Signal transducer and activator of transcription 3 (STAT3) is phosphorylated by various kinases, several of which have been implicated in aberrant fibroblast activation in fibrotic diseases including systemic sclerosis (SSc). Here we show that profibrotic signals converge on STAT3 and that STAT3 may be an important molecular checkpoint for tissue fibrosis. STAT3 signaling is hyperactivated in SSc in a TGFβ-dependent manner. Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK, SRC, c-ABL, and JNK kinases. STAT3-deficient fibroblasts are less sensitive to the pro-fibrotic effects of TGFβ. Fibroblast-specific knockout of STAT3, or its pharmacological inhibition, ameliorate skin fibrosis in experimental mouse models. STAT3 thus integrates several profibrotic signals and might be a core mediator of fibrosis. Considering that several STAT3 inhibitors are currently tested in clinical trials, STAT3 might be a candidate for molecular targeted therapies of SSc.

• MeSH
• aktivace enzymů MeSH
• benzensulfonáty chemie   MeSH
• biopsie MeSH
• bleomycin chemie   MeSH
• dospělí MeSH
• fibroblasty metabolismus   MeSH
• fibróza metabolismus   MeSH
• fosforylace MeSH
• kolagen chemie   MeSH
• konfokální mikroskopie MeSH
• kůže metabolismus   MeSH
• kyseliny aminosalicylové chemie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myši MeSH
• receptory transformujícího růstového faktoru beta metabolismus   MeSH
• senioři MeSH
• signální transdukce fyziologie   MeSH
• systémová sklerodermie metabolismus   MeSH
• transformující růstový faktor beta metabolismus   MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• benzensulfonáty MeSH
• bleomycin MeSH
• kolagen MeSH
• kyseliny aminosalicylové MeSH
• NSC 74859 MeSH Prohlížeč
• receptory transformujícího růstového faktoru beta MeSH
• STAT3 protein, human MeSH Prohlížeč
• Stat3 protein, mouse MeSH Prohlížeč
• transformující růstový faktor beta MeSH
• transkripční faktor STAT3 MeSH

OBJECTIVES: Hedgehog signalling plays a critical role during the pathogenesis of fibrosis in systemic sclerosis (SSc). Besides canonical hedgehog signalling with smoothened (SMO)-dependent activation of GLI transcription factors, GLI can be activated independently of classical hedgehog ligands and receptors (so-called non-canonical pathways). Here, we aimed to evaluate the role of non-canonical hedgehog signalling in SSc and to test the efficacy of direct GLI inhibitors that target simultaneously canonical and non-canonical hedgehog pathways. METHODS: The GLI inhibitor GANT-61 was used to inhibit canonical as well as non-canonical hedgehog signalling, while the SMO inhibitor vismodegib was used to selectively target canonical hedgehog signalling. Furthermore, GLI2 was selectively depleted in fibroblasts using the Cre-LoxP system. The effects of pharmacological or genetic of GLI2 on transforming growth factor-β (TGF-β) signalling were analysed in cultured fibroblasts, in bleomycin-induced pulmonary fibrosis and in mice with overexpression of a constitutively active TGF-β receptor I. RESULTS: TGF-β upregulated GLI2 in a Smad3-dependent manner and induced nuclear accumulation and DNA binding of GLI2. Fibroblast-specific knockout of GLI2 protected mice from TBRact-induced fibrosis. Combined targeting of canonical and non-canonical hedgehog signalling with direct GLI inhibitors exerted more potent antifibrotic effects than selective targeting of canonical hedgehog signalling with SMO inhibitors in experimental dermal and pulmonary fibrosis. CONCLUSIONS: Our data demonstrate that hedgehog pathways and TGF-β signalling both converge to GLI2 and that GLI2 integrates those signalling to promote tissue fibrosis. These findings may have translational implications as non-selective inhibitors of GLI2 are in clinical use and selective molecules are currently in development.

• Klíčová slova
• Fibroblasts, Systemic Sclerosis, Treatment,
• MeSH
• anilidy farmakologie   MeSH
• dospělí MeSH
• fibroblasty účinky léků   metabolismus   MeSH
• fibróza MeSH
• genový knockout MeSH
• inhibitor aktivátoru plazminogenu 1 genetika   MeSH
• kolagen typu I genetika   MeSH
• kultivované buňky MeSH
• kůže účinky léků   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• mladý dospělý MeSH
• myši knockoutované MeSH
• myši transgenní MeSH
• myši MeSH
• plicní fibróza chemicky indukované   metabolismus   MeSH
• protein Gli2 s motivem zinkových prstů MeSH
• protein Smad3 metabolismus   MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   genetika   MeSH
• proteiny hedgehog metabolismus   MeSH
• pteridiny farmakologie   MeSH
• pyridiny farmakologie   MeSH
• pyrimidiny farmakologie   MeSH
• receptor Smoothened antagonisté a inhibitory   MeSH
• receptory transformujícího růstového faktoru beta antagonisté a inhibitory   genetika   MeSH
• rekombinantní proteiny farmakologie   MeSH
• růstový faktor pojivové tkáně genetika   MeSH
• senioři MeSH
• signální transdukce účinky léků   MeSH
• systémová sklerodermie genetika   metabolismus   MeSH
• TGF-beta receptor I. typu MeSH
• transformující růstový faktor beta metabolismus   farmakologie   MeSH
• transkripční faktory Krüppel-like antagonisté a inhibitory   genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• anilidy MeSH
• GANT 61 MeSH Prohlížeč
• Gli2 protein, mouse MeSH Prohlížeč
• HhAntag691 MeSH Prohlížeč
• inhibitor aktivátoru plazminogenu 1 MeSH
• kolagen typu I MeSH
• messenger RNA MeSH
• protein Gli2 s motivem zinkových prstů MeSH
• protein Smad3 MeSH
• protein-serin-threoninkinasy MeSH
• proteiny hedgehog MeSH
• pteridiny MeSH
• pyridiny MeSH
• pyrimidiny MeSH
• receptor Smoothened MeSH
• receptory transformujícího růstového faktoru beta MeSH
• rekombinantní proteiny MeSH
• růstový faktor pojivové tkáně MeSH
• SD-208 MeSH Prohlížeč
• TGF-beta receptor I. typu MeSH
• transformující růstový faktor beta MeSH
• transkripční faktory Krüppel-like MeSH

OBJECTIVES: TWIST1 is a member of the class B of basic helix-loop-helix transcription factors that regulates cell lineage determination and differentiation and has been implicated in epithelial-to-mesenchymal transition. Here, we aimed to investigate the role of TWIST1 for the activation of resident fibroblasts in systemic sclerosis (SSc). METHODS: The expression of Twist1 in fibroblasts was modulated by forced overexpression or siRNA-mediated knockdown. Interaction of Twist1, E12 and inhibitor Of differentiation (Id) was analysed by co-immunoprecipitation. The role of Twist1 in vivo was evaluated using inducible, conditional knockout mice with either ubiquitous or fibroblast-specific depletion of Twist1. Mice were either challenged with bleomycin or overexpressing a constitutively active transforming growth factor (TGF)β receptor I. RESULT: The expression of TWIST1 was increased in fibroblasts in fibrotic human and murine skin in a TGFβ/SMAD3-dependent manner. TWIST1 in turn enhanced TGFβ-induced fibroblast activation in a p38-dependent manner. The stimulatory effects of TWIST1 on resident fibroblasts were mediated by TWIST1 homodimers. TGFβ promotes the formation of TWIST1 homodimers by upregulation of TWIST1 and by induction of inhibitor of DNA-binding proteins, which have high affinity for E12/E47 and compete against TWIST1 for E12/E47 binding. Mice with selective depletion of Twist1 in fibroblasts are protected from experimental skin fibrosis in different murine models to a comparable degree as mice with ubiquitous depletion of Twist1. CONCLUSIONS: Our data identify TWIST1 as a central pro-fibrotic factor in SSc, which facilitates fibroblast activation by amplifying TGFβ signalling. Targeting of TWIST1 may thus be a novel approach to normalise aberrant TGFβ signalling in SSc.

• Klíčová slova
• Fibroblasts, Systemic Sclerosis, Treatment,
• MeSH
• fibroblasty účinky léků   metabolismus   MeSH
• genový knockdown MeSH
• jaderné proteiny biosyntéza   nedostatek   genetika   metabolismus   fyziologie   MeSH
• kůže patologie   MeSH
• lidé MeSH
• malá interferující RNA genetika   MeSH
• messenger RNA genetika   MeSH
• multimerizace proteinu fyziologie   MeSH
• myši knockoutované MeSH
• regulace genové exprese účinky léků   fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• studie případů a kontrol MeSH
• systémová sklerodermie metabolismus   patologie   MeSH
• transformující růstový faktor beta farmakologie   MeSH
• transkripční faktor Twist biosyntéza   nedostatek   genetika   metabolismus   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• jaderné proteiny MeSH
• malá interferující RNA MeSH
• messenger RNA MeSH
• transformující růstový faktor beta MeSH
• transkripční faktor Twist MeSH
• TWIST1 protein, human MeSH Prohlížeč
• Twist1 protein, mouse MeSH Prohlížeč

OBJECTIVES: Tribbles homologue 3 (TRB3) is a pseudokinase that modifies the activation of various intracellular signalling pathways to control fundamental processes extending from mitosis and cell activation to apoptosis and modulation of gene expression. Here, we aimed to analyse the role of TRB3 in fibroblast activation in systemic sclerosis (SSc). METHODS: The expression of TRB3 was quantified by quantitative PCR, western blot and immunohistochemistry. The role of TRB3 was analysed in cultured fibroblasts and in experimental fibrosis using small interfering RNA (siRNA)-mediated knockdown and overexpression of TRB3. RESULTS: TRB3 expression was increased in fibroblasts of patients with SSc and in murine models of SSc in a transforming growth factor-β (TGF-β)/Smad-dependent manner. Overexpression of TRB3 stimulated canonical TGF-β signalling and induced an activated phenotype in resting fibroblasts. In contrast, knockdown of TRB3 reduced the profibrotic effects of TGF-β and decreased the collagen synthesis. Moreover, siRNA-mediated knockdown of TRB3 exerted potent antifibrotic effects and ameliorated bleomycin as well as constitutively active TGF-β receptor I-induced fibrosis with reduced dermal thickening, decreased hydroxyproline content and impaired myofibroblast differentiation. CONCLUSIONS: The present study characterises TRB3 as a novel profibrotic mediator in SSc. TGF-β induces TRB3, which in turn activates canonical TGF-β/Smad signalling and stimulates the release of collagen, thereby inducing a positive feedback loop that may contribute to aberrant TGF-β signalling in SSc.

• Klíčová slova
• Fibroblasts, Systemic Sclerosis, Treatment,
• MeSH
• bleomycin toxicita   MeSH
• dospělí MeSH
• fibroblasty metabolismus   MeSH
• fibróza chemicky indukované   genetika   MeSH
• genový knockdown MeSH
• genový knockin MeSH
• imunohistochemie MeSH
• kolagen metabolismus   MeSH
• kožní nemoci chemicky indukované   genetika   MeSH
• kultivované buňky MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• protein Smad3 metabolismus   MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• protinádorová antibiotika toxicita   MeSH
• receptory transformujícího růstového faktoru beta MeSH
• represorové proteiny genetika   metabolismus   MeSH
• senioři MeSH
• signální transdukce genetika   MeSH
• škára cytologie   MeSH
• studie případů a kontrol MeSH
• systémová sklerodermie genetika   metabolismus   MeSH
• TGF-beta receptor I. typu MeSH
• transformující růstový faktor beta metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bleomycin MeSH
• kolagen MeSH
• protein Smad3 MeSH
• protein-serin-threoninkinasy MeSH
• proteiny buněčného cyklu MeSH
• protinádorová antibiotika MeSH
• receptory transformujícího růstového faktoru beta MeSH
• represorové proteiny MeSH
• TGF-beta receptor I. typu MeSH
• transformující růstový faktor beta MeSH
• TRB3 protein, mouse MeSH Prohlížeč
• TRIB3 protein, human MeSH Prohlížeč

BACKGROUND: Sirt1 is a member of the sirtuin family of proteins. Sirt1 is a class III histone deacetylase with important regulatory roles in transcription, cellular differentiation, proliferation and metabolism. As aberrant epigenetic modifications have been linked to the pathogenesis of systemic sclerosis (SSc), we aimed to investigate the role of Sirt1 in fibroblast activation. METHODS: Sirt1 expression was analysed by real-time PCR, western blot and immunohistochemistry. Sirt1 signalling was modulated with the Sirt1 agonist resveratrol and by fibroblast-specific knockout. The role of Sirt1 was evaluated in bleomycin-induced skin fibrosis and in mice overexpressing a constitutively active transforming growth fac-tor-β (TGF-β) receptor I (TBRIact). RESULTS: The expression of Sirt1 was decreased in patients with SSc and in experimental fibrosis in a TGF-β-dependent manner. Activation of Sirt1 potentiated the profibrotic effects of TGF-β with increased Smad reporter activity, elevated transcription of TGF-β target genes and enhanced release of collagen. In contrast, knockdown of Sirt1 inhibited TGF-β/SMAD signalling and reduced release of collagen in fibroblasts. Consistently, mice with fibroblast-specific knockdown of Sirt1 were less susceptible to bleomycin- or TBRIact-induced fibrosis. CONCLUSIONS: We identified Sirt1 as a crucial regulator of TGF-β/Smad signalling in SSc. Although Sirt1 is downregulated, this decrease is not sufficient to counterbalance the excessive activation of TGF-β signalling in SSc. However, augmentation of this endogenous regulatory mechanism, for example, by knockdown of Sirt1, can effectively inhibit TGF-β signalling and exerts potent antifibrotic effects. Sirt1 may thus be a key regulator of fibroblast activation in SSc.

• Klíčová slova
• Fibroblasts, Systemic Sclerosis, Treatment,
• MeSH
• bleomycin MeSH
• dospělí MeSH
• down regulace fyziologie   MeSH
• fibroblasty metabolismus   MeSH
• fibróza MeSH
• kultivované buňky MeSH
• kůže metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované MeSH
• senioři MeSH
• signální transdukce fyziologie   MeSH
• sirtuin 1 fyziologie   MeSH
• studie případů a kontrol MeSH
• systémová sklerodermie metabolismus   patologie   MeSH
• transformující růstový faktor beta fyziologie   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bleomycin MeSH
• SIRT1 protein, human MeSH Prohlížeč
• Sirt1 protein, mouse MeSH Prohlížeč
• sirtuin 1 MeSH
• transformující růstový faktor beta MeSH

OBJECTIVES: S100A4 is a calcium binding protein with regulatory functions in cell homeostasis, proliferation and differentiation that has been shown to promote cancer progression and metastasis. In the present study, we evaluated the role of S100A4 in fibroblast activation in systemic sclerosis (SSc). METHODS: The expression of S100A4 was analysed in human samples, murine models of SSc and in cultured fibroblasts by real-time PCR, immunohistochemistry and western blot. The functional role of S100A4 was evaluated using siRNA, overexpression, recombinant protein and S100A4 knockout (S100A4(-/-)) mice. Transforming growth factor β (TGF-β) signalling was assessed by reporter assays, staining for phosphorylated Smad2/3 and analyses of target genes. RESULTS: The expression of S100A4 was increased in SSc skin and in experimental fibrosis in a TGF-β/Smad-dependent manner. Overexpression of S100A4 or stimulation with recombinant S100A4 induced an activated phenotype in resting normal fibroblasts. In contrast, knockdown of S100A4 reduced the pro-fibrotic effects of TGF-β and decreased the release of collagen. S100A4(-/-) mice were protected from bleomycin-induced skin fibrosis with reduced dermal thickening, decreased hydroxyproline content and lower myofibroblast counts. Deficiency of S100A4 also ameliorated fibrosis in the tight-skin-1 (Tsk-1) mouse model. CONCLUSIONS: We characterised S100A4 as a downstream mediator of the stimulatory effects of TGF-β on fibroblasts in SSc. TGF-β induces the expression of S100A4 to stimulate the release of collagen in SSc fibroblasts and induce fibrosis. Since S100A4 is essentially required for the pro-fibrotic effects of TGF-β and neutralising antibodies against S100A4 are currently evaluated, S100A4 might be a candidate for novel antifibrotic therapies.

• MeSH
• dospělí MeSH
• fibroblasty metabolismus   MeSH
• kůže metabolismus   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• modely nemocí na zvířatech MeSH
• myši knockoutované MeSH
• myši MeSH
• protein Smad2 metabolismus   MeSH
• protein Smad3 metabolismus   MeSH
• proteiny S100 metabolismus   MeSH
• S100 kalcium vázající protein A4 MeSH
• senioři MeSH
• systémová sklerodermie metabolismus   MeSH
• transformující růstový faktor beta metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• protein Smad2 MeSH
• protein Smad3 MeSH
• proteiny S100 MeSH
• S100 kalcium vázající protein A4 MeSH
• S100A4 protein, human MeSH Prohlížeč
• S100a4 protein, mouse MeSH Prohlížeč
• transformující růstový faktor beta MeSH

BACKGROUND: Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily. Its ligand, 1,25-(OH)2D, is a metabolically active hormone derived from vitamin D3. The levels of vitamin D3 are decreased in patients with systemic sclerosis (SSc). Here, we aimed to analyse the role of VDR signalling in fibrosis. METHODS: VDR expression was analysed in SSc skin, experimental fibrosis and human fibroblasts. VDR signalling was modulated by siRNA and with the selective agonist paricalcitol. The effects of VDR on Smad signalling were analysed by reporter assays, target gene analyses and coimmunoprecipitation. The effects of paricalcitol were evaluated in the models of bleomycin-induced fibrosis and fibrosis induced by overexpression of a constitutively active transforming growth factor-β (TGF-β) receptor I (TBRI(CA)). RESULTS: VDR expression was decreased in fibroblasts of SSc patients and murine models of SSc in a TGF-β-dependent manner. Knockdown of VDR enhanced the sensitivity of fibroblasts towards TGF-β. In contrast, activation of VDR by paricalcitol reduced the stimulatory effects of TGF-β on fibroblasts and inhibited collagen release and myofibroblast differentiation. Paricalcitol stimulated the formation of complexes between VDR and phosphorylated Smad3 in fibroblasts to inhibit Smad-dependent transcription. Preventive and therapeutic treatment with paricalcitol exerted potent antifibrotic effects and ameliorated bleomycin- as well as TBRI(CA)-induced fibrosis. CONCLUSIONS: We characterise VDR as a negative regulator of TGF-β/Smad signalling. Impaired VDR signalling with reduced expression of VDR and decreased levels of its ligand may thus contribute to hyperactive TGF-β signalling and aberrant fibroblast activation in SSc.

• Klíčová slova
• Fibroblasts, Systemic Sclerosis, Treatment,
• MeSH
• bleomycin toxicita   MeSH
• dospělí MeSH
• ergokalciferoly farmakologie   MeSH
• fibroblasty účinky léků   metabolismus   MeSH
• fibróza chemicky indukované   metabolismus   MeSH
• kůže účinky léků   metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• malá interferující RNA metabolismus   MeSH
• mladý dospělý MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• proteiny Smad účinky léků   metabolismus   MeSH
• receptory kalcitriolu agonisté   metabolismus   MeSH
• senioři MeSH
• signální transdukce účinky léků   fyziologie   MeSH
• systémová sklerodermie metabolismus   MeSH
• transformující růstový faktor beta účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• bleomycin MeSH
• ergokalciferoly MeSH
• malá interferující RNA MeSH
• paricalcitol MeSH Prohlížeč
• proteiny Smad MeSH
• receptory kalcitriolu MeSH
• transformující růstový faktor beta MeSH
• VDR protein, human MeSH Prohlížeč

Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-β (TGF-β) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-β target genes, thereby limiting pro-fibrotic TGF-β effects. Even though temporary upregulation of TGF-β in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-β signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-β signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.

• MeSH
• alkoholická cirhóza jater metabolismus   patologie   MeSH
• dospělí MeSH
• fibroblasty metabolismus   MeSH
• fibróza MeSH
• histondeacetylasa 1 metabolismus   MeSH
• histondeacetylasa Sin3 a korepresorový komplex MeSH
• histondemethylasy metabolismus   MeSH
• hojení ran MeSH
• idiopatická plicní fibróza metabolismus   patologie   MeSH
• jaderné receptory - podrodina 4, skupina A, člen 1 genetika   metabolismus   fyziologie   MeSH
• játra metabolismus   patologie   MeSH
• korepresorové proteiny metabolismus   MeSH
• kultivované buňky MeSH
• kůže cytologie   metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• myši knockoutované MeSH
• myši MeSH
• plíce metabolismus   patologie   MeSH
• represorové proteiny metabolismus   MeSH
• senioři MeSH
• signální transdukce MeSH
• studie případů a kontrol MeSH
• systémová sklerodermie metabolismus   patologie   MeSH
• transformující růstový faktor beta metabolismus   MeSH
• transkripční faktor Sp1 metabolismus   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• myši MeSH
• senioři MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• histondeacetylasa 1 MeSH
• histondeacetylasa Sin3 a korepresorový komplex MeSH
• histondemethylasy MeSH
• jaderné receptory - podrodina 4, skupina A, člen 1 MeSH
• korepresorové proteiny MeSH
• represorové proteiny MeSH
• SIN3A transcription factor MeSH Prohlížeč
• transformující růstový faktor beta MeSH
• transkripční faktor Sp1 MeSH

The aim of this study was to assess the degradation of collagen type I and proinflammatory cytokines in systemic and localized scleroderma compared with psoriasis and healthy controls. Total 99 individuals were examined - 24 with SSc, 22 with LSc, 39 patients with PsV and 14 healthy controls. U-PD and U-DPD were measured using a sensitive isocratic HPLC method. Serum levels of IL-6 and soluble IL-2R were assayed using commercial ELISA kits. In the SSc group U-PD and U-DPD levels (nmol/mmol creatinine) were increased compared with controls (P = 0.001) and with PsV (P = 0.006). IL-6 levels were increased compared with controls (P = 0.004) and with PsV (P = 0.002). IL-2R concentrations were insignificantly increased in comparison with controls and were lower than in PsV, but the difference was not significant. In the LSc group excretion of U-PD and U-DPD did not differ from controls, but was insignificantly decreased compared with PsV. IL-6 levels were increased compared with controls (P = 0.001) and also with PsV (P = 0.03). IL-2R concentrations were significantly increased in comparison with controls only (P = 0.03). In patients with SSc our data have shown the most intensive collagen degradation and simultaneously an active inflammation, as documented by IL-6, which reflects the pathological processes in the skin and visceral organs compared with PsV patients and healthy individuals. In the LSc group collagen degradation was similar to that in control groups, but a certain inflammatory activity was observed.

• MeSH
• cytokiny krev   MeSH
• demografie MeSH
• kolagen metabolismus   moč   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokalizovaná sklerodermie krev   metabolismus   MeSH
• mediátory zánětu krev   MeSH
• posttranslační úpravy proteinů * MeSH
• systémová sklerodermie krev   metabolismus   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• kolagen MeSH
• mediátory zánětu MeSH