Up regulated expression of tumour necrosis factor   converting enzyme in peripheral monocytes of patients with early systemic sclerosis

Bohgaki, Toshiyuki; Amasaki, Yoshiharu; Nishimura, Noriko; Bohgaki, Miyuki; Yamashita, Yugo; Nishio, Miwako; Ki, Sawada; Jodo, Satoshi; Atsumi, Tatsuya; Koike, Takao

doi:10.1136/ard.2004.030338

Cited by 27 publications

(26 citation statements)

References 46 publications

(22 reference statements)

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“…[7][8][9] In humans, TACE has also been demonstrated to be involved in the pathogenesis of inflammatory and fibrous connective tissue diseases, such as rheumatoid arthritis 13,14 and systemic sclerosis (SSc). 15 Bohgaki et al 15 reported that TACE was overexpressed in peripheral blood monocytes of Representative data are shown. PC: positive control (furin-treated TACETg skin lysates used in Figure 2).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of TNF-α-converting enzyme in fibroblasts augments dermal fibrosis after inflammation

Fukaya

Matsui

Tomaru

et al. 2013

Laboratory Investigation

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TNF-a-converting enzyme (TACE) can cleave transmembrane proteins, such as TNF-a, TNF receptors, and epidermal growth factor receptor (EGFR) ligands, to release the extracellular domains from the cell surface. Recent studies have suggested that overexpression of TACE may be associated with the pathogenesis of inflammation and fibrosis. To determine the roles of TACE in inflammation and fibrosis, TACE transgenic (TACE-Tg) mice, which overexpressed TACE systemically, were generated. As the transgene-derived TACE was expressed as an inactive form, no spontaneous phenotype developed in TACE-Tg mice. However, the transgene-derived TACE could be converted to an active form by furin in vitro and by phorbol myristate acetate (PMA) in vivo. Subcutaneous injection of PMA into mice induced inflammatory cell infiltration 1 day later and subsequent dermal fibrosis 7 days later. Interestingly, the degree of dermal fibrosis at day 7 was significantly higher in TACE-Tg mice than in wild-type mice. Correspondingly, PMA increased the expression of type I collagen in the primary culture of dermal fibroblasts derived from TACE-Tg mice. Furthermore, phosphorylated EGFR was increased in the fibroblasts by the PMA treatment. The collective findings suggest that TACE overexpression and activation in fibroblasts could shed off putative EGFR ligands. Subsequently, the soluble EGFR ligands could bind and activate EGFR on fibroblasts, and then increase the type I collagen expression resulting in induction of dermal fibrosis. These results also suggest that TACE and EGFR on fibroblasts may be novel therapeutic targets of dermal fibrosis, which is induced after diverse inflammatory disorders of the skin. KEYWORDS: EGFR; fibrosis; inflammation; PMA; TACE TNF-a-converting enzyme (TACE), which belongs to a disintegrin and metalloproteinase (ADAM) family, can cleave transmembrane proteins to release the extracellular domains from the cell surface. 1,2 Initially produced as an inactive 120 kDa protein, the N-terminus prodomain is removed by furin at the trans-golgi network, and consequently TACE is converted to an active form of 100 kDa protein. [3][4][5][6] The active form of TACE is transported to the plasma membrane and binds to its substrates on the cell surface. Substrates of TACE include TNF-a, TNF receptors, and epidermal growth factor receptor (EGFR) ligands.When focusing on the role of TNF-a in inflammation, it is considered that TACE contributes to promote inflammation by increasing soluble TNF-a. However, it is also considered that TACE plays a role in the suppression of inflammation by decreasing membrane-type TNF receptors and producing soluble TNF receptors, which can work as decoy receptors. These concepts seem contradictory, but TACE really functions to maintain the physiological homeostasis. The expression of TACE substrates is strictly regulated in a timedependent manner during the inflammation process.On the other hand, it has been demonstrated that rat collagen antibody-induced arthritis and lipopolysaccharide (LPS)-induced acu...

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Section: Discussionmentioning

confidence: 99%

Overexpression of TNF-α-converting enzyme in fibroblasts augments dermal fibrosis after inflammation

Fukaya

Matsui

Tomaru

et al. 2013

Laboratory Investigation

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“…2,3 Several inflammatory changes have been shown including elevated serum interleukin-6 (IL-6) 4,5 and tumor necrosis factor-a (TNF-a). 6,7 C-reactive protein (CRP) has been used for the monitoring of inflammatory change in several kinds of diseases including infective diseases and other inflammatory diseases in clinical practice. Conventional measurements of CRP, however, have provided no useful information for the monitoring of inflammatory change in SSc.…”

Section: Introductionmentioning

confidence: 99%

Serum interleukin‐6 level is reflected in elevated high‐sensitivity C‐reactive protein level in patients with systemic sclerosis

Ohtsuka

2010

The Journal of Dermatology

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Systemic sclerosis (SSc) is a systemic connective tissue disease of unknown etiology which presents immunological, vascular and connective tissue abnormalities. Serum interleukin (IL)-6 has been reported to be elevated in patients with SSc. Clinical and laboratory findings affecting the elevated level of high-sensitivity C-reactive protein (hs-CRP) were studied in patients with SSc. Clinical and laboratory findings also included serum IL-6 level. Thirty-nine SSc patients (male : female = 7:32, age 19-84 years, mean 62.6 years) were studied. hs-CRP was measured with a nephelometric assay. Serum IL-6 level was measured by enzyme-linked immunosorbent assay. The distributions of hs-CRP showed that 18 cases (46.2%) were not elevated (<0.07 mg/dL), but 21 cases (53.8%) were (≥0.07 mg/dL). Alkaline phosphatase and IL-6 in SSc patients with elevated hs-CRP (291 ± 95 U/L, 3.23 ± 2.74 pg/mL) were significantly more elevated than those in not elevated patients (221 ± 75 U/L, 1.53 ± 1.12 pg/mL) (P < 0.02, P < 0.01). The correlation between hs-CRP level and IL-6 level in SSc patients was 0.687 (P < 0.001). In conclusion, elevated serum IL-6 levels are reflected in elevated hs-CRP levels in SSc patients.

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“…Peripheral blood mononuclear cells (PBMCs) of SLE patients show increased Adam17 expression (9). Soluble shedding substrates of ADAM17 have been found in the plasma and urine of lupus mice and SLE patients, and some of these soluble factors are elevated prior to flare (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

Qing¹,

Chinenov²,

Redecha³

et al. 2018

Journal of Clinical Investigation

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Up regulated expression of tumour necrosis factor converting enzyme in peripheral monocytes of patients with early systemic sclerosis

Cited by 27 publications

References 46 publications

Overexpression of TNF-α-converting enzyme in fibroblasts augments dermal fibrosis after inflammation

Overexpression of TNF-α-converting enzyme in fibroblasts augments dermal fibrosis after inflammation

Serum interleukin‐6 level is reflected in elevated high‐sensitivity C‐reactive protein level in patients with systemic sclerosis

iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling

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