BACKGROUND: Chronic venous disease (CVD) is a common disorder of lower extremities. OBJECTIVES: The study was scheduled to investigate the relationship between polymorphisms in major proinflammatory genes TNF α (-238 A/G; -308 A/G), TNF β (NcoI), IL-1β (+3953 T/C); IL-6 (-174 G/C; -596 G/C) and ADAM17 (3'TACE) and CVD risk. Genotype-phenotype study was calculated to test possible association between examined genotypes and phenotypes of CVD. METHODS: Finally, 150 CVD patients and 227 control subjects were enrolled to the study. Genotypes in proinflammatory gene polymorphisms were identified from isolated DNA by PCR method and restriction analysis. RESULTS: Significant differences in genotype distribution/allelic frequencies in TNF β gene, IL-1 β gene and in ADAM17 gene polymorphisms were found between CVD women and control ones. In the genotype-phenotype study, identified genotypes were associated with arterial hypertension (ADAM17, IL-6-men), ischaemic heart disease (TNF α and β genes), diabetes mellitus (ADAM17-women, TNF β-men), age of CVD onset (TNF α and IL-6), ulceration (ADAM17), duration of ulceration (ADAM17), ulceration recurrence (ADAM17-women), home care necessity (TNF α), varices surgery (TNF α), erysipelas development (ADAM17-men) and tumour development (TNF α). CONCLUSION: Studying of these polymorphisms associations can help us better identify patients at higher risk of developing severe CVD.

• MeSH
• chronická nemoc MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• interleukin-1beta genetika   MeSH
• interleukin-6 genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• kardiovaskulární nemoci * genetika   MeSH
• lidé MeSH
• lymfotoxin-alfa genetika   MeSH
• protein ADAM17 genetika   MeSH
• TNF-alfa * genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Chronic inflammation represents a major threat to human health since long-term systemic inflammation is known to affect distinct tissues and organs. Recently, solid evidence demonstrated that chronic inflammation affects hematopoiesis; however, how chronic inflammation affects hematopoietic stem cells (HSCs) on the mechanistic level is poorly understood. Here, we employ a mouse model of chronic multifocal osteomyelitis (CMO) to assess the effects of a spontaneously developed inflammatory condition on HSCs. We demonstrate that hematopoietic and nonhematopoietic compartments in CMO BM contribute to HSC expansion and impair their function. Remarkably, our results suggest that the typical features of murine multifocal osteomyelitis and the HSC phenotype are mechanistically decoupled. We show that the CMO environment imprints a myeloid gene signature and imposes a pro-inflammatory profile on HSCs. We identify IL-6 and the Jak/Stat3 signaling pathway as critical mediators. However, while IL-6 and Stat3 blockage reduce HSC numbers in CMO mice, only inhibition of Stat3 activity significantly rescues their fitness. Our data emphasize the detrimental effects of chronic inflammation on stem cell function, opening new venues for treatment.

• MeSH
• hematopoetické kmenové buňky metabolismus   MeSH
• hematopoéza MeSH
• interleukin-6 * genetika   metabolismus   MeSH
• lidé MeSH
• myši MeSH
• signální transdukce MeSH
• transkripční faktor STAT3 genetika   metabolismus   MeSH
• zánět * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The cytokine interleukin-6 (IL-6) has considerable pro-inflammatory properties and is a driver of many physiological and pathophysiological processes. Cellular responses to IL-6 are mediated by membrane-bound or soluble forms of the IL-6 receptor (IL-6R) complexed with the signal-transducing subunit gp130. While expression of the membrane-bound IL-6R is restricted to selected cell types, soluble IL-6R (sIL-6R) enables gp130 engagement on all cells, a process termed IL-6 trans-signalling and considered to be pro-inflammatory. sIL-6R is predominantly generated through proteolytic processing by the metalloproteinase ADAM17. ADAM17 also liberates ligands of the epidermal growth factor receptor (EGFR), which is a prerequisite for EGFR activation and results in stimulation of proliferative signals. Hyperactivation of EGFR mostly due to activating mutations drives cancer development. Here, we reveal an important link between overshooting EGFR signalling and the IL-6 trans-signalling pathway. In epithelial cells, EGFR activity induces not only IL-6 expression but also the proteolytic release of sIL-6R from the cell membrane by increasing ADAM17 surface activity. We find that this derives from the transcriptional upregulation of iRhom2, a crucial regulator of ADAM17 trafficking and activation, upon EGFR engagement, which results in increased surface localization of ADAM17. Also, phosphorylation of the EGFR-downstream mediator ERK mediates ADAM17 activity via interaction with iRhom2. In sum, our study reveals an unforeseen interplay between EGFR activation and IL-6 trans-signalling, which has been shown to be fundamental in inflammation and cancer.

• MeSH
• cytokinový receptor gp130 genetika   MeSH
• epitelové buňky metabolismus   MeSH
• erbB receptory genetika   metabolismus   MeSH
• interleukin-6 * genetika   metabolismus   MeSH
• lidé MeSH
• protein ADAM17 * MeSH
• signální transdukce * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Gene inactivation of the cyclin-dependent kinase inhibitors p16INK4a, p15INK4b and p21WAF is frequently mediated by promoter gene methylation, whereas histone deacetylases (HDACs) control gene expression through their ability to deacetylate proteins. The effect of suberohydroxamic acid (SBHA) and 5-Aza-2'-deoxycytidine (Decitabine) (DAC) treatments on the transcription of CDKN2A, CDKN2B and CDKN1A genes, and their effects on molecular biological behavior were examined in two myeloma cell lines, RPMI8226 and U266, which differ in p53-functionality and IL-6 expression. In both tested myeloma cell lines, a non-methylated state of the CDKN2B gene promoter region was detected with normal gene expression, and the same level of p15INK4b protein was detected by immunocytochemical staining. Furthermore, in myeloma cells treated with SBHA and DAC alone, the expression of both p15INK4b and p21WAF was significantly upregulated in RPMI8226 cells (p53-functional, without IL-6 expression), whereas in the U266 cell line (p53 deleted, expressing IL-6) only p21WAF expression was significantly increased. Moreover, the analysis revealed that treatment with DAC induced DNMT3B enhancement in U266 cells. In conclusion, in myeloma cells with IL-6 expression, significantly increased DNMT3B expression indicated the tumorigenic consequences of 5-Aza-2'deoxycytidine treatment, which requires careful use in diseases involving epigenetic dysregulation, such as multiple myeloma (MM).

• MeSH
• decitabin * farmakologie   MeSH
• DNA-(cytosin-5-)methyltransferasa * genetika   metabolismus   MeSH
• epigeneze genetická * MeSH
• inhibitor p15 cyklin-dependentní kinasy genetika   metabolismus   MeSH
• inhibitor p16 cyklin-dependentní kinasy genetika   metabolismus   MeSH
• interleukin-6 genetika   metabolismus   MeSH
• lidé MeSH
• metylace DNA MeSH
• mnohočetný myelom * genetika   metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 genetika   metabolismus   MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• umlčování genů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Of all kidney transplants, half are still lost in the first decade after transplantation. Here, using genetics, we probed whether interleukin 6 (IL-6) could be a target in kidney transplantation to improve graft survival. Additionally, we investigated if a genetic risk score (GRS) based on IL6 and IL10 variants could improve prognostication of graft loss. In a prospective cohort study, DNA of 1271 donor-recipient kidney transplant pairs was analyzed for the presence of IL6, IL6R, IL10, IL10RA, and IL10RB variants. These polymorphisms and their GRS were then associated with 15-year death-censored allograft survival. The C|C-genotype of the IL6 polymorphism in donor kidneys and the combined C|C-genotype in donor-recipient pairs were both associated with a reduced risk of graft loss (p = .043 and p = .042, respectively). Additionally, the GRS based on IL6, IL6R, IL10, IL10RA, and IL10RB variants was independently associated with the risk of graft loss (HR 1.53, 95%-CI [1.32-1.84]; p < .001). Notably, the GRS improved risk stratification and prediction of graft loss beyond the level of contemporary clinical markers. Our findings reveal the merits of a polygenic IL-6-based risk score strengthened with IL-10- polymorphisms for the prognostication and risk stratification of late graft failure in kidney transplantation.

• MeSH
• alografty MeSH
• interleukin-10 * genetika   MeSH
• interleukin-6 * genetika   MeSH
• ledviny MeSH
• lidé MeSH
• prospektivní studie MeSH
• rizikové faktory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE OF THE STUDY The aim of the present study was to determine the potential effects of single nucleotide polymorphisms (SNPs) of TGFB1 and IL-6 on the development and severity of the disease in patients with DDH and investigate the relationship of these two gene polymorphisms. MATERIAL AND METHODS This case control study was conducted on 105 patients diagnosed with DDH and 119 healthy control subjects of any age. The DDH patients were classified according to the Hartofilakidis and IHDI classifications for adult and pediatric patients, respectively. Genomic DNA was isolated from peripheral blood samples using the Salting-out method. TGFB1 gene p.Pro10Leu (c.29C>T) (rs1800470) and IL-6 572G>C (rs1800796) polymorphisms were analyzed using Sanger DNA sequencing. RESULTS There was no statistically significant relationship of TGFB1 and IL-6 SNPs for DDH. When the rs1800470 and rs1800796 polymorphisms were compared according to family history, the homozygous mutation rate of TGFB1 gene was found to be significantly higher in patients with a positive family history than in patients with a negative family history. No significant relationship was found between rs1800796 polymorphisms and family history. TGFB1 homozygous mutation rate was determined to be statistically higher in the positive family history group than control group. No similar relationship was found between the negative family history group and the control group. No statistically significant relationship was determined between rs1800470 and rs1800796 and the severity of DDH. CONCLUSIONS rs1800796 and rs1800470 polymorphisms do not appear to be major responsible genetic factors for DDH. However, the determination of a correlation between a positive family history and homozygous mutation rate of the TGFB1 gene indicates that this gene may have a greater effect on DDH development. Key words: developmental dysplasia of the hip, interleukin-6, transforming growth factor beta 1, case control study.

• MeSH
• dítě MeSH
• dospělí MeSH
• frekvence genu MeSH
• interleukin-6 * genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• studie případů a kontrol MeSH
• transformující růstový faktor beta1 genetika   MeSH
• vývojová dysplazie kyčelního kloubu * MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

A host's immune system can be invaded by mycotoxin deoxynivalenol (DON) poisoning and porcine circovirus type 2 (PCV2) infections, which affect the host's natural immune function. Pro-inflammatory cytokines, IL-1β and IL-6, are important regulators in the process of natural immune response, which participate in inflammatory response and enhance immune-mediated tissue damage. Preliminary studies have shown that DON promotes PCV2 infection by activating the MAPK signaling pathway. Here, we explored whether the mRNA expression of IL-1β and IL-6, induced by the combination of DON and PCV2, would depend on the MAPK signaling pathway. Specific pharmacological antagonists U0126, SP600125 and SB203580, were used to inhibit the activities of ERK, JNK and p38 in the MAPK signaling pathway, respectively. Then, the mRNA expression of IL-1β and IL-6 in PK-15 cells was detected to explore the effect of the MAPK signaling pathway on IL-1β and IL-6 mRNA induced by DON and PCV2. The results showed that PK-15 cells treated with DON or PCV2 induced the mRNA expression of IL-1β and IL-6 in a time- and dose-dependent manner. The combination of DON and PCV2 has an additive effect on inducing the mRNA expression of IL-1β and IL-6. Additionally, both DON and PCV2 could induce the mRNA expression of IL-1β and IL-6 via the ERK and the p38 MAPK signal pathways, while PCV2 could induce it via the JNK signal pathway. Taken together, our results suggest that MAPKs play a contributory role in IL-1β and IL-6 mRNA expression when induced by both DON and PCV2.

• MeSH
• buněčné linie MeSH
• Circovirus * MeSH
• infekce viry čeledi Circoviridae genetika   metabolismus   MeSH
• interleukin-1beta genetika   MeSH
• interleukin-6 genetika   MeSH
• MAP kinasový signální systém účinky léků   MeSH
• messenger RNA MeSH
• prasata MeSH
• trichotheceny toxicita   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The FDA-approved drugs raloxifene and bazedoxifene could be among the best candidates to prevent mortality in severe COVID-19 patients. Raloxifene and bazedoxifene inhibit IL-6 signaling at therapeutic doses, suggesting they have the potential to prevent the cytokine storm, ARDS and mortality in severe COVID-19 patients, as is being shown with humanized antibodies blocking IL-6 signaling. In addition, raloxifene and bazedoxifene are selective estrogen receptor modulators with strong antiviral activity.

• MeSH
• Betacoronavirus účinky léků   patogenita   MeSH
• cytokiny antagonisté a inhibitory   genetika   MeSH
• indoly farmakologie   MeSH
• interleukin-6 antagonisté a inhibitory   genetika   MeSH
• koronavirové infekce farmakoterapie   genetika   mortalita   virologie   MeSH
• lidé MeSH
• pandemie MeSH
• raloxifen hydrochlorid farmakologie   MeSH
• receptory pro estrogeny antagonisté a inhibitory   MeSH
• selektivní modulátory estrogenních receptorů farmakologie   MeSH
• signální transdukce účinky léků   MeSH
• syndrom dechové tísně farmakoterapie   prevence a kontrola   virologie   MeSH
• virová pneumonie farmakoterapie   genetika   mortalita   virologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The inhalation of metal (including lead) nanoparticles poses a real health issue to people and animals living in polluted and/or industrial areas. In this study, we exposed mice to lead(II) nitrate nanoparticles [Pb(NO3)2 NPs], which represent a highly soluble form of lead, by inhalation. We aimed to uncover the effects of their exposure on individual target organs and to reveal potential variability in the lead clearance. We examined (i) lead biodistribution in target organs using laser ablation and inductively coupled plasma mass spectrometry (LA-ICP-MS) and atomic absorption spectrometry (AAS), (ii) lead effect on histopathological changes and immune cells response in secondary target organs and (iii) the clearance ability of target organs. In the lungs and liver, Pb(NO3)2 NP inhalation induced serious structural changes and their damage was present even after a 5-week clearance period despite the lead having been almost completely eliminated from the tissues. The numbers of macrophages significantly decreased after 11-week Pb(NO3)2 NP inhalation; conversely, abundance of alpha-smooth muscle actin (α-SMA)-positive cells, which are responsible for augmented collagen production, increased in both tissues. Moreover, the expression of nuclear factor κB (NF-κB) and selected cytokines, such as tumor necrosis factor alpha (TNFα), transforming growth factor beta 1 (TGFβ1), interleukin 6(IL-6), IL-1α and IL-1β , displayed a tissue-specific response to lead exposure. In summary, diminished inflammatory response in tissues after Pb(NO3)2 NPs inhalation was associated with prolonged negative effect of lead on tissues, as demonstrated by sustained pathological changes in target organs, even after long clearance period.

• MeSH
• aktiny agonisté   genetika   imunologie   MeSH
• alveolární makrofágy účinky léků   imunologie   patologie   MeSH
• aplikace inhalační MeSH
• biologická dostupnost MeSH
• dusičnany farmakokinetika   toxicita   MeSH
• exprese genu MeSH
• inhalační expozice analýza   MeSH
• interleukin-1alfa agonisté   genetika   imunologie   MeSH
• interleukin-1beta agonisté   genetika   imunologie   MeSH
• interleukin-6 agonisté   genetika   imunologie   MeSH
• játra účinky léků   imunologie   patologie   MeSH
• kovové nanočástice aplikace a dávkování   toxicita   MeSH
• látky znečišťující vzduch farmakokinetika   toxicita   MeSH
• myši inbrední ICR MeSH
• myši MeSH
• NF-kappa B agonisté   genetika   imunologie   MeSH
• olovo farmakokinetika   toxicita   MeSH
• plíce účinky léků   imunologie   patologie   MeSH
• poločas MeSH
• spektrofotometrie atomová MeSH
• tkáňová distribuce MeSH
• TNF-alfa agonisté   genetika   imunologie   MeSH
• transformující růstový faktor beta1 agonisté   genetika   imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Interleukin-6 (IL-6) is a cytokine with multifaceted effects playing a remarkable role in the initiation of the immune response. The increased level of this cytokine in the elderly seems to be associated with the chronic inflammatory setting of the microenvironment in aged individuals. IL-6 also represents one of the main signals in communication between cancer cells and their non-malignant neighbours within the tumour niche. IL-6 also participates in the development of a premetastatic niche and in the adjustment of the metabolism in terminal-stage patients suffering from a malignant disease. IL-6 is a fundamental factor of the cytokine storm in patients with severe COVID-19, where it is responsible for the fatal outcome of the disease. A better understanding of the role of IL-6 under physiological as well as pathological conditions and the preparation of new strategies for the therapeutic control of the IL-6 axis may help to manage the problems associated with the elderly, cancer, and serious viral infections.

• MeSH
• COVID-19 MeSH
• interleukin-6 genetika   metabolismus   MeSH
• koronavirové infekce metabolismus   patologie   MeSH
• lidé MeSH
• nádory metabolismus   patologie   MeSH
• pandemie MeSH
• signální transdukce MeSH
• stárnutí metabolismus   patologie   MeSH
• virová pneumonie metabolismus   patologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH