Wu C, Warrier R R, Wang X, Presky D H, Gately M K
Department of Inflammation/Autoimmune Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
Eur J Immunol. 1997 Jan;27(1):147-54. doi: 10.1002/eji.1830270122.
The interleukin-12 receptor (IL-12R)beta1 chain is an essential component of the functional IL-12R on both human T and natural killer cells. In this report it is shown that activation of human peripheral blood mononuclear cells (PBMC) with anti-CD3 monoclonal antibody (mAb) or phytohemagglutinin resulted in the up-regulation of IL-12Rbeta1 expression and IL-12 binding. Kinetic studies revealed that maximum expression of IL-12Rbeta1 and IL-12 binding occurred on days 3-4. Anti-CD3-induced expression of IL-12Rbeta1 chain and IL-12 binding by PBMC was augmented by anti-CD28 mAb, indicating that the potentiating effect of anti-CD28 on T cell responses to IL-12 could be mediated, at least in part, by the enhancement of IL-12R expression. Among 16 cytokines tested, IL-2, IL-7 and IL-15 markedly induced IL-12Rbeta1 expression and IL-12 binding on resting PBMC, whereas IL-1alpha and tumor necrosis factor-alpha had a minimal enhancing effect. In contrast, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, interferon (IFN)-alpha, IFN-gamma, granulocyte/macrophage colony-stimulating factor and transforming growth factor (TGF)-beta2 had no detectable enhancing effect. Anti-CD3-induced expression of IL-12Rbeta1 and of low-affinity IL-12 binding sites was partially inhibited by TGF-beta2, IL-10 and IL-4; however, TGF-beta2 and IL-10 completely abolished anti-CD3-induced expression of high-affinity IL-12 binding sites. Consistent with the reduction of high affinity IL-12 binding sites, PBMC activated with anti-CD3 mAb in the presence of TGF-beta2 or IL-10 failed to produce IFN-gamma or to proliferate in response to IL-12. These results suggest that Th2 cell-derived cytokines can inhibit IL-12-induced biological functions by inhibiting IL-12R expression and that expression of a second subunit of the IL-12R (IL-12Rbeta2), required for the formation of high-affinity IL-12 binding sites, may be more highly regulated by TGF-beta2 and IL-10 than is expression of IL-12Rbeta1.
白细胞介素12受体（IL-12R）β1链是人类T细胞和自然杀伤细胞上功能性IL-12R的重要组成部分。本报告显示，用抗CD3单克隆抗体（mAb）或植物血凝素激活人外周血单个核细胞（PBMC）可导致IL-12Rβ1表达上调和IL-12结合增加。动力学研究表明，IL-12Rβ1和IL-12结合的最大表达出现在第3 - 4天。抗CD28 mAb增强了抗CD3诱导的PBMC中IL-12Rβ1链的表达和IL-12结合，这表明抗CD28对T细胞对IL-12反应的增强作用至少部分可通过增强IL-12R表达来介导。在所测试的16种细胞因子中，IL-2、IL-7和IL-15显著诱导静息PBMC上的IL-12Rβ1表达和IL-12结合，而IL-1α和肿瘤坏死因子-α的增强作用最小。相比之下，IL-3、IL-4、IL-5、IL-6、IL-8、IL-10、IL-12、干扰素（IFN）-α、IFN-γ、粒细胞/巨噬细胞集落刺激因子和转化生长因子（TGF）-β2没有可检测到的增强作用。TGF-β2、IL-10和IL-4部分抑制了抗CD3诱导的IL-12Rβ1表达和低亲和力IL-12结合位点；然而，TGF-β2和IL-10完全消除了抗CD3诱导的高亲和力IL-12结合位点的表达。与高亲和力IL-12结合位点的减少一致，在TGF-β2或IL-10存在下用抗CD3 mAb激活的PBMC未能产生IFN-γ或对IL-12作出增殖反应。这些结果表明，Th2细胞衍生的细胞因子可通过抑制IL-12R表达来抑制IL-12诱导的生物学功能，并且高亲和力IL-12结合位点形成所需的IL-12R（IL-12Rβ2）第二个亚基的表达可能比IL-12Rβ1的表达受到TGF-β2和IL-10的调控更强。
