NORMAL AND PATHOLOGIC MECHANISMS OF INFLAMMATION AND REPAIR

转化生长因子β（TGF-β），分泌于 炎症部位或局部注射，诱导白细胞边集， 趋化性和积累。 除了其强大的直接 趋化活性，TGF-β通过以下方式促进这种白细胞反应： 影响细胞表面整合素表达。 皮摩尔 浓度，TGF-β增加稳态mRNA水平为两个 α 5、α 3和β 1分子。 在功能上， TGF-β以剂量和时间依赖性方式促进单核细胞 与IV型胶原、层粘连蛋白和纤连蛋白的粘附。 TGF-β还 触发IV型转录和转录后调节 胶原酶 因此，TGF-β可能在早期阶段发挥关键作用， 炎症和修复的能力，通过其调解单核细胞 细胞外基质的粘附、趋化性和酶消化， 而在慢性病变中，过量的TGF-β可能有助于持续性的 白细胞积聚。 因此，在探索潜在的拮抗剂时， 我们已经鉴定出Th2衍生的细胞因子IL-4，作为TGF-β的一种抑制因子。 TGF-β刺激的单核细胞功能的内源性抑制剂，包括 粘附和胶原酶产生。 有趣的是，TGF-β刺激的 单核细胞表达升高水平的IL-4受体mRNA和蛋白， 增加了它们对IL-4抗炎作用的敏感性。 在另外的研究中，IL-4显示出抑制TGF-β和IL-4。 TGF-β诱导1 β基因表达。 抑制IL-1 β IL-4发生在TGF-β与其受体相互作用之后， 信号传导，并在转录水平上进行调节。 重合 在抑制IL-1 β的情况下，IL-4增强TGF-β诱导的IL-1 受体拮抗剂（IL-1ra）的生产，扩大其抗炎 潜力 因此，这些数据表明，IL-4拮抗 TGF-β对未成熟单核细胞的炎症作用，但 与TGF-β一起通过灭活 刺激单核细胞/巨噬细胞和诱导IL-1ra。

Transforming growth factor beta (TGF-beta), secreted within an inflammatory site or injected locally, induces leukocyte margination, chemotaxis, and accumulation. In addition to its potent direct chemotactic activity, TGF-beta promotes this leukocyte response by influencing cell surface integrin expression. At picomolar concentrations, TGF-beta increases steady-state mRNA levels for both the alpha5, alpha3, and beta1 molecules on the cell surface. Functionally, TGF-beta promotes, in a dose- and time-dependent fashion, monocyte adhesion to type IV collagen, laminin, and fibronectin. TGF-beta also triggers transcriptional and posttranscriptional regulation of type IV collagenase. Thus, TGF-beta may play a pivotal role in the early phases of inflammation and repair through its ability to mediate monocyte adhesion, chemotaxis, and enzymatic digestion of extracellular matrix, whereas in chronic lesions, excess TGF-beta may contribute to persistent leukocyte accumulation. Therefore, in exploring potential antagonists of TGF-beta, we have identified the Th2-derived cytokine, IL-4, as an endogenous inhibitor of TGF-beta-stimulated monocyte functions including adhesion and collagenase production. Interestingly, TGF-beta-stimulated monocytes expressed elevated levels of IL-4 receptor mRNA and protein, augmenting their susceptibility to the anti-inflammatory effects of IL-4. In additional studies, IL-4 was shown to suppress both TGF-beta and IL- 1beta gene expression induced by TGF-beta. Suppression of IL-1beta by IL-4 occurred subsequent to TGF-beta interaction with its receptor and signalling, and was regulated at the transcriptional level. Coincident with the suppression of IL-1beta, IL-4 augmented TGF-beta-induced IL-1 receptor antagonist (IL-1ra) production, expanding its anti-inflammatory potential. Thus, these data indicate that IL-4 antagonizes the inflammatory actions of TGF-beta on immature monocytes, but works together with TGF-beta to mediate immune suppression by deactivating stimulated monocyte/macrophages and by inducing IL-1ra.