Transforming growth factor-β1 regulates macrophage migration via RhoA

Abstract

Brief treatment with transforming growth factor (TGF)-␤1 stimulated the migration of macrophages, whereas long-term exposure decreased their migration. Cell migration stimulated by TGF-␤1 was markedly inhibited by 10 g/mL Tat-C3 exoenzyme. TGF-␤1 increased mRNA and protein levels of macrophage inflammatory protein (MIP)-1␣ in the initial period, and these effects also were inhibited by 10 g/mL Tat IntroductionTransforming growth factor (TGF)-␤ regulates diverse cellular functions, including tissue differentiation, cell proliferation, and cell migration. Monocytes/macrophages, in particular, secrete TGF-␤, which in turn stimulates numerous responses: production of a variety of cytokines, including interleukin-1␣ (IL-1␣) and -␤ (IL-1␤), tumor necrosis factor (TNF)-␣, platelet-derived growth factor (PDGF)-BB, and basic fibroblast growth factor (bFGF); recruitment of monocytes to sites of injury or inflammation; phagocytic activity (by up-regulating the expression of cell-surface Fc␥RIII); and the expression of several integrin receptors on monocytes, including leukocyte function-associated antigen-1 (LFA-1: integrin ␣L␤2), ␣3␤1, and ␣5␤1, thereby increasing their cell-cell and cell-matrix interactions. 1 These observation indicate a proinflammatory function for TGF-␤ on monocytes. 2 In contrast to its activating effects on peripheral blood monocytes, TGF-␤ reduces the host response to a variety of inflammatory stimuli and is a potent immunosuppressive, anti-inflammatory, and macrophage deactivating agent. 3 Resting monocytes express high levels of TGF-␤ type 1 and 2 receptors, whereas receptor levels decline as cells mature and are then activated by agents such as lipopolysaccharide (LPS) and interferon-␥ (IFN-␥). 1 The functional complex of TGF-␤1 receptors at the cell surface is composed of 2 type 2 (T␤RII) and 2 type 1 (T␤RI) transmembrane Ser/Thr kinase receptors. 4 Receptor-activated Smads (Rsmads: Smad1, Smad2, Smad3, Smad5, and Smad 8), which are phosphorylated by type 1 receptors, are released from the receptor complex to form a heterotrimeric complex of 2 R-Smads and a common Smad4 (Co-Smad); the complex then translocates to the nucleus, where it regulates transcription. The structurally distinct Smads, Smad6 and Smad7, act as inhibitory Smads (I-Smads) by competing with R-Smads for receptors. 5 The expression of I-Smads is strongly regulated by extracellular signals, and the induction of Smad6 and Smad7 expression by TGF-␤1 reveals an inhibitory feedback mechanism for ligand-induced signaling. 6 In addition to the R-Smad/Co-Smad activation pathway, TGF-␤ can activate the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38MAPK pathways, the last 2 of which are activated via TGF-␤-activated kinase 1 (TAK1). 4 Rho GTPases regulate the actin cytoskeleton, cell polarity, gene expression, microtubule dynamics, and vesicular trafficking. 7 Regulation of the nucleotide-bound state of RhoGTPases, alternative cycling between active GTP-and inactive GDP-bound states, is accomplished ...

The activating effect of IFN-γ on monocytes/macrophages is regulated by the LIF–trophoblast–IL-10 axis via Stat1 inhibition and Stat3 activation

“…71 One of these genes encodes the nuclear repressor protein glucocorticoid receptor DNA binding factor-1 that antagonizes the inhibitory effect of transforming growth factor beta 1 on monocyte migration. 72 In this context, our results suggest that trophoblast cells could favor the movement of monocytes and Mws via a similar mechanism, antagonizing the potential blocking effects of IFN-c on monocyte/Mw motility.…”

IκB Kinase γ/Nuclear Factor-κB-Essential Modulator (IKKγ/NEMO) Facilitates RhoA GTPase Activation, which, in Turn, Activates Rho-associated Kinase (ROCK) to Phosphorylate IKKβ in Response to Transforming Growth Factor (TGF)-β1

“…Recombinant Tat-C3 toxin was purified from Escherichia coli (17). GST-Rho binding domain (RBD) of rhotekin (GST-rhotekin-RBD) beads were prepared from cultured E. coli or obtained from Pierce.…”

“…Furthermore, TGF-␤1 induces the activation of NF-B signaling (3,19,20) leading to cell motility (16,21). Although the relevance of TGF-␤1, Rho GTPases, and NF-B has been reported in a variety of cells, the molecular mechanism of the activation of NF-B by TGF-␤1 via RhoA GTPase activation in macrophages has not been well elucidated (17).…”

Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling

“…The gradient of TGF-β created during osteoclast bone resorption can limit further osteoclast activity. In the short term, low concentrations of active TGF-β can induce macrophage migration via activation of RhoA; however, high concentrations or prolonged exposure of macrophages/monocytes to active TGF-β have been shown to inhibit migration of osteoclast precursors (69). Both high concentrations of and prolonged exposure to TGF-β activate SMAD3-SMAD4 complexes, which in turn activate PKA, resulting in phosphorylation and inactivation of RhoA (69,70).…”

“…In the short term, low concentrations of active TGF-β can induce macrophage migration via activation of RhoA; however, high concentrations or prolonged exposure of macrophages/monocytes to active TGF-β have been shown to inhibit migration of osteoclast precursors (69). Both high concentrations of and prolonged exposure to TGF-β activate SMAD3-SMAD4 complexes, which in turn activate PKA, resulting in phosphorylation and inactivation of RhoA (69,70). Thus, the gradient of TGF-β1 generated at the resorption sites likely prohibits further recruitment of osteoclast precursors, protecting it from further resorption during the reversal phase of bone remodeling.…”