Transforming growth factor-β1 regulates macrophage migration via RhoA
Transforming growth factor-β1 regulates macrophage migration via RhoA
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DOI：
10.1182/blood-2005-10-009191
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发表时间：
2006-09-15
期刊：
影响因子：
20.3
通讯作者：
Park, Jae-Bong
中科院分区：
文献类型：
--
作者：
Kim, Jun-Sub;Kim, Jae-Gyu;Park, Jae-Bong
短暂的转化生长因子(TGF)- β 1刺激了巨噬细胞的迁移，而长期暴露则减少了巨噬细胞的迁移。tgf - β 1刺激的细胞迁移被10 μ g/mL的Tat-C3外泌酶明显抑制。tgf - β 1在初始阶段增加巨噬细胞炎症蛋白(MIP)-1 α的mRNA和蛋白水平，10 μ g/mL Tat-C3和显性阴性(DN)-RhoA （N19RhoA）也能抑制这些作用。环己亚胺、放线菌素D和抗MIP-1 α和单核细胞化学引诱蛋白-1 （MCP-1）的抗体消除了tgf - β 1对细胞迁移的刺激。这些发现表明，这些细胞的迁移是通过RhoA介导的趋化因子如MIP-1 α和MCP-1的表达直接或间接调节的，以响应tgf - β 1。tgf - β 1在初始阶段激活RhoA，随后使其失活，这表明RhoA的失活可能是后期响应tgf - β 1的细胞迁移减少的原因。因此，我们试图阐明tgf - β 1使RhoA失活的分子机制。首先，tgf - β 1通过蛋白激酶A磷酸化RhoA，导致RhoA失活。其次，野生型p190Rho GTPase激活蛋白（p190RhoGAP）减少，DN-p190RhoGAP逆转了tgf - β诱导的细胞迁移减少，提示其通过p190RhoGAP灭活RhoA。
Brief treatment with transforming growth factor (TGF)-beta 1 stimulated the migration of macrophages, whereas long-term exposure decreased their migration. Cell migration stimulated by TGF-beta 1 was markedly inhibited by 10 mu g/mL Tat-C3 exoenzyme. TGF-beta 1 increased mRNA and protein levels of macrophage inflammatory protein (MIP)-1 alpha in the initial period, and these effects also were inhibited by 10 mu g/mL Tat-C3 and a dominant-negative (DN)-RhoA (N19RhoA). Cycloheximide, actinomycin D, and antibodies against MIP-1 alpha and monocyte chemoattractant protein-1 (MCP-1) abolished the stimulation of cell migration by TGF-beta 1. These findings suggest that migration of these cells is regulated directly and indirectly via the expression of chemokines such as MIP-1 alpha and MCP-1 mediated by RhoA in response to TGF-beta 1. TGF-beta 1 activated RhoA in the initial period, and thereafter inactivated them, suggesting that the inactivation of RhoA may be the cause of the reduced cell migration in response to TGF-beta 1 at later times. We therefore attempted to elucidate the molecular mechanism of the inactivation of RhoA by TGF-beta 1. First, TGF-beta 1 phosphorylated RhoA via protein kinase A, leading to inactivation of RhoA. Second, wild-type p190 Rho GTPase activating protein (p190RhoGAP) reduced and DN-p190RhoGAP reversed the reduction of cell migration induced by TGF-beta, suggesting that it inactivated RhoA via p190 Rho GAP.