Transforming growth factor-β1 regulates macrophage migration via RhoA

• Published in: Blood Vol. 108; no. 6; pp. 1821 - 1829
• Main Authors: Kim, Jun-Sub, Kim, Jae-Gyu, Moon, Mi-Young, Jeon, Chan-Young, Won, Ha-Young, Kim, Hee-Jun, Jeon, Yee-Jin, Seo, Ji-Yeon, Kim, Jong-Il, Kim, Jaebong, Lee, Jae-Yong, Kim, Pyeung-Hyeun, Park, Jae-Bong
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.09.2006; The Americain Society of Hematology
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Immunobiology; Monocytes, macrophages; Myeloid cells: ontogeny, maturation, markers, receptors; Animal model; Rodentia; Chemokine; Signal transduction; Vertebrata; Regulation(control); Mammalia; Treatment; Mouse; Transforming growth factor β1; Rho GTPase; Cell migration; Macrophage
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2005-10-009191

Brief treatment with transforming growth factor (TGF)–β1 stimulated the migration of macrophages, whereas long-term exposure decreased their migration. Cell migration stimulated by TGF-β1 was markedly inhibited by 10 μg/mL Tat-C3 exoenzyme. TGF-β1 increased mRNA and protein levels of macrophage inflammatory protein (MIP)–1α in the initial period, and these effects also were inhibited by 10 μg/mL Tat-C3 and a dominant-negative (DN)–RhoA (N19RhoA). Cycloheximide, actinomycin D, and antibodies against MIP-1α and monocyte chemoattractant protein-1 (MCP-1) abolished the stimulation of cell migration by TGF-β1. These findings suggest that migration of these cells is regulated directly and indirectly via the expression of chemokines such as MIP-1α and MCP-1 mediated by RhoA in response to TGF-β1. TGF-β1 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-β1 at later times. We therefore attempted to elucidate the molecular mechanism of the inactivation of RhoA by TGF-β1. First, TGF-β1 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-β, suggesting that it inactivated RhoA via p190 Rho GAP.