显著抑制对各种刺激作出反应时的IFN-γ产生，并且NKSF/IL-12和IL-1β可以克服IL-10介导的对IFN-γ的抑制，这表明IL-10对IFN-γ产生的抑制主要是由于其阻断了IFN-γ诱导剂NKSF/IL-12以及共刺激分子IL-1β从辅助细胞的产生。
