Transforming Growth Factor-β1 Inhibition of Macrophage Activation Is Mediated via Smad3

Werner, Frank; Jain, Mukesh K.; Feinberg, Mark W.; Sibinga, Nicholas E.S.; Pellacani, Andrea; Wiesel, Philippe; Chin, Michael T.; Topper, James N.; Perrella, Mark A.; Lee, Mu En

doi:10.1074/jbc.m004536200

Cited by 159 publications

(117 citation statements)

References 60 publications

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“…In addition, TGF-␤ inhibits LPS-induced activation of macrophages. This cytokine inhibits LPS-induced iNOS expression (34) or reduces the expression of proinflammatory cytokines during septic shock (35).…”

Section: Discussionmentioning

confidence: 99%

Decorin Reverses the Repressive Effect of Autocrine-Produced TGF-β on Mouse Macrophage Activation

Comalada

Cardó

Xaus

et al. 2003

The Journal of Immunology

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Several cytokines or growth factors induce macrophages to proliferate, become activated, differentiate, or die through apoptosis. Like the major macrophage activator IFN-γ, the extracellular matrix protein decorin inhibits proliferation and protects macrophages from the induction of apoptosis. Decorin enhances the IFN-γ-induced expression of the IAα and IAβ MHC class II genes. Moreover, it increases the IFN-γ- or LPS-induced expression of inducible NO synthase, TNF-α, IL-1β, and IL-6 genes and the secretion of these cytokines. Using a number of extracellular matrix proteins, we found a negative correlation between adhesion and proliferation. However, the effects of decorin on macrophage activation do not seem to be mediated through its effect on adhesion or proliferation. Instead, this proteoglycan abolishes the binding of TGF-β to macrophages, as shown by Scatchard analysis of 125I-labeled TGF-β, which, in the absence of decorin, showed a Kd of 0.11 ± 0.03 nM and ∼5000 receptors/cell. This was confirmed when we treated macrophages with Abs to block the endogenously produced TGF-β, which enhanced macrophage activation in a way similar to decorin. The increase in activation mediated by decorin demonstrates that macrophages are under negative regulation that can be reversed by proteins of the extracellular matrix.

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Section: Discussionmentioning

confidence: 99%

Decorin Reverses the Repressive Effect of Autocrine-Produced TGF-β on Mouse Macrophage Activation

Comalada

Cardó

Xaus

et al. 2003

The Journal of Immunology

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“…Mice that are deficient in TGF-␤1 develop a lethal multiorgan inflammation at 3 wk of age (7). TGF-␤ inhibits the production of proinflammatory cytokines from macrophages and T cells (30,31). Administration of TGF-␤ attenuates autoimmune diseases, including collagen-induced arthritis (32), allergic encephalomyelitis (33), and experimental colitis (34).…”

Section: Discussionmentioning

confidence: 99%

Signaling Mechanism of TGF-β1 in Prevention of Renal Inflammation

Wang¹,

Huang²,

Li³

et al. 2005

Journal of the American Society of Nephrology

230

231

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TGF-␤ has been shown to play a critical role in anti-inflammation; however, the signaling mechanisms of TGF-␤ in anti-inflammatory response remains largely unclear. This study reported that mice that overexpress latent TGF-␤1 on skin are protected against renal inflammation in a model of obstructive kidney disease and investigated the signaling mechanism of TGF-␤1 in inhibition of renal inflammation in vivo and in vitro. Seven days after urinary obstruction, wild-type mice developed severe renal inflammation, including massive T cell and macrophage infiltration and marked upregulation of IL-1␤, TNF-␣, and intercellular adhesion molecule-1 (all P < 0.001). Surprising, renal inflammation was prevented in transgenic mice. This was associated with an increase in latent TGF-␤1 in circulation (a 10-fold increase) and renal tissues (a 2.5-fold increase). Further studies showed that inhibition of renal inflammation in TGF-␤1 transgenic mice was also associated with a marked upregulation of renal Smad7 and IB␣ and a suppression of NF-B activation in the diseased kidney (all P < 0.01). These in vivo findings suggested the importance of TGF-␤-NF-B cross-talk signaling pathway in regulating renal inflammation. This was tested in vitro in a doxycycline-regulated Smad7-expressing renal tubular cell line. Overexpression of Smad7 was able to upregulate IB␣ directly in a time-and dose-dependent manner, thereby inhibiting NF-B activation and NF-B-driven inflammatory response. In conclusion, latent TGF-␤ may have protective roles in renal inflammation. Smad7-mediated inhibition of NF-B activation via the induction of IkB␣ may be the central mechanism by which latent TGF-␤ prevents renal inflammation.

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“…Picomolar TGF-β concentrations stimulate synthesis of a variety of proinflammatory cytokines and chemokines by monocytes (54,55). In contrast to its pro-inflammatory actions in monocytes, TGF-β is known to deactivate macrophages, suppressing MCP-1/CCL2, IL-1β and TNF-α synthesis (56)(57)(58). It should be emphasized that effects of TGF-β on immune cells can be either pro-or anti-inflammatory depending on the cytokine milieu, the tissue origin of the cells, and the experimental context (59).…”

Section: Effects Of Tgf-β On Immune Cellsmentioning

confidence: 99%

The role of transforming growth factor (TGF)-β in the infarcted myocardium

Frangogiannis

2017

J. Thorac. Dis.

117

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The adult mammalian heart has negligible regenerative capacity. Following myocardial infarction, sudden necrosis of cardiomyocytes triggers an intense inflammatory reaction that clears the wound from dead cells and matrix debris, while activating a reparative program. A growing body of evidence suggests that members of the transforming growth factor (TGF)-β family critically regulate the inflammatory and reparative response following infarction. Although all three TGF-β isoforms (TGF-β1, -β2 and -β3) are markedly upregulated in the infarcted myocardium, information on isoform-specific actions is limited.Experimental studies have suggested that TGF-β exerts a wide range of actions on cardiomyocytes, fibroblasts, immune cells, and vascular cells. The findings are often conflicting, reflecting the contextdependence of TGF-β-mediated effects; conclusions are often based exclusively on in vitro studies and on associative evidence. TGF-β has been reported to modulate cardiomyocyte survival responses, promote monocyte recruitment, inhibit macrophage pro-inflammatory gene expression, suppress adhesion molecule synthesis by endothelial cells, promote myofibroblast conversion and extracellular matrix synthesis, and mediate both angiogenic and angiostatic effects. This review manuscript discusses our understanding of the cell biological effects of TGF-β in myocardial infarction. We discuss the relative significance of downstream TGF-β-mediated Smad-dependent and -independent pathways, and the risks and challenges of therapeutic TGF-β targeting. Considering the high significance of TGF-β-mediated actions in vivo, study of cell-specific effects and dissection of downstream signaling pathways are needed in order to design safe and effective therapeutic approaches.

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Transforming Growth Factor-β1 Inhibition of Macrophage Activation Is Mediated via Smad3

Cited by 159 publications

References 60 publications

Decorin Reverses the Repressive Effect of Autocrine-Produced TGF-β on Mouse Macrophage Activation

Decorin Reverses the Repressive Effect of Autocrine-Produced TGF-β on Mouse Macrophage Activation

Signaling Mechanism of TGF-β1 in Prevention of Renal Inflammation

The role of transforming growth factor (TGF)-β in the infarcted myocardium

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