NORMAL AND PATHOLOGIC MECHANISMS OF INFLAMMATION AND REPAIR

转化生长因子β(TGF-β)，在血管内分泌 炎症部位或局部注射，诱导白细胞边际， 趋化性和蓄积性。除了其强大的直接性 趋化活性，转化生长因子-β通过促进这种白细胞反应 影响细胞表面整合素的表达。在皮摩尔 浓度，转化生长因子-β可增加两种细胞的稳态mRNA水平 细胞表面有α5、α3和β1分子。在功能上， 转化生长因子-β以剂量和时间依赖的方式促进单核细胞 黏附于IV型胶原、层粘连蛋白和纤维连接蛋白。转化生长因子-β也 触发IV型转录和转录后调控 胶原酶。因此，转化生长因子-β可能在早期阶段发挥关键作用。 通过其介导单核细胞的能力进行炎症和修复 细胞外基质的黏附、趋化和酶消化， 而在慢性皮损中，过量的转化生长因子-β可能有助于持续性 白细胞积聚。因此，在探索潜在的拮抗者时 对于转化生长因子-β，我们已经确定Th2衍生的细胞因子IL-4是一种 转化生长因子-β刺激单核细胞功能的内源性抑制物包括 粘连和胶原酶的产生。有趣的是，转化生长因子-β刺激 单核细胞表达IL-4受体mRNA和蛋白水平升高， 增强他们对IL-4抗炎作用的敏感性。 在另一项研究中，IL-4被证明同时抑制转化生长因子-β和IL-4。 1转化生长因子β诱导的β基因表达。对IL-1β的抑制作用 IL-4是在转化生长因子-β与其受体相互作用后产生的 信号传递，并在转录水平上受到调控。重合 在抑制IL-1β的同时，IL-4增强转化生长因子-β诱导的IL-1 受体拮抗剂(IL-1ra)的产生，扩大其抗炎作用 潜力。因此，这些数据表明IL-4拮抗 转化生长因子-β对未成熟单核细胞的炎症作用，但有效 与转化生长因子-β共同失活介导免疫抑制 刺激单核/巨噬细胞，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.