Secretion and binding of transforming growth factor β by scleroderma and normal dermal fibroblasts

Needleman, Barbara White; Choi, Jung Min; Burrows‐Mezu, Alicia; Fontana, Joseph A.

doi:10.1002/art.1780330507

Cited by 59 publications

(35 citation statements)

References 40 publications

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“…This cytokine, able to stimulate fibroblasts to produce matrix proteins in vitro, is not involved in our models and seems not to be involved human SSc. Although the data regarding the presence of this cytokine in the skin of SSc patients are contradictory (43,44), it has been clearly shown that fibroblasts from patients with SSc do not secrete more TGF-␤ than normal cells (45). Thus, we believe that we have created a more representative model of human SSc than the bleomycin model.…”

Section: Discussionmentioning

confidence: 94%

Selective Oxidation of DNA Topoisomerase 1 Induces Systemic Sclerosis in the Mouse

Servettaz¹,

Goulvestre²,

Kavian³

et al. 2009

The Journal of Immunology

179

184

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Systemic sclerosis (SSc) is a connective tissue disorder of great clinical heterogeneity. Its pathophysiology remains unclear. Our aim was to evaluate the relative roles of reactive oxygen species (ROS) and of the immune system using an original model of SSc. BALB/c and immunodeficient BALB/c SCID mice were injected s.c. with prooxidative agents (hydroxyl radicals, hypochlorous acid, peroxynitrites, superoxide anions), bleomycin, or PBS everyday for 6 wk. Skin and lung fibrosis were assessed by histological and biochemical methods. Autoantibodies were detected by ELISA. The effects of mouse sera on H 2 O 2 production by endothelial cells and on fibroblast proliferation, and serum concentrations in advanced oxidation protein products (AOPP) were compared with sera from patients with limited or diffuse SSc. We observed that s.c. peroxynitrites induced skin fibrosis and serum anti-CENP-B Abs that characterize limited SSc, whereas hypochlorite or hydroxyl radicals induced cutaneous and lung fibrosis and anti-DNA topoisomerase 1 autoantibodies that characterize human diffuse SSc. Sera from hypochlorite-or hydroxyl radical-treated mice and of patients with diffuse SSc contained high levels of AOPP that triggered endothelial production of H 2 O 2 and fibroblast hyperproliferation. Oxidized topoisomerase 1 recapitulated the effects of whole serum AOPP. SCID mice developed an attenuated form of SSc, demonstrating the synergistic role of the immune system with AOPP in disease propagation. We demonstrate a direct role for ROS in SSc and show that the nature of the ROS dictates the form of SSc. Moreover, this demonstration is the first that shows the specific oxidation of an autoantigen directly participates in the pathogenesis of an autoimmune disease. The Journal of Immunology, 2009, 182: 5855-5864. S ystemic sclerosis (SSc)4 is a connective tissue disorder of unknown etiology characterized by vascular hyperreactivity, fibrosis of skin and visceral organs, and immunological alterations, including a distinct pattern of autoantibodies in the sera (1). The mechanisms that determine the clinical manifestations of the disease remain unclear (2). Several reports have suggested that reactive oxygen species (ROS) are involved in the pathogenesis of SSc (3-9). Indeed, skin fibroblasts from SSc patients spontaneously produce large amounts of ROS that trigger collagen synthesis (7, 10). In addition, autoantibodies found in SSc patients against the platelet-derived growth factor receptor expressed on fibroblasts also induce the production of ROS (11). Recently, we have demonstrated that sera from patients with SSc could induce not only the production of ROS by endothelial cells but also the hyperproliferation of fibroblasts (6).However, no direct proof for the involvement of oxidative stress in SSc pathogenesis has been brought forth to date. Moreover, the origin and nature of the oxidative stress remain to be elucidated. Environmental factors, and in particular silica dust, may be involved, which generate hydroxyl radicals (OH⅐) (12...

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Section: Discussionmentioning

confidence: 94%

Selective Oxidation of DNA Topoisomerase 1 Induces Systemic Sclerosis in the Mouse

Servettaz¹,

Goulvestre²,

Kavian³

et al. 2009

The Journal of Immunology

179

184

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“…Regarding scleroderma, it was reported that scleroderma fibroblasts of the involved area did not secrete increased levels of TGF-β1 (16,32). The mechanism of tissue fibrosis in such diseases remains to be clarified.…”

Section: Discussionmentioning

confidence: 99%

Impaired Smad7-Smurf–mediated negative regulation of TGF-β signaling in scleroderma fibroblasts

Asano¹,

Ihn²,

Yamane³

et al. 2004

J. Clin. Invest.

184

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“…Upregulation of T␤R expression would result in the deposition of ECM components, which are the chief pathologic features of fibrotic disorders. With respect to SSc, in which progressive fibrosis in the skin is the major cause of the disease, it was reported that scleroderma fibroblasts in the involved area secrete similar levels of TGF-␤1 to normal fibroblasts (22,51). The mechanism of tissue fibrosis in such diseases remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Antagonistic Effects of TNF-α on TGF-β Signaling Through Down-Regulation of TGF-β Receptor Type II in Human Dermal Fibroblasts

Yamane

Ihn

Asano

et al. 2003

The Journal of Immunology

103

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Transforming growth factor-β stimulates the production of the extracellular matrix, whereas TNF-α has antifibrotic activity. Understanding the molecular mechanism underlying the antagonistic activities of TNF-α against TGF-β is critical in the context of tissue repair and maintenance of tissue homeostasis. In the present study, we demonstrated a novel mechanism by which TNF-α blocks TGF-β-induced gene and signaling pathways in human dermal fibroblasts. We showed that TNF-α prevents TGF-β-induced gene trans activation, such as α2(I) collagen or tissue inhibitor of metalloproteinases 1, and TGF-β signaling pathways, such as Smad3, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases, without inducing levels of inhibitory Smad7 in human dermal fibroblasts. TNF-α down-regulates the expression of type II TGF-β receptor (TβRII) proteins, but not type I TGF-β receptor (TβRI), in human dermal fibroblasts. However, neither TβRII mRNA nor TβRII promoter activity was decreased by TNF-α. TNF-α-mediated decrease of TβRII protein expression was not inhibited by the treatment of fibroblasts with either a selective inhibitor of I-κB-α phosphorylation, BAY 11-7082, or a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, PD98059. Calpain inhibitor I (ALLN), a protease inhibitor, inhibits TNF-α-mediated down-regulation of TβRII. We found that TNF-α triggered down-regulation of TβRII, leading to desensitization of human dermal fibroblasts toward TGF-β. Furthermore, these events seemed to cause a dramatic down-regulation of α2(I) collagen and tissue inhibitor of metalloproteinases 1 in systemic sclerosis fibroblasts. These results indicated that TNF-α impaired the response of the cells to TGF-β by regulating the turnover of TβRII.

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Secretion and binding of transforming growth factor β by scleroderma and normal dermal fibroblasts

Cited by 59 publications

References 40 publications

Selective Oxidation of DNA Topoisomerase 1 Induces Systemic Sclerosis in the Mouse

Selective Oxidation of DNA Topoisomerase 1 Induces Systemic Sclerosis in the Mouse

Impaired Smad7-Smurf–mediated negative regulation of TGF-β signaling in scleroderma fibroblasts

Antagonistic Effects of TNF-α on TGF-β Signaling Through Down-Regulation of TGF-β Receptor Type II in Human Dermal Fibroblasts

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