CHRONIC INFLAMMATION AND IMMUNOMODULATION OF CONNECTIVE TISSUE METABOLISM

单核细胞的募集和激活是细胞增殖的核心。 慢性炎症的发生、持续和消退 病变 在这个实验室的调查继续表征 白细胞对炎症刺激的趋化性机制。 转化生长因子β（TGF-β）由 血小板、淋巴细胞和单核细胞是一种非常有效的 来自单核细胞和中性粒细胞的化学引诱物， 浓度的 这种水平的活性可能使TGF-β 已知对白细胞最有效的趋化物质。 在 更高的浓度，TGF β激活单核细胞， 多肽生长因子 TGF-β诱导增加 白细胞介素1 β转录和翻译与肿瘤 坏死因子与TGF-β诱导 纤维化和血管生成。 虽然TGF-β可以促进 通过这种机制，TGF-β也起作用， 一种极其活跃的免疫抑制剂 在飞摩尔 TGF-β抑制IL-1依赖性T淋巴细胞 增殖 TGF-β的抑制作用发生在 生长因子-受体相互作用，不抑制信号 导致IL 2或IL 2受体转录的转导，或 表情 因此，TGF-β选择性下调 淋巴细胞有丝分裂，但似乎不抑制 淋巴因子产生 这种免疫抑制机制 作用将TGF-β与环孢菌素A（CsA），一种真菌 特异性抑制T淋巴细胞增殖的代谢物 和淋巴因子合成。 在最近完成的一项随机 双盲临床试验，CsA的免疫抑制活性 已经发现在治疗以下疾病中具有治疗益处 类风湿关节炎 TGF-β逆转 糜烂性多关节炎正在实验动物中进行研究 模型

Mononuclear cell recruitment and activation are central to the initiation, perpetuation and resolution of chronic inflammatory lesions. Investigations in this laboratory continue to characterize mechanisms of leukocyte chemotaxis to inflammatory stimuli. Transforming growth factor beta (TGF-beta) produced by platelets, lymphocytes and monocytes is an extremely potent chemoattractant from monocytes and neutrophils at femtomolar concentrations. This level of activity may make TGF-beta the most potent known chemotactic substance for leukocytes. At higher concentrations, TGF beta activates monocytes to elaborate polypeptide growth factors. TGF-beta induces increased transcription and translation of interleukin 1 beta and tumor necrosis factor consistent with the ability of TGF-beta to induce fibrosis and angiogenesis in vivo. While TGF-beta may promote wound healing by such a mechanism, TGF-beta also functions as an extremely active immunosuppressive agent. At femtomolar concentrations, TGF-beta inhibits IL1-dependent T lymphocyte proliferation. The inhibitory effect of TGF-beta occurs distal to the growth factor-receptor interaction and does not inhibit signal transduction leading to IL2 or IL2 receptor transcription or expression. Thus, TGF-beta selectively down-regulates lymphocyte mitogenesis, but does not appear to inhibit lymphokine production. This immunosuppressive mechanism of action distinguishes TGF-beta from cyclosporin A (CsA), a fungal metabolite which specifically inhibits T lymphocyte proliferation and lymphokine synthesis. In a recently completed randomized double-blind clinical trial, the immunosuppressive activity of CsA has been found to be of therapeutic benefit in the treatment of rheumatoid arthritis. The efficacy of TGF-beta in reversing erosive polyarthritis is under study in experimental animal models.