A blocking peptide for transforming growth factor-β1 activation prevents hepatic fibrosis in vivo

Kondou, Hiroki; Mushiake, Sotaro; Etani, Yuri; Miyoshi, Yoko; Michigami, Toshimi; Ozono, Keiichi

doi:10.1016/s0168-8278(03)00377-5

Cited by 94 publications

(82 citation statements)

References 27 publications

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“…We observed, however, that mice receiving LSKL peptide had decreased activation of TGF-β1 consistent with previous reports. 17,19,[30][31][32] Our findings are similar to previous observations in a rat model of diabetes mellitus, where LSKL administration did not alter TSP-1 levels in myocardial extracts. 17 Expression of TGFBRI, TGFBRII, and Smad4 mRNA were significantly lower in mice receiving LSKL.…”

Section: Discussionsupporting

confidence: 90%

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A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

Krishna

Seto

Jose

et al. 2015

ATVB

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This activation was observed to be dependent on the interaction between a specific TSP-1 sequence (lysine-argininephenylalanine-lysine; KRFK) and a conserved sequence (leucine-serine-lysine-leucine [LSKL]) near the amino terminus in the latency-associated peptide.14 The lysine--arginine-phenylalanine-lysine sequence interacts with the © 2014 American Heart Association, Inc.Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.114.304732Objective-Interaction of the activating sequence in thrombospondin-1 (TSP-1) with the conserved sequence (leucine-serinelysine-leucine [LSKL]) in the latency-associated peptide region of latent transforming growth factor (TGF)-β complex is important in regulating TGF-β1 activity. We aimed to assess the effect of blocking peptide LSKL on the progression of pre-established abdominal aortic aneurysm in angiotensin II-infused apolipoprotein E-deficient (ApoE −/− ) mice. Approach and Results-Abdominal aortic aneurysm was established in 3-month-old male ApoE −/− mice with subcutaneous infusion of angiotensin II for 28 days. After this, mice received LSKL peptide or control SLLK (serine-leucine-leucinelysine) peptide (4 mg/kg) via daily intraperitoneal injection for an additional 2 weeks. Administration of LSKL peptide promoted larger suprarenal aortic diameter, as determined by ultrasound and morphometric analysis, and stimulated more severe atherosclerosis within the aortic arch. In addition, mice receiving LSKL peptide exhibited elevated circulating proinflammatory cytokine levels and greater inflammatory cells within the suprarenal aorta compared with controls. Mice receiving LSKL peptide showed low plasma TGF-β1 activity and low levels of aortic tissue phosphorylated to total Smad2/3. Aortic gene expression of TGF-β receptor 1 (TGFBRI) and receptor 2 (TGFBRII), but not TGF-β1 and thrombospondin-1, were lower in mice receiving LSKL peptide than controls. LSKL peptide administration was associated with greater aortic elastin fragmentation and lower expression and activity of the TGF-β1-target gene lysyl oxidase like 1 (LOXL1). LSKL sequence to displace the latency-associated peptide and make the TGF-β1 accessible to its receptors, TGFBR I and II. 15 Previous studies have indicated that the conserved sequence (LSKL) is required for activation of TGF-β1 and that mimetic peptides of the sequence act as selective antagonists of TSP-1-mediated TGF-β1 activation in vitro and in vivo. [16][17][18] Previous reports suggest that LSKL peptide-mediated attenuation of TGF-β1 activation can prevent the progression of cardiac, hepatic, and renal interstitial fibrosis. 15,17,19 Complete deficiency of TGF-β1 pathway proteins has marked pathological effects, leading to in utero death. Conclusions-Attenuation 20,21Because TSP-1 provides only one of the means by which TGF-β1 is activated, targeting this protein could have clinical relevance as a less severe strategy with potential to be applied to patients. [22][23][24][25] We are aware of no previous studies whi...

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Section: Discussionsupporting

confidence: 90%

“…[16][17][18] Previous reports suggest that LSKL peptide-mediated attenuation of TGF-β1 activation can prevent the progression of cardiac, hepatic, and renal interstitial fibrosis. 15,17,19 Complete deficiency of TGF-β1 pathway proteins has marked pathological effects, leading to in utero death. …”

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confidence: 99%

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

Krishna

Seto

Jose

et al. 2015

ATVB

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“…Recent studies have shown that peptides that specifically inhibit TSP1-mediated activation ameliorate TGF-␤-induced fibrosis in renal and hepatic model systems (34,35). In neoplasia, TSP1-mediated TGF-␤ activation may have a role in promoting invasion of tumors of the oral cavity, pancreas, and brain (36 -39).…”

Section: Discussionmentioning

confidence: 99%

The Tryptophan-rich Motifs of the Thrombospondin Type 1 Repeats Bind VLAL Motifs in the Latent Transforming Growth Factor-β Complex

Young

Murphy-Ullrich

2004

Journal of Biological Chemistry

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Transforming growth factor-␤ (TGF-␤) is secreted as a latent complex of the latency-associated peptide (LAP) and the mature domain, which must be activated for TGF-␤ to signal. We previously identified thrombospondin 1 (TSP1) as a physiologic activator of TGF-␤ in vitro and in vivo. The WSXW sequences in the type 1 repeats of TSP1 interact with the mature domain of TGF-␤, and WSXW peptides inhibit TSP1-mediated activation by blocking TSP1 binding to the TGF-␤ latent complex. However, the binding site for the WSXW sequence was not identified. In this report, we show that the WSXW sequences bind the 61 VLAL sequence in mature TGF-␤ and also bind 77 VLAL in LAP. A glutathione S-transferase (GST) fusion protein of the second TSP1 type 1 repeat (GST-TSR2) binds immobilized VLAL peptide. VLAL peptides inhibit binding of LAP and mature TGF-␤ to soluble GST-TSR2 and immobilized WSXW peptide. VLAL peptide inhibits TSP1-mediated activation of recombinant and endothelial cell-derived latent TGF-␤. Furthermore, TGF-␤ or LAP deleted in the VLAL sequence fails to bind immobilized WSXW or soluble GST-TSR2, indicating that binding to both VLAL sequences is important for association of TSP1 and the latent complex. Additionally, TSP1 is unable to activate latent TGF-␤ when VLAL is deleted from the mature domain. These data show that the WSXW motif binds VLAL on both LAP and mature TGF-␤, and these interactions are critical for TSP1-mediated activation of the TGF-␤ latent complex.

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“…Resistin directly and indirectly modulates HSC behaviour towards a more pro-fibrogenic phenotype [153]. It has been shown that blockade of thrombospondin 1 (TGFb1 activator) protects rats from liver damage and fibrosis induced by dimethylnitrosamine [154] and the inhibition of…”

Section: Tgfb1 and Fibrosismentioning

confidence: 99%

Transforming growth factor beta1 (TGFbeta1) in physiology and pathology

Kajdaniuk¹,

Marek²,

Borgiel−Marek³

et al. 2013

Endokrynologia Polska

166

118

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This review describes precisely the consequence of TGFb1 prevalence in the organism, and its significant influence on physiological and pathophysiological processes. Organ and tissue distinctiveness hinder unambiguous characterisation of the cytokine. However, there are constant functions of TGFb1 inducing no controversy: it participates in foetal development, control of cell growth and differentiation, induces fibrosis and scar formation (the process of 'wound healing'), causes the suppression of immune response, is involved in angiogenesis, the development of tumours, and inflammatory processes. Thus, TGFb1 is a multifunctional cytokine. There are three fundamental directions of its activities: I. TGFb1 regulates cell proliferation, growth, differentiation and cells movement. II. TGFb1 has immunomodulatory effects. III. TGFb1 has profibrogenic effects. TGFb1 action can be local and systemic. This review describes TGFb1 in pathology: colitis ulcerosa, Crohn's disease, coeliac disease, diabetic nephropathy, diabetic retinopathy and diabetic foot, pulmonary hypertension, and Alzheimer's disease. TGFb1 and its receptors are also of interest to endocrinologists. Lack of TGFb1-dependent growth control may result in oncogenesis: papillary, follicular and anaplastic thyroid cancers, prostate, breast and uterine cervical cancer, oesophagus, gastric, colorectal and liver cancers, NSCLC, and malignant melanoma. Excessive TGFb1 activity is an integral part of the fibrotic processes occurring in the response to injury. An increased TGFb1 expression has been observed in patients with pulmonary, kidney, and liver fibrosis. In chronic hepatitis, the prolonged stimulation of hepatic stellate cells being the result of chronic damage to hepatocytes results in the release of profibrogenic abundant factors such as TGFb1 and leads to the development of liver cirrhosis. The results of experimental procedures and treatment known as anti-TGFb1 strategy acting against the fibrosis in various tissues leads to hope regarding the use of anti-TGFb1 strategy in clinical practice. StreszczenieW artykule poglądowym szczegółowo opisano konsekwencje rozpowszechnienia TGFb1 w organizmie oraz jego wpływ na szereg procesów fizjologicznych i patofizjologicznych. Istotne odrębności narządowe i tkankowe utrudniają jednoznaczną charakterystykę tej cytokiny. Istnieją jednak stałe funkcje TGFb1 nie wzbudzające kontrowersji: uczestniczy w rozwoju płodu, regulacji wzrostu i różnicowa-nia komórek, indukuje proces włóknienia i bliznowacenia (proces "gojenia rany"), powoduje hamowanie odpowiedzi immunologicznej, uczestniczy w angiogenezie, w rozwoju nowotworów, w procesach zapalnych -jest więc cytokiną wieloczynnościową. Można wyróżnić trzy fundamentalne kierunki jego działania: I -TGFb1 reguluje proliferację, wzrost, różnicowanie i przemieszczanie komórek; II -TGFb1 wykazuje działanie immunomodulujące; III -TGFb1 wykazuje działanie profibrogenne. Działanie TGFb1 może mieć charakter miejscowy i systemowy. Opisano udział TGFb1 w stanach patologicznyc...

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A blocking peptide for transforming growth factor-β1 activation prevents hepatic fibrosis in vivo

Cited by 94 publications

References 27 publications

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

A Peptide Antagonist of Thrombospondin-1 Promotes Abdominal Aortic Aneurysm Progression in the Angiotensin II–Infused Apolipoprotein-E–Deficient Mouse

The Tryptophan-rich Motifs of the Thrombospondin Type 1 Repeats Bind VLAL Motifs in the Latent Transforming Growth Factor-β Complex

Transforming growth factor beta1 (TGFbeta1) in physiology and pathology

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