Wahl S M, Allen J B, Wong H L, Dougherty S F, Ellingsworth L R
Laboratory of Immunology, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892.
J Immunol. 1990 Oct 15;145(8):2514-9.
We investigated potential mechanisms by which lymphocytes infiltrating rheumatoid synovium become immunosuppressed. In 20 of 22 synovial fluids and 12 of 13 synovial tissue culture supernatants, no IL-1 bioactivity could be detected in the thymocyte proliferation assay. These same preparations could, however, support proliferation of fibroblast monolayers, consistent with the presence of IL-1 and/or other fibroblast growth factors. Addition of either rheumatoid synovial fluids or synovial culture supernatants to exogenous IL-1 in the IL-1 bioassay caused marked inhibition of the assay indicative of an IL-1 inhibitor. This inhibition of IL-1 could be reversed by treating the effusions or supernatants with a neutralizing antibody to transforming growth factor-beta (TGF-beta). Furthermore, monocyte-macrophages isolated from rheumatoid synovial fluid constitutively released both latent and active TGF-beta in culture at levels sufficient to completely block the biologic activity of 100 U/ml IL-1. The production of substantial levels of TGF-beta by synovial macrophages, as well as the apparent ability of these inflammatory macrophages to activate latent TGF-beta, implicates TGF-beta not only as an important inhibitor of IL-1-induced lymphocyte proliferation, but also as a key cytokine in promoting synovial fibroblast hyperplasia and pathology.
我们研究了浸润类风湿性滑膜的淋巴细胞发生免疫抑制的潜在机制。在22份滑膜液中的20份以及13份滑膜组织培养上清液中的12份中，在胸腺细胞增殖试验中未检测到IL-1生物活性。然而，这些相同的制剂能够支持成纤维细胞单层的增殖，这与IL-1和/或其他成纤维细胞生长因子的存在一致。在IL-1生物测定中，向外源性IL-1中添加类风湿性滑膜液或滑膜培养上清液会导致该测定受到明显抑制，这表明存在IL-1抑制剂。用转化生长因子-β（TGF-β）的中和抗体处理积液或上清液可逆转这种对IL-1的抑制作用。此外，从类风湿性滑膜液中分离出的单核细胞-巨噬细胞在培养中持续释放潜伏性和活性TGF-β，其水平足以完全阻断100 U/ml IL-1的生物活性。滑膜巨噬细胞产生大量的TGF-β，以及这些炎性巨噬细胞激活潜伏性TGF-β的明显能力，这表明TGF-β不仅是IL-1诱导的淋巴细胞增殖的重要抑制剂，而且是促进滑膜成纤维细胞增生和病变的关键细胞因子。
