Role of apoptosis and transforming growth factor β1 in fibroblast selection and activation in systemic sclerosis

Jelaska, Ante; Korn, Joseph H.

doi:10.1002/1529-0131(200010)43:10<2230::aid-anr10>3.0.co;2-8

Cited by 161 publications

(129 citation statements)

References 44 publications

(45 reference statements)

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“…Untreated cultures showed only occasional ␣-SMA-positive cells. Cultures treated with TGF␤ showed a dramatic increase in ␣-SMA-positive cells (Figure 4), as previously reported (30). TGF␤-induced fibrillin fibers were generally associated with ␣-SMA-positive cells (Figure 4, white arrows).…”

Section: Resultssupporting

confidence: 85%

“…Alternatively, fibrillin matrix might protect myofibroblasts from apoptosis. Jelaska and Korn have shown previously that prolonged treatment with TGF␤ induces myofibroblasts and protects dermal fibroblasts from apoptosis (30). Perhaps fibrillin, alone or through interactions with other matrix proteins, protects myofibroblasts from apoptosis (44)(45)(46).…”

Section: Discussionmentioning

confidence: 98%

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Transforming growth factor β induces fibroblast fibrillin‐1 matrix formation

Kissin¹,

Lemaire²,

Korn³

et al. 2002

Arthritis & Rheumatism

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Objective. Fibrillin, an extracellular matrix protein implicated in dermal fibrosis, is increased in the reticular dermis of systemic sclerosis (SSc) skin. We undertook this study to investigate the hypothesis that transforming growth factor ␤ (TGF␤) or other cytokines regulate fibrillin matrix formation by normal and SSc fibroblasts. We further investigated the mechanism of TGF␤-induced fibrillin fibrillogenesis and its relationship to myofibroblasts.Methods. Fibrillin and fibronectin matrix deposition and ␣-smooth muscle actin expression by fibroblast cultures from normal and SSc skin treated with TGF␤ or other cytokines were analyzed by immunofluorescence. Supernatant and extracellular matrix from normal and SSc fibroblasts treated with or without TGF␤ were evaluated by Western blot and Northern blot for fibrillin protein and messenger RNA (mRNA) expression, respectively.Results. Immunofluorescence demonstrated increased fibrillin matrix formation by normal and scleroderma fibroblasts after TGF␤ treatment. Other cytokines, including tumor necrosis factor ␣, interleukin-1␤ (IL-1␤), IL-4, granulocyte-macrophage colonystimulating factor, and platelet-derived growth factor, did not affect fibrillin fibrillogenesis. Fibrillin matrix formed in proximity to myofibroblasts and independently of up-regulation of fibronectin matrix or cell number. Western blot analysis of extracellular matrix confirmed increased fibrillin after TGF␤ stimulation of normal or scleroderma fibroblasts. However, TGF␤ did not alter the expression of either soluble fibrillin protein or fibrillin mRNA.Conclusion. Our data show that TGF␤ induces fibrillin protein incorporation into the extracellular matrix without affecting fibrillin gene expression or protein synthesis, suggesting that fibrillin matrix assembly is regulated extracellularly. TGF␤ might increase fibrillin matrix by activating myofibroblasts. Such TGF␤-mediated effects could account for the increased fibrillin matrix observed in SSc skin.

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Section: Resultssupporting

confidence: 85%

Section: Discussionmentioning

confidence: 98%

Transforming growth factor β induces fibroblast fibrillin‐1 matrix formation

Kissin¹,

Lemaire²,

Korn³

et al. 2002

Arthritis & Rheumatism

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“…Effects of TGF-β1 on target cells are highly cell-specific and contextual [1]. Despite the recognition that TGF-β1 functions as an anti-apoptotic signal for fibroblasts/myofibroblasts [7,8,32], mechanisms for this effect have not been well defined. TGF-β superfamily ligands signal via heterotetrameric complexes of type II and type I receptors (TβR-II and TβR-I, respectively) leading to activation of SMAD proteins which represent the central mediators of downstream signalling [1].…”

Section: Discussionmentioning

confidence: 99%

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Horowitz

Rogers

Sharma

et al. 2007

Cellular Signalling

224

177

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Transforming growth factor-β (TGF-β) is a prototypical tumour-suppressor cytokine with cytostatic and pro-apoptotic effects on most target cells; however, mechanisms of its pro-survival/antiapoptotic signalling in certain cell types and contexts remain unclear. In human lung fibroblasts, TGF-β1 is known to induce myofibroblast differentiation in association with the delayed activation of focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Here, we demonstrate that FAK and AKT are independently regulated by early activation of SMAD3 and p38 MAPK, respectively. Pharmacologic or genetic approaches that disrupt SMAD3 signalling block TGF-β1-induced activation of FAK, but not AKT; in contrast, disruption of early p38 MAPK signalling abrogates AKT activation, but does not alter FAK activation. TGF-β1 is able to activate AKT in cells expressing mutant FAK or in cells treated with an RGD-containing peptide that interferes with integrin signalling, inhibits FAK activation and induces anoikis (apoptosis induced by loss of adhesion signalling). TGF-β1 protects myofibroblasts from anoikis, in part, by activation of the PI3K-AKT pathway. Thus, TGF-β1 co-ordinately and independently activates the FAK and AKT protein kinase pathways to confer an anoikis-resistant phenotype to myofibroblasts. Activation of these prosurvival/anti-anoikis pathways in myofibroblasts likely contributes to essential roles of TGF-β1 in tissue fibrosis and tumour-promotion.

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“…[18][19][20] OPN-mediated initiation of healing appears to be associated with the upregulation of transforming growth factor b1 (TGFb1), which induces restitution of the intestinal epithelial barrier, decreases apoptosis of fibroblasts, and results in increased matrix deposition. [21][22][23][24] Our previous study using the experimental acute colitis model found a greater susceptibility of OPN À/À mice than wild-type (WT) mice to DSS-induced colitis. 16 Clinical parameters of colitis, such as weight loss, disease activity scores, colon shortening, and spleen enlargement, were significantly greater in OPN À/À mice and accompanied by an exacerbation of intestinal tissue damage.…”

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confidence: 98%

Osteopontin attenuation of dextran sulfate sodium-induced colitis in mice

Silva

Ellen

Sørensen

et al. 2009

Laboratory Investigation

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Osteopontin (OPN) is a matricellular cytokine present in most tissues and body fluids; it is known to modulate immune responses. In previous studies using the dextran sulfate sodium (DSS) acute colitis model, we found exacerbated tissue destruction and reduced repair in OPN-null (À/À) mice compared with wild-type (WT) controls. As OPN is normally present in milk, we hypothesized that administration of OPN may protect the intestines from the adverse effects of experimental colitis. A volume of 20 or 2 mg/ml bovine milk OPN, dissolved in drinking water, was given to mice 24 h before, and during administration of DSS. Clinical parameters of colitis and neutrophil functions were analyzed as previously reported. Orally administered OPN was absorbed and detected in the colon mucosa by immunohistochemistry. The 20 mg/ml OPN-and DSS-treated WT mice showed 37% less weight loss and reduced colon shortening and spleen enlargements than control mice (Po0.05). OPN administration also reduced the disease activity index, improved red blood cell counts, and reduced gut neutrophil activity compared with the DSS-treated WT mice that were not administered OPN (Po0.05). Immunohistochemical detection of F4/80-labelled cells (macrophages) was also less frequent. The level of transforming growth factor b1 (TGF-b1) was increased and the levels of pro-inflammatory mediators decreased in colon tissue samples of OPN-treated mice analyzed by ELISA. The reversal of experimental colitis parameters by exogenous OPN was not as robust in the OPN À/À mice. Administration of prokaryotic-expressed recombinant OPN and bovine serum albumin were ineffective. This study shows that administration of a physiological concentration of milk OPN in drinking water ameliorates the destructive host response in DSS-induced acute colitis.

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Role of apoptosis and transforming growth factor β1 in fibroblast selection and activation in systemic sclerosis

Abstract: Our results show that resistance to apoptosis is an important part of the SSc phenotype. TGFbeta1 may play a role by inducing apoptosis-resistant fibroblast populations, and also by inducing myofibroblasts and by enhancing extracellular matrix synthesis.

Cited by 161 publications

References 44 publications

Transforming growth factor β induces fibroblast fibrillin‐1 matrix formation

Transforming growth factor β induces fibroblast fibrillin‐1 matrix formation

Combinatorial activation of FAK and AKT by transforming growth factor-β1 confers an anoikis-resistant phenotype to myofibroblasts

Osteopontin attenuation of dextran sulfate sodium-induced colitis in mice

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