Autoantibody against caspase-3, an executioner of apoptosis, in patients with systemic sclerosis

Okazaki, Satoru; Ogawa, Fumihide; Iwata, Y.; Hara, Toshihide; Muroi, Eiji; Komura, Kazuhiro; Takenaka, Motoi; Shimizu, Kazuhiro; Hasegawa, Minoru; Fujimoto, Manabu; Sato, Shinichi

doi:10.1007/s00296-009-1068-3

Cited by 9 publications

(5 citation statements)

References 34 publications

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“…Alveolar epithelium is the main source of MET in lung [46] and is the primary site of lung damage and activation of caspase-3 in SSc-ILD [47]. An increase in caspase-3 activity in SSc [47] suggests that in vivo cleavage of MET can occur.…”

Section: Discussionmentioning

confidence: 99%

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D1398G Variant of MET Is Associated with Impaired Signaling of Hepatocyte Growth Factor in Alveolar Epithelial Cells and Lung Fibroblasts

et al. 2016

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Pulmonary fibrosis represents the terminal stage of a diverse group of lung diseases including scleroderma associated interstitial lung disease. The molecular mechanisms underlying the pathogenesis of lung fibrosis are not well understood and there is a great need for more effective treatment for this lethal disease. We recently discovered a small fragment of hepatocyte growth factor (HGF) receptor MET as a peptide designated “M10,” with strong antifibrotic properties. Furthermore, we showed that aspartic acid at position 1398 of MET is essential for M10 generation. The current study was undertaken to investigate the D1398G variant of MET in which aspartic acid at position 1398 was mutated to glycine resulting in loss of M10. We demonstrate that lung fibroblasts, A549, and primary alveolar epithelial cells (AEC) expressing D1398G MET exhibit reduced auto-phosphorylation on tyrosine residues and reduced activation of Ras and MAPK. HGF treatment of scleroderma lung fibroblasts as well as HGF treatment of TGFβ-treated normal lung fibroblasts transfected with wild type MET is associated with decreased collagen, connective tissue growth factor (CTGF, CCN2) and smooth muscle α-actin (SMA). However, HGF has no such effects in cells transfected with MET D1398G. Cisplatin- and FasL-induced apoptosis is significantly reduced in AEC transfected with MET wild type, but not in AEC transfected with MET D1398G. We conclude that the D1398G variant of MET is associated with compromised phosphorylation and impaired HGF signaling in lung fibroblasts and AEC, two cell types implicated in the pathogenesis of pulmonary fibrosis associated with scleroderma. Ongoing studies will explore the frequency of this variant and its relationship to pulmonary outcomes in scleroderma patients.

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Section: Discussionmentioning

confidence: 99%

“…An increase in caspase-3 activity in SSc [47] suggests that in vivo cleavage of MET can occur. Indeed, immunofluorescent studies using antibodies that differentially recognize MET expressing or not expressing the terminal 10 amino acids (TRPASFWETS) support the notion that such cleavage can indeed occur in vivo .…”

Section: Discussionmentioning

confidence: 99%

D1398G Variant of MET Is Associated with Impaired Signaling of Hepatocyte Growth Factor in Alveolar Epithelial Cells and Lung Fibroblasts

et al. 2016

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“…Caspase-3 which is considered to be a key executor of apoptosis has been shown to be involved in T cell activation and homeostasis. Antibodies against caspase-3 were generated in SSc patients and were shown to be related to severity of pulmonary fibrosis, vascular damage and inflammation [39]. In SSc patients with pulmonary arterial hypertension, the detection of anti-fibroblast antibodies in their serum has shown to activate fibroblasts and promote collagen synthesis, reflecting the direct effect to the remodelling process [40,41].…”

Section: Autoantibodiesmentioning

confidence: 99%

Cytokines in the immunopathology of systemic sclerosis

Raja

Denton²

2015

Semin Immunopathol

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Cytokines and growth factors are key regulators of immune activation, vascular alteration and excessive production of extracellular matrix which are hallmark events in the pathogenesis of systemic sclerosis (SSc). They modulate cell-cell and cell-matrix interactions. In particular, cytokines play a central role in the immunopathogenesis of SSc on the basis of molecular pathways which are complex and not completely understood. The majority of cytokines that may be involved in SSc pathogenesis have effect upon or are derived from cells of the immune system, including both the innate and adaptive compartments. Novel therapies that block key mediators that drive the fibrotic response are being developed and appear as potential therapeutic tools in the treatment of SSc, highlighting the importance for an effective therapy targeted towards the molecular and cellular pathways. This article reviews cytokine biology in that context, with particular emphasis on immunopathology of the disease, therapeutic targeting and the way that current or emerging treatments for SSc might impact on cytokine biology.

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“…Moreover, it was demonstrated that autoantibody response to survivin is related to a more benign (nonerosive) course of RA. We recently found that serum levels of autoantibodies against caspase-3 are elevated in patients with SSc 17 . In addition, this autoantibody inhibits caspase-3 enzymatic activity and is related to the severity of pulmonary fibrosis, vascular damage, and inflammation.…”

mentioning

confidence: 99%