Suppressor of cytokine signalling (SOCS) proteins bind to certain cytokine receptors, Janus kinases and signalling molecules to regulate signalling pathways, thus controlling immune and inflammatory responses. Dysregulated expression of various types of SOCS molecules was indicated in multiple types of allergic diseases. SOCS1, SOCS2, SOCS3, SOCS5, and cytokine-inducible SH2 domain protein (CISH) can differentially exert anti-allergic impacts through different mechanisms, such as suppressing Th2 cell development and activation, reducing eosinophilia, decreasing IgE production, repressing production of pro-allergic chemokines, promoting Treg cell differentiation and activation, suppressing Th17 cell differentiation and activation, increasing anti-allergic Th1 responses, inhibiting M2 macrophage polarization, modulating survival and development of mast cells, reducing pro-allergic activity of keratinocytes, and suppressing pulmonary fibrosis. Although some anti-allergic effects were attributed to SOCS3, it can perform pro-allergic impacts through several pathways, such as promoting Th2 cell development and activation, supporting eosinophilia, boosting pro-allergic activity of eosinophils, increasing IgE production, enhancing the expression of the pro-allergic chemokine receptor, reducing Treg cell differentiation, increasing pro-allergic Th9 responses, as well as supporting mucus secretion and collagen deposition. In this review, we discuss the contrasting roles of SOCS proteins in contexts of allergic disorders to provide new insights regarding the pathophysiology of these diseases and possibly explore SOCS proteins as potential therapeutic targets for alleviating allergies.

• Klíčová slova
• SOCS molecules, T cells, allergic diseases, cytokines, immunopathology responses,
• MeSH
• alergie * metabolismus   MeSH
• antialergika * MeSH
• cytokiny metabolismus   MeSH
• eozinofilie * MeSH
• imunoglobulin E metabolismus   MeSH
• lidé MeSH
• proteiny SOCS genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antialergika * MeSH
• cytokiny MeSH
• imunoglobulin E MeSH
• proteiny SOCS MeSH

The resistance to interferons (IFNs) limits their anticancer therapeutic efficacy. Here we studied the antiproliferative effect of interferon gamma in relation to SOCS3 expression in a panel of breast cancer cell lines and normal mammary epithelial cells. Compared to normal cells most breast cancer lines (7/8) were highly resistant to IFN-gamma. Using Northern blot and real time RT-PCR we investigated transcription of SOCS3 genes. All normal epithelial cells (4/4) showed SOCS3 induction (2-14 fold) while most breast cancer lines did not or weakly activated SOCS3 after the interferon gamma treatment. Among the cancer lines, the MDA-MB-468 cells showed increased sensitivity to IFN-gamma and relatively high level of SOCS3 induction (2-3 fold). Together, there was a good correlation

• MeSH
• chemorezistence MeSH
• fosforylace MeSH
• interferon gama farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   metabolismus   patologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• protein SOCS3 MeSH
• proteiny SOCS genetika   MeSH
• prsy účinky léků   metabolismus   MeSH
• transkripční faktor STAT1 metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• interferon gama MeSH
• protein SOCS3 MeSH
• proteiny SOCS MeSH
• SOCS3 protein, human MeSH Prohlížeč
• STAT1 protein, human MeSH Prohlížeč
• transkripční faktor STAT1 MeSH

Activation of fibroblast growth factor receptor 3 (FGFR3) leads to attenuation of cartilage growth. The members of the STAT family of transcription factors are believed to participate in FGFR3 signaling in cartilage, however the molecular mechanism of this action is poorly understood. Here, we demonstrate that a chronic FGF stimulus leads to accumulation of STAT1, 3, 5 and 6, evident in both in vitro chondrocyte model and murine limb explant cultures. Despite the accumulation, both endogenous and cytokine-induced activation of STAT1 and STAT3 is impaired by FGF, as demonstrated by imaging of active STAT nuclear translocation and analyses of STAT activatory phosphorylation and transcriptional activation. Further, we demonstrate that FGF induces expression of CIS, SOCS1 and SOCS3 inhibitors of gp130, a common receptor for the IL6-family of cytokines. Since cytokine-gp130 signaling represents an important positive regulator of cartilage, its inhibition may contribute to the growth-inhibitory effect of FGFR3 in cartilage.

• MeSH
• chondrocyty účinky léků   metabolismus   MeSH
• cytokinový receptor gp130 metabolismus   MeSH
• fibroblastový růstový faktor 2 farmakologie   MeSH
• interferon gama antagonisté a inhibitory   farmakologie   MeSH
• interleukin-6 antagonisté a inhibitory   farmakologie   MeSH
• myši MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• protein SOCS1 MeSH
• protein SOCS3 MeSH
• proteiny SOCS metabolismus   MeSH
• receptor fibroblastových růstových faktorů, typ 3 metabolismus   MeSH
• sekvence nukleotidů MeSH
• signální transdukce MeSH
• transkripční faktor STAT1 antagonisté a inhibitory   metabolismus   MeSH
• transkripční faktor STAT3 antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• cytokine inducible SH2-containing protein MeSH Prohlížeč
• cytokinový receptor gp130 MeSH
• fibroblastový růstový faktor 2 MeSH
• interferon gama MeSH
• interleukin-6 MeSH
• protein SOCS1 MeSH
• protein SOCS3 MeSH
• proteiny SOCS MeSH
• receptor fibroblastových růstových faktorů, typ 3 MeSH
• Socs1 protein, mouse MeSH Prohlížeč
• Socs3 protein, mouse MeSH Prohlížeč
• transkripční faktor STAT1 MeSH
• transkripční faktor STAT3 MeSH

Proteins of STAT family belongs to the transcription factors. Through their binding to the DNA specific sites and consequent regulation of transcription of various genes, these signaling proteins play an important role in many cell functions. Recent studies demonstrated persistent activation of STATs and loss of their natural inhibitors SOCS and PIAS in various human cancers. There is also evidence that experimental pharmacologic or genetic modulation of their function mignt by a new approach in anticancer treatment. The aim of this study was in vitro assesment and analysis of expression of STATs, SOCS and PIAS in glioblastoma cell lines undergoing treatment by PPARgamma agonists/antagonists because PPARgamma and STATs are tightly regulated by an overlapping set of nuclear regulatory proteins. We further analysed immunohistochemical expression of these proteins in vivo, with its correlation to grading in various brain tumors. The results of in vitro study showed decreased expression of phosphorylated form of STAT3 and increase of its inhibitors SOCS3 and PIAS3 in glioblastoma cell lines after treatment with IC50 of PPARgamma agonist ciglitazone. In vivo study failed to reveal changes in STAT3 and SOCS3 expression in either low and high grade astrocytomas, however we detect lower expression of STAT2 in low grade astrocytomas when comparing with high grade astrocytomas and lower expression of STAT3 in ependymomas when comparing with anaplastic ones. The results showed existing relationship between STAT and PPARgamma signaling in glial tumors and further suppport expected important role of STATs in regulation of growth and differentiation in these tumors.

• MeSH
• aktivace transkripce MeSH
• aktivované STAT proteiny - proteinové inhibitory metabolismus   MeSH
• exprese genu MeSH
• fosforylace MeSH
• glioblastom farmakoterapie   metabolismus   MeSH
• lidé MeSH
• malé modifikační proteiny související s ubikvitinem metabolismus   MeSH
• molekulární chaperony metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory mozku farmakoterapie   metabolismus   MeSH
• PPAR gama antagonisté a inhibitory   MeSH
• protein SOCS3 MeSH
• proteiny SOCS metabolismus   MeSH
• signální transdukce MeSH
• thiazolidindiony terapeutické užití   MeSH
• transkripční faktor STAT3 metabolismus   MeSH
• transkripční faktory STAT antagonisté a inhibitory   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aktivované STAT proteiny - proteinové inhibitory MeSH
• ciglitazone MeSH Prohlížeč
• malé modifikační proteiny související s ubikvitinem MeSH
• molekulární chaperony MeSH
• PIAS1 protein, human MeSH Prohlížeč
• PIAS3 protein, human MeSH Prohlížeč
• PPAR gama MeSH
• protein SOCS3 MeSH
• proteiny SOCS MeSH
• SOCS3 protein, human MeSH Prohlížeč
• thiazolidindiony MeSH
• transkripční faktor STAT3 MeSH
• transkripční faktory STAT MeSH

The resistance to interferons (IFNs) limits their anticancer therapeutic efficacy. Here we studied the evolution of an IFN-resistant state in vitro using melanoma cell lines. We found that the cells became less sensitive to antiproliferative effect of IFN-gamma after prolonged cultivation enabling us to isolate sensitive and resistant subclones of the parental line. We investigated transcription of signal transducer and activator of transcription (STAT) 1-6 and suppressor of cytokine signalling (SOCS) 1-3 genes, and phosphorylation of STAT 1 protein. The resistant subline (termed WM 1158R) differed from the sensitive subline (WM 1158S) by a constitutive expression of SOCS 3, lack or weak SOCS 1-3 activation following IFN-gamma, and short duration of cytokine activatory signal. Similar correlations were observed in additional melanoma lines differing in IFN sensitivities. At the protein level, IFN-gamma induced strong and prolonged STAT 1 activation at serine 727 (S727) in WM 1158R while in WM 1158S cells phosphorylation of this amino acid was much less pronounced. On the other hand, phosphorylation of tyrosine 701 (Y701) was stimulated regardless of the sensitivity phenotype. In conclusion, constitutive expression of SOCS 3 is correlated with attenuation of its induction following IFN treatment. These results suggest that progression of melanoma cells from IFN sensitivity to IFN insensitivity associates with changes in SOCS expression.

• MeSH
• chemorezistence genetika   MeSH
• exprese genu MeSH
• fosforylace MeSH
• interferon gama farmakologie   terapeutické užití   MeSH
• lidé MeSH
• melanom farmakoterapie   genetika   MeSH
• nádorové buněčné linie MeSH
• nádory kůže farmakoterapie   genetika   MeSH
• proliferace buněk účinky léků   MeSH
• protein SOCS3 MeSH
• proteiny SOCS genetika   MeSH
• regulace genové exprese u nádorů * MeSH
• stanovení celkové genové exprese MeSH
• transkripční faktor STAT1 metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interferon gama MeSH
• protein SOCS3 MeSH
• proteiny SOCS MeSH
• SOCS3 protein, human MeSH Prohlížeč
• STAT1 protein, human MeSH Prohlížeč
• transkripční faktor STAT1 MeSH

The currently used standard treatment for chronic hepatitis C using a dual combination of IFNalpha/RBV is only successful in 50% cases. With the exception of some clinical and biochemical factors, degree of inflammation (grading) and degree of fibrosis (staging), there are no other known markers which may serve as valid predictors of response to therapy. Interference of hepatitis C virus (HCV) with signaling pathways modulated by JAK-STAT, ERK 1/2, NFkappaB and MAP proteins is one mechanism which may influence the interaction between HCV and IFNalpha. These proteins regulate different cell processes such as activation of cytokines, activation of apoptosis, regulation of cell proliferation etc. Therefore, it is possible that impaired signaling or inhibition/dysregulation of some of these proteins by HCV infection may cause resistance to IFNalpha treatment. This review is completed by results of preliminary study the aim of which was immunohistochemical assessment and analysis of expression of STAT 2, 3 proteins, their inhibitors SOCS 2, 3 and PIAS 3 and proteins JAK 1 and ERK 1/2 in liver biopsies of 26 patients with chronic hepatitis C treated by dual combination IFNalpha/RBV and subsequent correlation of the results of immunohistochemical analysis (histoscore) with histological picture and clinical response to treatment. The results shows increased expression of STAT 3, STAT 2 and ERK 1 proteins and decreased expression of SOCS 3 and SOCS 2 in hepatocytes of patients with more marked inflammation and fibrosis. In patients with sustained virological response there was increased expression of SOCS 3 and JAK 1 and decreased expression of SOCS 2. Relapse was associated with increased expression of SOCS 3 and PIAS 3. However, owing to the small sample size, the results only approximated statistical significance, but we suggest that proteins of STAT family and their inhibitors SOCS and PIAS probably play an important regulatory role during response to treatment for chronic hepatitis C.

• MeSH
• aktivované STAT proteiny - proteinové inhibitory metabolismus   MeSH
• antivirové látky terapeutické užití   MeSH
• biopsie MeSH
• chronická hepatitida C farmakoterapie   metabolismus   patologie   virologie   MeSH
• interferon alfa terapeutické užití   MeSH
• Janus kinasa 1 MeSH
• játra metabolismus   patologie   MeSH
• lidé MeSH
• malé modifikační proteiny související s ubikvitinem metabolismus   MeSH
• mitogenem aktivovaná proteinkinasa 3 metabolismus   MeSH
• proteiny SOCS metabolismus   MeSH
• ribavirin terapeutické užití   MeSH
• signální transdukce MeSH
• transkripční faktory STAT metabolismus   MeSH
• tyrosinkinasy metabolismus   MeSH
• virová nálož MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• aktivované STAT proteiny - proteinové inhibitory MeSH
• antivirové látky MeSH
• interferon alfa MeSH
• JAK1 protein, human MeSH Prohlížeč
• Janus kinasa 1 MeSH
• malé modifikační proteiny související s ubikvitinem MeSH
• mitogenem aktivovaná proteinkinasa 3 MeSH
• PIAS1 protein, human MeSH Prohlížeč
• proteiny SOCS MeSH
• ribavirin MeSH
• transkripční faktory STAT MeSH
• tyrosinkinasy MeSH

The signal transducers and transcription activators (STATs) and their endogenous inhibitors of the suppressors of cytokine signalling (SOCS) family are major proteins harmonizing the transmission of external signals from the surface membrane to target genes in the nucleus. To correlate the induction of SOCS 3 by interferons (IFNs) on messenger RNA and protein levels with STAT 1 phosphorylation in human malignant melanoma cell lines, we used a unique collection of 18 established malignant melanoma cell lines and six human non-malignant normal cells (two melanocytes, two skin keratinocytes and two fibroblasts). IFN-gamma induced SOCS 3 in 83% of melanoma cell lines, whereas IFN-alpha stimulated SOCS 3 expression in only 11% of cases. Similarly, melanocytes showed strong induction of SOCS 3 by IFN-gamma and, to a lesser extent, by IFN-alpha. In most cases, SOCS 3 expression was paralleled by STAT 1 phosphorylation at tyrosine residues (Y701). In several lines, however, SOCS 3 was not induced despite STAT 1 phosphorylation and, in a few lines, SOCS 3 induction occurred without detectable STAT 1 phosphorylation, indicating that STAT 1 might not be an exclusive inducer of SOCS 3. Similarly, non-malignant cells displayed STAT 1 activation and high levels of SOCS 3 expression after IFN-gamma (but not IFN-alpha) treatment. In conclusion, in contrast to IFN-alpha, IFN-gamma appeared to induce SOCS 3 apparently at the transcription level and exhibited higher cytotoxic effects regardless of the cell origin.

• MeSH
• buňky - růstové procesy účinky léků   MeSH
• fosforylace MeSH
• interferon gama farmakologie   MeSH
• interferon typ I farmakologie   MeSH
• lidé MeSH
• melanom farmakoterapie   genetika   metabolismus   MeSH
• messenger RNA biosyntéza   genetika   MeSH
• nádorové buněčné linie MeSH
• northern blotting MeSH
• protein SOCS3 MeSH
• proteiny SOCS biosyntéza   genetika   MeSH
• rekombinantní proteiny MeSH
• signální transdukce MeSH
• transkripční faktor STAT1 metabolismus   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interferon gama MeSH
• interferon typ I MeSH
• messenger RNA MeSH
• protein SOCS3 MeSH
• proteiny SOCS MeSH
• rekombinantní proteiny MeSH
• SOCS3 protein, human MeSH Prohlížeč
• STAT1 protein, human MeSH Prohlížeč
• transkripční faktor STAT1 MeSH