BACKGROUND: Great progress has been made in the understanding of inflammatory processes in psoriasis. However, clarifying the role of genetic variability in processes regulating inflammation, including post-transcriptional regulation by microRNA (miRNA), remains a challenge. OBJECTIVES: We therefore investigated single nucleotide polymorphisms (SNPs) with a predicted change in the miRNA/mRNA interaction of genes involved in the psoriasis inflammatory processes. METHODS: Studied SNPs rs2910164 C/G-miR-146a, rs4597342 T/C-ITGAM, rs1368439 G/T-IL12B, rs1468488 C/T-IL17RA were selected using a bioinformatics analysis of psoriasis inflammation-associated genes. These SNPs were then genotyped using a large cohort of women with psoriasis (n = 241) and healthy controls (n = 516). RESULTS: No significant association with psoriasis was observed for rs2910164, rs1368439, and rs1468488 genotypes. However, the major allele T of rs4597342 -ITGAM was associated with approximately 28% higher risk for psoriasis in comparison to the patients with the C allele (OR = 1.28, 95% CI 1.01-1.61, p = 0.037). In case of genotypes, the effect of the T allele indicates the dominant model of disease penetrance as the CT and TT genotypes increase the chance of psoriasis up to 42% in comparison to CC homozygotes of rs4597342 (OR = 1.42, 95% CI = 1.05-1.94, p = 0.025). CONCLUSION: SNP rs4597342 in 3'UTR of ITGAM influencing miR-21 binding may be considered a risk factor for psoriasis development. Upregulated miR-21 in psoriasis is likely to inhibit CD11b production in the case of the rs4597342 T allele which may lead to Mac-1 dysfunction, resulting in an aberrant function of innate immune cells and leading to the production of cytokines involved in psoriasis pathogenesis.

• MeSH
• 3' nepřekládaná oblast genetika   MeSH
• alely MeSH
• antigeny CD11b genetika   MeSH
• Asijci MeSH
• genetická predispozice k nemoci MeSH
• genetické asociační studie MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• psoriáza genetika   patologie   MeSH
• rizikové faktory MeSH
• vazebná místa genetika   MeSH
• zánět genetika   patologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Adenylate cyclase toxin-hemolysin (CyaA, ACT or AC-Hly) of the whooping cough agent Bordetella pertussis penetrates phagocytes expressing the integrin complement receptor 3 (CR3, CD11b/CD18, α(M)β(2) or Mac-1). CyaA translocates its adenylate cyclase (AC) enzyme domain into cell cytosol and catalyzes unregulated conversion of ATP to cAMP, thereby subverting cellular signaling. In parallel, CyaA forms small cation-selective membrane pores that permeabilize cells for potassium efflux, contributing to cytotoxicity of CyaA and eventually provoking colloid-osmotic cell lysis. To investigate whether the single-pass α-helical transmembrane segments of CR3 subunits CD11b and CD18 do directly participate in AC domain translocation and/or pore formation by the toxin, we expressed in CHO cells variants of CR3 that contained artificial transmembrane segments, or lacked the transmembrane segment(s) at all. The results demonstrate that the transmembrane segments of CR3 are not directly involved in the cytotoxic activities of CyaA but serve for maintaining CR3 in a conformation that is required for efficient toxin binding and action.

• MeSH
• adenosintrifosfát chemie   MeSH
• adenylátcyklasový toxin metabolismus   MeSH
• AMP cyklický biosyntéza   MeSH
• antigeny CD11b genetika   metabolismus   MeSH
• antigeny CD18 genetika   metabolismus   MeSH
• biologický transport fyziologie   MeSH
• Bordetella pertussis metabolismus   MeSH
• buněčné linie MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• fagocyty metabolismus   MeSH
• lidé MeSH
• makrofágový antigen 1 biosyntéza   genetika   metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.

• MeSH
• antigeny CD11b genetika   MeSH
• celogenomová asociační studie MeSH
• genetická pleiotropie genetika   MeSH
• genetické lokusy genetika   MeSH
• HLA-D antigeny genetika   MeSH
• IgA nefropatie genetika   MeSH
• imunita genetika   MeSH
• interakce hostitele a patogenu genetika   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• protoonkogenní proteiny c-vav genetika   MeSH
• signální adaptorové proteiny CARD genetika   MeSH
• střeva imunologie   parazitologie   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

The aim of this study was to compare two methods for quantification of changes in intracellular potassium concentration (decrease from ∼140 to ∼20mM) due to the action of a pore-forming toxin, the adenylate cyclase toxin (CyaA) from the pathogenic bacterium Bordetella pertussis. CyaA was incubated with stably transfected K1 Chinese hamster ovary cells expressing the toxin receptor CD11b/CD18 and the decrease in potassium concentration in the cells was followed by inductively coupled plasma mass spectrometry (ICP-MS). It is shown that this method is superior in terms of sensitivity, accuracy, and temporal resolution over the method employing the potassium-binding benzofuran isophthalate-acetoxymethyl ester fluorescent indicator. The ICP-MS procedure was found to be a reliable and straightforward analytical approach enabling kinetic studies of CyaA action at physiologically relevant toxin concentrations (<1000ng/ml) in biological microsamples.

• MeSH
• adenylátcyklasový toxin toxicita   MeSH
• antigeny CD11b genetika   MeSH
• antigeny CD18 genetika   MeSH
• Bordetella pertussis enzymologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• draslík chemie   metabolismus   MeSH
• fluorescenční barviva chemie   MeSH
• hmotnostní spektrometrie metody   MeSH
• intracelulární prostor účinky léků   metabolismus   MeSH
• křečci praví MeSH
• lidé MeSH
• transfekce MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• antigeny CD11b genetika   MeSH
• celogenomová asociační studie * MeSH
• chronické selhání ledvin MeSH
• genetická pleiotropie genetika   MeSH
• genetické lokusy genetika   MeSH
• HLA-D antigeny genetika   MeSH
• IgA nefropatie * genetika   MeSH
• imunita genetika   MeSH
• interakce hostitele a patogenu genetika   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé MeSH
• protoonkogenní proteiny c-vav genetika   MeSH
• signální adaptorové proteiny CARD genetika   MeSH
• střeva imunologie   MeSH
• věk při počátku nemoci MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• komentáře MeSH

One of the promising approaches in the therapy of ulcerative colitis is administration of butyrate, an energy source for colonocytes, into the lumen of the colon. This study investigates the effect of butyrate producing bacterium Clostridium tyrobutyricum on dextran sodium sulphate (DSS)-induced colitis in mice. Immunocompetent BALB/c and immunodeficient severe combined immunodeficiency (SCID) mice reared in specific-pathogen-free (SPF) conditions were treated intrarectally with C. tyrobutyricum 1 week prior to the induction of DSS colitis and during oral DSS treatment. Administration of DSS without C. tyrobutyricum treatment led to an appearance of clinical symptoms - bleeding, rectal prolapses and colitis-induced increase in the antigen CD11b, a marker of infiltrating inflammatory cells in the lamina propria. The severity of colitis was similar in BALB/c and SCID mice as judged by the histological damage score and colon shortening after 7 days of DSS treatment. Both strains of mice also showed a similar reduction in tight junction (TJ) protein zonula occludens (ZO)-1 expression and of MUC-2 mucin depression. Highly elevated levels of cytokine tumour necrosis factor (TNF)-α in the colon of SCID mice and of interleukin (IL)-18 in BALB/c mice were observed. Intrarectal administration of C. tyrobutyricum prevented appearance of clinical symptoms of DSS-colitis, restored normal MUC-2 production, unaltered expression of TJ protein ZO-1 and decreased levels of TNF-α and IL-18 in the descending colon of SCID and BALB/c mice, respectively. Some of these features can be ascribed to the increased production of butyrate in the lumen of the colon and its role in protection of barrier functions and regulation of IL-18 expression.

• MeSH
• akutní nemoc MeSH
• antigeny CD11b biosyntéza   genetika   MeSH
• aplikace rektální MeSH
• bakteriální translokace MeSH
• butyráty metabolismus   MeSH
• Clostridium tyrobutyricum fyziologie   MeSH
• fosfoproteiny biosyntéza   genetika   MeSH
• imunokompetence MeSH
• interleukin-18 biosyntéza   genetika   MeSH
• kolon metabolismus   mikrobiologie   patologie   MeSH
• mastné kyseliny metabolismus   MeSH
• membránové proteiny biosyntéza   genetika   MeSH
• mucin 2 biosyntéza   genetika   MeSH
• muciny biosyntéza   MeSH
• myši inbrední BALB C MeSH
• myši SCID MeSH
• myši MeSH
• organismy bez specifických patogenů MeSH
• probiotika terapeutické užití   MeSH
• síran dextranu toxicita   MeSH
• těžká kombinovaná imunodeficience genetika   imunologie   MeSH
• TNF-alfa biosyntéza   genetika   MeSH
• ulcerózní kolitida chemicky indukované   genetika   imunologie   mikrobiologie   patologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Adenylate cyclase toxin (CyaA or ACT) is a key virulence factor of pathogenic Bordetellae. It penetrates phagocytes expressing the alpha(M)beta(2) integrin (CD11b/CD18, Mac-1 or CR3) and paralyzes their bactericidal capacities by uncontrolled conversion of ATP into a key signaling molecule, cAMP. Using pull-down activity assays and transfections with mutant Rho family GTPases, we show that cAMP signaling of CyaA causes transient and selective inactivation of RhoA in mouse macrophages in the absence of detectable activation of Rac1, Rac2, or RhoG. This CyaA/cAMP-induced drop of RhoA activity yielded dephosphorylation of the actin filament severing protein cofilin and massive actin cytoskeleton rearrangements, which were paralleled by rapidly manifested macrophage ruffling and a rapid and unexpected loss of macropinocytic fluid phase uptake. As shown in this study for the first time, CyaA/cAMP signaling further caused a rapid and near-complete block of complement-mediated phagocytosis. Induction of unproductive membrane ruffling, hence, represents a novel sophisticated mechanism of down-modulation of bactericidal activities of macrophages and a new paradigm for action of bacterial toxins that hijack host cell signaling by manipulating cellular cAMP levels.

• MeSH
• adenylátcyklasový toxin imunologie   metabolismus   MeSH
• AMP cyklický imunologie   MeSH
• antigeny CD11b genetika   imunologie   MeSH
• antigeny CD18 genetika   imunologie   MeSH
• Bordetella pertussis enzymologie   imunologie   MeSH
• buněčná membrána imunologie   metabolismus   MeSH
• buněčné linie MeSH
• faktory depolymerizující aktin imunologie   metabolismus   MeSH
• financování organizované MeSH
• GTP-fosfohydrolasy imunologie   metabolismus   MeSH
• makrofágový antigen 1 imunologie   metabolismus   MeSH
• makrofágy imunologie   metabolismus   MeSH
• mikrofilamenta imunologie   metabolismus   MeSH
• myši MeSH
• neuropeptidy imunologie   metabolismus   MeSH
• pertuse enzymologie   imunologie   MeSH
• rac proteiny vázající GTP imunologie   metabolismus   MeSH
• rho proteiny vázající GTP imunologie   metabolismus   MeSH
• signální transdukce imunologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH