Macrolide antibiotics such as azithromycin or clarithromycin are known to have potent anti-inflammatory and immunomodulatory effects but these properties cannot be widely used due to a risk of bacterial resistance. We studied another polyketide antibiotic, structurally related manumycin A known as a streptomycete derived farnesyltransferase inhibitor with limited antibacterial effects, with respect to its potential regulation of mRNA expression of several genes associated with proinflammatory responses. Downregulation of mRNA for IL-6, TLR-8, IL-1 beta and IL-10 was found in THP-1 cells after 4h stimulation with TNF alpha in the presence of manumycin A and downregulated TLR-8 and EGR-1 genes were observed after 8h. Among the genes upregulated in response to manumycin were HMOX-1, TNFRSF10A, IL-1R1, TICAM2, NLRP12 after 4h and only IL-1R1 after 8h. Furthermore, manumycin A was found to inhibit IL-1beta, IL-6, and IL-8 production in TNF alpha stimulated THP-1 cells and peripheral blood monocytes in a dose dependent manner (0.25-1 μM of manumycin A) without affecting cell viability. Cell viability of blood monocytes decreased by about 30% at manumycin A doses of 2-5 μM. Manumycin A also inhibited IL-18 release from THP-1 cells, while in cultures of blood monocytes, this cytokine was not detectable. That manumycin A mediated downregulation of proinflammatory genes in human monocytes confirmed by a measurement of cytokine levels in culture supernatants, together with a very limited effect on cell viability, might suggest potential anti-inflammatory properties of this polyketide antibiotic.
- MeSH
- antibakteriální látky farmakologie MeSH
- antiflogistika farmakologie MeSH
- buněčné linie MeSH
- cytokiny genetika metabolismus MeSH
- imunomodulace MeSH
- lidé MeSH
- messenger RNA genetika MeSH
- monocyty účinky léků imunologie MeSH
- polyeny farmakologie MeSH
- polynenasycené alkamidy farmakologie MeSH
- protein 1 časné růstové odpovědi genetika metabolismus MeSH
- receptory interleukinu-1 genetika metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- TNF-alfa metabolismus MeSH
- toll-like receptor 8 genetika metabolismus MeSH
- zánět farmakoterapie imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
ST2 je členem skupiny receptorů interleukinu 1 (IL1), skládá se z transmembránového ligandu (ST2L) a solubilní formy (sST2). sST2 se uvolňuje z kardiomyocytů a srdečních fibroblastů při mechanickém zatěžování. Byl nově označen za nový ukazatel myokardiálního zatížení, fibrózy a remodelace. Řada studií prokázala, že stanovení sST2 přináší významnou prognostickou informaci u pacientů se srdečním selháním. Zvýšené koncentrace sST2 předpovídaly riziko hospitalizace a úmrtí, a to nezávisle na koncentraci natriuretických peptidů a nezávisle na některých klinických parametrech. Některé práce rovněž prokázaly diagnostický význam stanovení sST2 u pacientů se srdečním selháním a normální ejekční frakcí levé komory.
ST2 is a member of the interleukin 1 (IL1) receptor family and consists of a trans-membrane ligand (STL2) and a soluble form (sST2). sST2 is released from cardiomyocytes and fibroblasts after mechanical strain and has been identified as a novel biomarker of cardiac stress, fibrosis and remodelling. Many studies showed that sST2 brings important prognostic information in patients with heart failure. Elevated sST2 concentrations predicted risk of hospitalization and mortality independently on natriuretic peptides levels and on other clinical variables. Some studies showed diagnostic role of sST2 u patients with heart failure and normal ejection fraction.
- Klíčová slova
- solubilní receptor ST2,
- MeSH
- biologické markery * krev MeSH
- dyspnoe etiologie krev MeSH
- lidé MeSH
- prognóza MeSH
- receptory interleukinu-1 * krev metabolismus MeSH
- srdeční selhání * diagnóza krev metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: Microbial sensing by Toll-like receptors (TLR) and its negative regulation have an important role in the pathogenesis of inflammation-related cancer. In this study, we investigated the role of negative regulation of Toll-like receptors signaling and gut microbiota in the development of colitis-associated cancer in mouse model. METHODS: Colitis-associated cancer was induced by azoxymethane and dextran sodium sulfate in wild-type and in interleukin-1 receptor-associated kinase M (IRAK-M)-deficient mice with or without antibiotic (ATB) treatment. Local cytokine production was analyzed by multiplex cytokine assay or enzyme-linked immunosorbent assay, and regulatory T cells were analyzed by flow cytometry. Changes in microbiota composition during tumorigenesis were analyzed by pyrosequencing, and β-glucuronidase activity was measured in intestinal content by fluorescence assay. RESULTS: ATB treatment of wild-type mice reduced the incidence and severity of tumors. Compared with nontreated mice, ATB-treated mice had significantly lower numbers of regulatory T cells in colon, altered gut microbiota composition, and decreased β-glucuronidase activity. However, the β-glucuronidase activity was not as low as in germ-free mice. IRAK-M-deficient mice not only developed invasive tumors, but ATB-induced decrease in β-glucuronidase activity did not rescue them from severe carcinogenesis phenotype. Furthermore, IRAK-M-deficient mice had significantly increased levels of proinflammatory cytokines in the tumor tissue. CONCLUSIONS: We conclude that gut microbiota promotes tumorigenesis by increasing the exposure of gut epithelium to carcinogens and that IRAK-M-negative regulation is essential for colon cancer resistance even in conditions of altered microbiota. Therefore, gut microbiota and its metabolic activity could be potential targets for colitis-associated cancer therapy.
- MeSH
- azoxymethan toxicita MeSH
- cytokiny genetika metabolismus MeSH
- gastrointestinální trakt mikrobiologie MeSH
- karcinogeny toxicita MeSH
- kinázy asociované s receptory interleukinu-1 fyziologie MeSH
- kolitida chemicky indukované komplikace MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- messenger RNA genetika MeSH
- metagenom * MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- nádory tračníku etiologie metabolismus patologie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- průtoková cytometrie MeSH
- receptory interleukinu-1 metabolismus MeSH
- regulační T-lymfocyty imunologie metabolismus patologie MeSH
- signální transdukce MeSH
- síran dextranu toxicita MeSH
- toll-like receptory genetika metabolismus MeSH
- western blotting MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Primary OA is a common multifactorial disease with not fully clarified molecular factors influencing the development of the disease. Among factors disturbing the cartilage integrity are cytokines, such as IL-1, which can stimulate proteinases, resulting in the cartilage destruction. In this regard, IL-1RA competing with IL-1 for binding to its receptor may act as an inhibitor of cartilage breakdown. Because of the possible functional implications, we tested VNTR polymorphism in the second intron of the IL-1RN gene as a putative factor of susceptibility to knee OA. Fifty patients with primary knee OA (diagnosed according to ACR criteria) and 170 healthy controls were included into the study. PCR using primers flanking the VNTR region containing variable numbers of an 86-bp tandem repeat was employed to test the hypothesis. An increased frequency and carriage rate of the IL-1RN*2 allele was found in OA patients in comparison with controls (28 % vs. 15 %, P = 0.0013, OR = 2.97; 95% CI 1.55-5.68 for frequency; 52.5 % vs. 25.3 %, P = 0.0019, OR = 2.95; 95% CI 1.54-5.68 for carriage rate). In addition, a higher frequency of genotype IL-1RN*1/*2 in OA patients was observed as compared with controls (42 % vs. 20.6 %, P = 0.0032, OR = 2.79; 95% CI 1.42-5.48). These results suggest that the IL-1RN*2 allele might represent a factor of susceptibility to OA; however, no correlation between this allele and the markers of cartilage degradation was found.
- MeSH
- antagonista receptoru pro interleukin 1 genetika metabolismus MeSH
- antirevmatika metabolismus MeSH
- artróza kolenních kloubů genetika imunologie patologie MeSH
- běloši genetika MeSH
- biologické markery metabolismus MeSH
- frekvence genu MeSH
- genetická predispozice k nemoci MeSH
- kloubní chrupavka patologie MeSH
- lidé MeSH
- minisatelitní repetice MeSH
- polymorfismus genetický MeSH
- receptory interleukinu-1 genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Geografické názvy
- Česká republika MeSH
