Spontaneously increased production of nitric oxide and aberrant expression of the inducible nitric oxide synthase in vivo in the transforming growth factor beta 1 null mouse.

Vodovotz, Yoram; Geiser, Andrew G.; Chesler, Louis; Letterio, John J.; Campbell, Andrew; Lucia, M. Scott; Sporn, Michael B.; Roberts, Anita B.

doi:10.1084/jem.183.5.2337

Cited by 104 publications

(54 citation statements)

References 34 publications

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“…Also contributing to the milieu of inflammatory mediators, iNOS gene expression was elevated, most dramatically in the hearts of the null mice (Fig. 1C) and was reflected in the circulation by increased levels of nitrite and nitrate, decomposition products of NO, in the plasma (7,8). This dysregulation of proinflammatory cytokine and iNOS gene expression in the absence of TGF-␤1 likely drives the pathology observed in the TGF-␤1 null mice.…”

Section: Inflammatory Phenotype Of Tgf-␤1 Null Micementioning

confidence: 98%

“…The shared, albeit less severe, pathophysiology in mice lacking a functional TGF-␤R (TGF-␤RII dominant negative) (3)(4)(5) or the TGF-␤ transcription factor Smad3 (6) highlights the essential function of TGF-␤. In the TGF-␤1 null mouse, the infiltration of mononuclear cells into vital organs is accompanied by the overexpression of IFN-␥ and inducible NO synthase (iNOS) 2 and the resulting toxic levels of NO contribute to the lethal phenotype of the TGF-␤1 null mice (7,8). Key to the regulation of inflammation and the expression of iNOS and other proinflammatory mediators is the activation of NF-B, a critical transcription factor involved in the activation of a large number of target genes (9).…”

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confidence: 99%

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Aberrant Toll Receptor Expression and Endotoxin Hypersensitivity in Mice Lacking a Functional TGF-β1 Signaling Pathway

McCartney-Francis

Jin

Wahl

2004

The Journal of Immunology

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TGF-β1 plays a central role in maintaining normal immune function and deficiency of this potent immunosuppressive molecule is linked to uncontrolled inflammation, cachexia, and multiorgan failure as seen in the TGF-β1 null mouse. Infiltration of inflammatory cells into vital organs of the null mouse is accompanied by increased gene expression of inflammatory cytokines, including TNF-α and IL-1β, as well as inducible NO synthase, each regulated by NF-κB. Treatment with the proteasome inhibitor MG132 to prevent NF-κB activation dramatically reduced NO production and expression of inflammatory cytokines. This inflammatory phenotype with NF-κB activation in the TGF-β1 null mouse, in the absence of any identifiable pathogen, suggested activation of innate immune responses. Because Toll-like receptors (TLR) are essential in the activation of innate immunity, we examined inflamed tissue from TGF-β1 null and wild-type mice for expression of TLR4, the receptor that interacts with bacterial cell wall LPS to initiate an NF-κB-dependent signaling pathway, leading to gene transcription of inflammatory mediators. Increased TLR4 mRNA expression observed in TGF-β1 null mice as well as in mice lacking the TGF-β transcription factor Smad3 was associated with LPS hyperresponsiveness leading to increased expression of inflammatory cytokines and NO and endotoxemia. Furthermore, mice lacking both TGF-β1 and a functional TLR4 were resistant to endotoxin shock. Constitutive and/or environmental activation of TLR4 and downstream elements, in the absence of TGF-β suppression, may impact on innate and adaptive immunity and contribute to massive uncontrolled inflammation.

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Section: Inflammatory Phenotype Of Tgf-␤1 Null Micementioning

confidence: 98%

mentioning

confidence: 99%

Aberrant Toll Receptor Expression and Endotoxin Hypersensitivity in Mice Lacking a Functional TGF-β1 Signaling Pathway

McCartney-Francis

Jin

Wahl

2004

The Journal of Immunology

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“…In fact, studies involving mouse models in which TGF-␤ was inactivated through disruption of the gene show an excessive inflammatory response (36), an increased expression of MHC II genes (37), and an increased production of NO (38). In addition, the inflammatory process in TGF-␤1 knockout mice seems to be closely associated with the development of autoimmunity, as shown by the development of a massive mononuclear cell infiltration in multiple tissues, including lungs, heart, and salivary glands (36 -38).…”

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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“…Whereas Toll-like receptors (TLRs), which recognize signature structures of various pathogens, induce inflammation and subsequently activate the adaptive immune responses, TGF␤ generally plays an anti-inflammatory and immunosuppressive role (Letterio and Roberts 1997;Aderem and Ulevitch 2000). Many important target genes of proinflammatory stimuli contain binding sites for both NF-B and Smads in their promoters, which can be activated or repressed by the Toll pathway and the TGF␤ pathway, respectively (Geiser et al 1993;Vodovotz et al 1996). An additional means through which antagonism between these pathways is mediated is through inhibitory Smads.…”

Section: Interplay Of Toll Pathway and Tgf␤/bmp Pathwaysmentioning

confidence: 99%

Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis

Xiao¹,

Shim²,

Klüppel³

et al. 2003

Genes Dev.

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Bone morphogenetic proteins (Bmps) are members of the transforming growth factor ␤ (TGF␤) superfamily that play critical roles during mouse embryogenesis. Signaling by Bmp receptors is mediated mainly by Smad proteins. In this study, we show that a targeted null mutation of Ecsit, encoding a signaling intermediate of the Toll pathway, leads to reduced cell proliferation, altered epiblast patterning, impairment of mesoderm formation, and embryonic lethality at embryonic day 7.5 (E7.5), phenotypes that mimic the Bmp receptor type1a ( The transforming growth factor ␤ (TGF␤) superfamily comprises a large number of secreted polypeptide factors, with >30 members in mammals and about a dozen in worms and flies. TGF␤s control numerous cellular functions and regulate many developmental and homeostatic processes. However, a simple scheme lies at the core of all TGF␤ signaling pathways. The receptor for TGF␤ is a complex of two distinct transmembrane proteins, known as type I and type II receptors, with serine/threonine kinase activity within their cytoplasmic domains. Ligand binding to the type II receptor induces the association, phosphorylation, and activation of the type I receptor. The activated type I receptor then signals through the Smad family of signal transducers. Smad proteins can be divided into three classes: receptor-regulated Smads or R-Smads (Smad1, 2, 3, 5, 8); co-Smad (Smad4); and inhibitory Smads or I-Smads (Smad6 and 7). After stimulation, R-Smads are phosphorylated by type I receptors, detach from the receptor complex, associate with Smad4, and accumulate in the nucleus, where they regulate gene expression by interacting with various cofactors. Smad access to target genes and the recruitment of transcriptional coactivators or corepressors to these genes depend on cell-type-specific cofactors. Although many Smad cofactors have been identified for the TGF␤ pathways, very few are known for the Bmp pathways (Wrana 2000;Shi and Massague 2003).Genetic evidence has shown that Bmp4 plays pivotal roles in the gastrulation of mouse embryo, a process that lays down the future body plan (Lu et al. 2001). Bmp4 regulates the proliferation, survival, and patterning of the epiblast; the induction of primordial germ cell precursors; and formation of the mesoderm (Mishina et al. 1995;Winnier et al. 1995;Lawson et al. 1999). Bmp4 signals through Bmpr1a, a type I Bmp receptor, to induce the up-regulation of target genes including Tlx2, a homeobox gene that is a critical effector of Bmp signaling

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Spontaneously increased production of nitric oxide and aberrant expression of the inducible nitric oxide synthase in vivo in the transforming growth factor beta 1 null mouse.

Cited by 104 publications

References 34 publications

Aberrant Toll Receptor Expression and Endotoxin Hypersensitivity in Mice Lacking a Functional TGF-β1 Signaling Pathway

Aberrant Toll Receptor Expression and Endotoxin Hypersensitivity in Mice Lacking a Functional TGF-β1 Signaling Pathway

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

Ecsit is required for Bmp signaling and mesoderm formation during mouse embryogenesis

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