Live biotherapeutic products constitute an emerging therapeutic approach to prevent or treat inflammatory bowel diseases. Lactobacillus acidophilus is a constituent of the human microbiota with probiotic potential, that is illustrated by improvement of intestinal inflammation and antimicrobial activity against several pathogens. In this study, we evaluated the immunomodulatory properties of the L. acidophilus strain BIO5768 at steady state and upon acute inflammation. Supplementation of naïve mice with BIO5768 heightened the transcript level of some IL-17 target genes encoding for protein with microbicidal activity independently of NOD2 signaling. Of these, the BIO5768-induced expression of Angiogenin-4 was blunted in monocolonized mice that are deficient for the receptor of IL-17 (but not for NOD2). Interestingly, priming of bone marrow derived dendritic cells by BIO5768 enhanced their ability to support the secretion of IL-17 by CD4+ T cells. Equally of importance, the production of IL-22 by type 3 innate lymphoid cells is concomitantly heightened in response to BIO5768. When administered alone or in combination with Bifidobacterium animalis spp. lactis BIO5764 and Limosilactobacillus reuteri, BIO5768 was able to alleviate at least partially intestinal inflammation induced by Citrobacter rodentium infection. Furthermore, BIO5768 was also able to improve colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). In conclusion, we identify a new potential probiotic strain for the management of inflammatory bowel diseases, and provide some insights into its IL-17-dependent and independent mode of action.

• MeSH
• Bifidobacterium animalis MeSH
• enterobakteriální infekce terapie   MeSH
• idiopatické střevní záněty * terapie   MeSH
• interleukin-17 MeSH
• kolitida * chemicky indukované   terapie   mikrobiologie   MeSH
• kyselina trinitrobenzensulfonová škodlivé účinky   MeSH
• Lactobacillus acidophilus * MeSH
• lymfocyty MeSH
• myši MeSH
• přirozená imunita * MeSH
• probiotika * farmakologie   terapeutické užití   MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• interleukin-17 MeSH
• kyselina trinitrobenzensulfonová MeSH

Alterations in the gut microbiota composition and diversity seem to play a role in the development of chronic diseases, including inflammatory bowel disease (IBD), leading to gut barrier disruption and induction of proinflammatory immune responses. This opens the door for the use of novel health-promoting bacteria. We selected five Parabacteroides distasonis strains isolated from human adult and neonates gut microbiota. We evaluated in vitro their immunomodulation capacities and their ability to reinforce the gut barrier and characterized in vivo their protective effects in an acute murine model of colitis. The in vitro beneficial activities were highly strain dependent: two strains exhibited a potent anti-inflammatory potential and restored the gut barrier while a third strain reinstated the epithelial barrier. While their survival to in vitro gastric conditions was variable, the levels of P. distasonis DNA were higher in the stools of bacteria-treated animals. The strains that were positively scored in vitro displayed a strong ability to rescue mice from colitis. We further showed that two strains primed dendritic cells to induce regulatory T lymphocytes from naïve CD4+ T cells. This study provides better insights on the functionality of commensal bacteria and crucial clues to design live biotherapeutics able to target inflammatory chronic diseases such as IBD.

• Klíčová slova
• IBD, colitis, functional screening, holobiont, immune response, live biotherapeutic products (LBP), microbiota, probiotics,
• MeSH
• Bacteroidetes genetika   imunologie   izolace a purifikace   MeSH
• Caco-2 buňky MeSH
• DNA bakterií genetika   metabolismus   MeSH
• dospělí MeSH
• feces mikrobiologie   MeSH
• idiopatické střevní záněty imunologie   mikrobiologie   MeSH
• kolitida chemicky indukované   imunologie   mikrobiologie   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• kyselina trinitrobenzensulfonová škodlivé účinky   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• novorozenec MeSH
• regulační T-lymfocyty imunologie   MeSH
• střevní mikroflóra imunologie   MeSH
• střevní sliznice imunologie   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• myši MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA bakterií MeSH
• kyselina trinitrobenzensulfonová MeSH

Crohn's disease is linked to a decreased diversity in gut microbiota composition as a potential consequence of an impaired anti-microbial response and an altered polarization of T helper cells. Here, we evaluated the immunomodulatory properties of two potential probiotic strains, namely a Bifidobacterium animalis spp. lactis Bl 5764 and a Lactobacillus reuteri Lr 5454 strains. Both strains improved colitis triggered by either 2,4,6-trinitrobenzenesulfonic acid (TNBS) or Citrobacter rodentium infection in mice. Training of dendritic cells (DC) with Lr 5454 efficiently triggered IL-22 secretion and regulatory T cells induction in vitro, while IL-17A production by CD4+ T lymphocytes was stronger when cultured with DCs that were primed with Bl 5764. This strain was sufficient for significantly inducing expression of antimicrobial peptides in vivo through the Crohn's disease predisposing gene encoding for the nucleotide-binding oligomerization domain, containing protein 2 (NOD2). In contrast, NOD2 was dispensable for the impact on antimicrobial peptide expression in mice that were monocolonized with Lr 5454. In conclusion, our work highlights a differential mode of action of two potential probiotic strains that protect mice against colitis, providing the rational for a personalized supportive preventive therapy by probiotics for individuals that are genetically predisposed to Crohn's disease.

• MeSH
• antiflogistika nesteroidní farmakologie   MeSH
• Bifidobacterium animalis * MeSH
• Citrobacter rodentium patogenita   MeSH
• dendritické buňky fyziologie   MeSH
• enterobakteriální infekce mikrobiologie   MeSH
• gnotobiologické modely MeSH
• kolitida chemicky indukované   mikrobiologie   patologie   terapie   MeSH
• kyselina trinitrobenzensulfonová toxicita   MeSH
• Limosilactobacillus reuteri * MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• probiotika farmakologie   MeSH
• proteiny asociované s pankreatitidou genetika   MeSH
• regulační T-lymfocyty fyziologie   MeSH
• střevní mikroflóra MeSH
• T-lymfocyty pomocné-indukující fyziologie   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiflogistika nesteroidní MeSH
• kyselina trinitrobenzensulfonová MeSH
• proteiny asociované s pankreatitidou MeSH
• Reg3b protein, mouse MeSH Prohlížeč

Morusin is a prenylated flavonoid isolated from the root bark of Morus alba. Many studies have shown the ability of flavonoids to act as anti-inflammatory agents. The aim of this study was to evaluate the effect of morusin on experimentally colitis induced by 2,4,6-trinitrobenzensulfonic acid in Wistar rats and to compare it with sulfasalazine, a drug conventionally used in the treatment of inflammatory bowel disease. Morusin was administered by gavage at doses of 12.5, 25, or 50 mg/kg/day for five days. The colonic tissue was evaluated macroscopically, histologically, and by performing immunodetection and zymographic analysis to determine the levels of antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)], interleukin (IL)-1β, and transforming growth factor (TGF)-β1 and the activities of matrix metalloproteinases (MMP) 2 and 9. The tissue damage scores were significantly reduced with increasing dose of morusin, however efficacy was not demonstrated at the highest dose. At the dose of 12.5 mg/kg, morusin exerted therapeutic effectivity similar to that of sulfasalazine (50 mg/kg). This was associated with significant reduction of TGF-β1 levels and MMP2 and MMP9 activities, and slight reduction of IL-1β. Our results suggest that morusin possesses therapeutic potential for the treatment of chronic inflammatory diseases.

• MeSH
• flavonoidy farmakologie   MeSH
• kolitida chemicky indukované   enzymologie   prevence a kontrola   MeSH
• kolon účinky léků   enzymologie   patologie   MeSH
• kyselina trinitrobenzensulfonová MeSH
• matrixová metaloproteinasa 2 metabolismus   MeSH
• potkani Wistar MeSH
• prenylace MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• flavonoidy MeSH
• kyselina trinitrobenzensulfonová MeSH
• matrixová metaloproteinasa 2 MeSH
• Mmp2 protein, rat MeSH Prohlížeč
• morusin MeSH Prohlížeč

OBJECTIVE AND DESIGN: Elucidate the mechanism of action of the small molecule inhibitor of protein binding to glycosaminoglycans, RX-111 and assay its anti-inflammatory activity in animal models of inflammatory disease. MATERIALS: The glycosaminoglycan, heparin, was used in the mechanism of action study of RX-111. Human T lymphocytes and umbilical vein endothelial cells were used to assay the in vitro activity of RX-111. Mouse and rat models of disease were used to assay the anti-inflammatory activity of RX-111 in vivo. METHODS: Circular dichroism and UV/Vis absorption spectroscopy were used to study the binding of RX-111 to the glycosaminoglycan, heparin. T lymphocyte rolling on endothelial cells under shear flow was used to assay RX-111 activity in vitro. Delayed-type hypersensitivity (DTH) and tri-nitrobenzene sulfonic acid (TNBS)-induced colitis in mice and experimental autoimmune encephalomyelitis (EAE) in rats were used to assay anti-inflammatory activity of RX-111 in vivo. RESULTS: RX-111 was shown to bind directly to heparin. It inhibited leukocyte rolling on endothelial cells under shear flow and reduced inflammation in the mouse model of DTH. RX-111 was efficacious in the mouse model of inflammatory bowel disease, TNBS-induced colitis and the rat model of multiple sclerosis, EAE. CONCLUSIONS: RX-111 exercises its broad spectrum anti-inflammatory activity by a singular mechanism of action, inhibition of protein binding to the cell surface GAG, heparan sulfate. RX-111 and related thieno[2,3-c]pyridine derivatives are potential therapeutics for the treatment of inflammatory and autoimmune diseases.

• Klíčová slova
• Autoimmune disease, Glycosaminoglycan, Heparan sulfate, Heparin binding protein, Inflammation, Small molecule drug,
• MeSH
• antiflogistika farmakologie   terapeutické užití   MeSH
• encefalitogenní základní proteiny imunologie   MeSH
• encefalomyelitida autoimunitní experimentální farmakoterapie   imunologie   MeSH
• endoteliální buňky pupečníkové žíly (lidské) účinky léků   imunologie   MeSH
• heparitinsulfát metabolismus   MeSH
• kolitida chemicky indukované   farmakoterapie   imunologie   MeSH
• krysa rodu Rattus MeSH
• kyselina trinitrobenzensulfonová MeSH
• lidé MeSH
• myši inbrední BALB C MeSH
• nádorové buněčné linie MeSH
• oxazolon MeSH
• potkani inbrední LEW MeSH
• pozdní přecitlivělost chemicky indukované   farmakoterapie   imunologie   MeSH
• pyridiny farmakologie   terapeutické užití   MeSH
• rolling leukocytů účinky léků   MeSH
• T-lymfocyty účinky léků   imunologie   MeSH
• thiofeny farmakologie   terapeutické užití   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antiflogistika MeSH
• encefalitogenní základní proteiny MeSH
• heparitinsulfát MeSH
• kyselina trinitrobenzensulfonová MeSH
• oxazolon MeSH
• pyridiny MeSH
• RX-111 MeSH Prohlížeč
• thiofeny MeSH

Preparation of coated pellets intended for rutin colon delivery, their evaluation in vitro and in vivo in experimental colitis in rats was the purpose of this study. Pellets were obtained using extrusion/spheronization and coated with three types of coatings (caffeic acid/hypromellose/alginic acid; sodium alginate/hypromellose/zinc acetate; sodium alginate/chitosan). Dissolution using buffers of pH values, β-glucosidase and times corresponding to gastrointestinal tract (GIT) was provided. Pellets coated with alginate/chitosan showed low rutin dissolution (12-14%) in upper GIT conditions and fast release (87-89%) under colon conditions; that is a good presumption of intended rutin release. After colitis induction and development, the rats were treated with pellets and rutin solution administered orally, solution also rectally. Colon/body weight ratio, myeloperoxidase activity and histological evaluation were performed. Rutin was able to promote colonic healing at the dose of 10mg/kg: colon/body weight ratio decreased and myeloperoxidase activity was significantly suppressed. Pellets coated with alginate/chitosan applied orally and rutin solution administered rectally showed the best efficacy. The combination of rutin as natural product, mucoadhesive chitosan degraded in the colon and sodium alginate as the main coating substance in the form of pellets create a promising preparation for therapy of this severe illness.

• MeSH
• algináty chemie   MeSH
• antiflogistika aplikace a dávkování   chemie   farmakologie   MeSH
• aplikace orální MeSH
• časové faktory MeSH
• chitosan chemie   MeSH
• deriváty hypromelózy MeSH
• farmaceutická chemie MeSH
• farmaceutická technologie metody   MeSH
• gastrointestinální látky aplikace a dávkování   chemie   farmakologie   MeSH
• implantované léky MeSH
• kolitida chemicky indukované   farmakoterapie   patologie   MeSH
• kolon účinky léků   patologie   MeSH
• koncentrace vodíkových iontů MeSH
• krysa rodu Rattus MeSH
• kyselina glukuronová chemie   MeSH
• kyselina trinitrobenzensulfonová MeSH
• kyseliny hexuronové chemie   MeSH
• kyseliny kávové chemie   MeSH
• methylcelulosa analogy a deriváty   chemie   MeSH
• modely nemocí na zvířatech MeSH
• octan zinečnatý chemie   MeSH
• potkani Wistar MeSH
• příprava léků MeSH
• pufry MeSH
• rozpustnost MeSH
• rutin aplikace a dávkování   chemie   farmakologie   MeSH
• stabilita léku MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• algináty MeSH
• antiflogistika MeSH
• caffeic acid MeSH Prohlížeč
• chitosan MeSH
• deriváty hypromelózy MeSH
• gastrointestinální látky MeSH
• implantované léky MeSH
• kyselina glukuronová MeSH
• kyselina trinitrobenzensulfonová MeSH
• kyseliny hexuronové MeSH
• kyseliny kávové MeSH
• methylcelulosa MeSH
• octan zinečnatý MeSH
• pufry MeSH
• rutin MeSH

Glucocorticoids exert anti-inflammatory and immunomodulatory effects that may be regulated in part by the activities of the glucocorticoid-activating and -inactivating enzymes, 11β-hydroxysteroid dehydrogenase type 1 (11HSD1) and type 2 (11HSD2), respectively. Previous studies have demonstrated that inflammatory bowel diseases in humans and experimental animals upregulate 11HSD1 and downregulate 11HSD2. We investigated whether proinflammatory cytokines modulate colonic 11HSDs as well as whether lymphoid organs exhibit any 11HSD response to inflammation. Colon tissue explants exposed to tumor necrosis factor α exhibited an upregulation of 11HSD1 mRNA whereas interleukin 1β downregulated 11HSD2 mRNA. Experimental colitis induced by the intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid stimulated 11HSD1 activity not only in the colon but also in mesenteric lymph nodes and the spleen. Analysis of mRNA for 11HSD1 in colon-draining lymph nodes and the spleen showed that inflammation upregulates the expression of this enzyme in mobile lymphoid cells similar to the intraepithelial and lamina propria leukocytes isolated from the colon. It is inferred that inflammation stimulates the reactivation of glucocorticoids in lymphoid organs and in gut-associated lymphoid tissue.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 1 biosyntéza   genetika   MeSH
• interleukin-1beta farmakologie   MeSH
• kolitida chemicky indukované   enzymologie   MeSH
• kolon účinky léků   MeSH
• krysa rodu Rattus MeSH
• kyselina trinitrobenzensulfonová farmakologie   MeSH
• lymfatické uzliny enzymologie   MeSH
• messenger RNA biosyntéza   genetika   MeSH
• mezenterium MeSH
• potkani Wistar MeSH
• slezina enzymologie   MeSH
• TNF-alfa farmakologie   MeSH
• upregulace MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 1 MeSH
• interleukin-1beta MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA MeSH
• TNF-alfa MeSH

Recent in vitro studies have shown the involvement of pro-inflammatory cytokines in the regulation of the local metabolism of glucocorticoids via 11beta-hydroxysteroid dehydrogenase type 1 and type 2 (11HSD1 and 11HSD2). However, direct in vivo evidence for a relationship among the local metabolism of glucocorticoids, inflammation and steroid enzymes is still lacking. We have therefore examined the changes in the local metabolism of glucocorticoids during colonic inflammation induced by TNBS and the consequences of corticosterone metabolism inhibition by carbenoxolone on 11HSD1, 11HSD2, cyclooxygenase 2 (COX-2), mucin 2 (MUC-2), tumor necrosis factor alpha (TNF-alpha), and interleukin 1beta (IL-1beta). The metabolism of glucocorticoids was measured in tissue slices in vitro and their 11HSD1, 11HSD2, COX-2, MUC-2, TNF-alpha, and IL-1beta mRNA abundances by quantitative reverse transcription-polymerase chain reaction. Colitis produced an up-regulation of colonic 11HSD1 and down-regulation of 11HSD2 in a dose-dependent manner, and these changes resulted in a decreased capacity of the inflamed tissue to inactivate tissue corticosterone. Similarly, 11HSD1 transcript was increased in colonic intraepithelial lymphocytes of TNBS-treated rats. Topical intracolonic application of carbenoxolone stimulated 11HSD1 mRNA and partially inhibited 11HSD2 mRNA and tissue corticosterone inactivation and these changes were blocked by RU-486. The administration of budesonide mimicked the effect of carbenoxolone. In contrast to the local metabolism of glucocorticoids, carbenoxolone neither potentiates nor diminishes gene expression for COX-2, TNF-alpha, and IL-1beta, despite the fact that budesonide down-regulated all of them. These data indicate that inflammation is associated with the down-regulation of tissue glucocorticoid catabolism. However, these changes in the local metabolism of glucocorticoids do not modulate the expression of COX-2, TNF-alpha, and IL-1beta in inflamed tissue.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 1 genetika   metabolismus   MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 genetika   metabolismus   MeSH
• antagonisté hormonů farmakologie   MeSH
• budesonid farmakologie   MeSH
• cyklooxygenasa 2 genetika   metabolismus   MeSH
• glukokortikoidy antagonisté a inhibitory   metabolismus   farmakologie   MeSH
• interleukin-1beta genetika   metabolismus   MeSH
• karbenoxolon farmakologie   MeSH
• kolitida chemicky indukované   metabolismus   MeSH
• kolon účinky léků   enzymologie   metabolismus   MeSH
• kortikosteron metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA metabolismus   MeSH
• mifepriston farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• mucin 2 MeSH
• muciny genetika   metabolismus   MeSH
• peroxidasa metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• potkani Wistar MeSH
• TNF-alfa genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 1 MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• antagonisté hormonů MeSH
• budesonid MeSH
• cyklooxygenasa 2 MeSH
• glukokortikoidy MeSH
• interleukin-1beta MeSH
• karbenoxolon MeSH
• kortikosteron MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA MeSH
• mifepriston MeSH
• Muc2 protein, rat MeSH Prohlížeč
• mucin 2 MeSH
• muciny MeSH
• peroxidasa MeSH
• Ptgs2 protein, rat MeSH Prohlížeč
• TNF-alfa MeSH

Components of plant essential oils have been reported to have health benefit properties, including antioxidative, anti-tumour, antimicrobial, anti-stress, and immunomodulative activities. We examined the anti-inflammatory effects of thymoquinone, the active ingredient in the volatile oil of Nigella sativa seeds, and borneol, the active component of Salvia officinalis essential oil, on TNBS-induced colitis in mice. Thymoquinone was added to the commercial diet at a concentration of 0.05 % and borneol at two concentrations (0.09% and 0.18%) and fed to ICR mice 5 days before induction of TNBS colitis. Seven days after TNBS administration the mice were killed and macroscopic and histological scores were evaluated. Cytokine mRNA expression in colonic tissue was assessed using quantitative realtime RT-PCR. We did not detect any significant changes in macroscopic and histological scores between experimental and control groups, but we observed a significant decrease in proinflammatory cytokine (IL-1beta and IL-6) mRNA expression in colon tissue in the 0.09% and 0.18% borneol-treated groups of mice in comparison to the control group. Surprisingly, we were not able to confirm anti-inflammatory effects of thymoquinone in TNBS colitis. In conclusion, our data show that borneol is able to significantly suppress proinflammatory cytokine mRNA expression in colonic inflammation, although no significant morphological changes are visible.

• MeSH
• benzochinony farmakologie   MeSH
• cytokiny genetika   metabolismus   MeSH
• DNA metabolismus   MeSH
• kamfany farmakologie   MeSH
• kolitida chemicky indukované   patologie   MeSH
• kolon účinky léků   patologie   MeSH
• kyselina trinitrobenzensulfonová farmakologie   MeSH
• messenger RNA genetika   metabolismus   MeSH
• myši MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• regulace genové exprese účinky léků   MeSH
• restrikční enzymy metabolismus   MeSH
• tělesná hmotnost účinky léků   MeSH
• velikost orgánu účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• benzochinony MeSH
• cytokiny MeSH
• DNA MeSH
• isoborneol MeSH Prohlížeč
• kamfany MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA MeSH
• restrikční enzymy MeSH
• thymoquinone MeSH Prohlížeč

BACKGROUND: Pro-inflammatory processes are counteracted by anti-inflammatory factors such as glucocorticoids. The response of target cells to glucocorticoids depends on several factors including prereceptor modulation of glucocorticoid signals via local glucocorticoid metabolism. This is determined by two isoforms of 11beta-hydroxysteroid dehydrogenase (11betaHSD); 11betaHSD1 operates in vivo as a reductase converting inactive 11-oxo glucocorticoids to active glucocorticoids cortisol or corticosterone, whereas 11betaHSD2 catalyses oxidation of active glucocorticoids to their inactive 11-oxo derivatives. The aim of this study was to investigate the changes in local metabolism of glucocorticoids and in the expression of 11betaHSD1 and 11betaHSD2 mRNA during colonic inflammation. METHODS: Acute colitis was induced by intracolonic administration of 2,4,6-trinitrobenzenesulphonic acid (TNBS) or by drinking a dextran sodium sulphate (DSS) solution. Metabolism of glucocorticoids was measured in tissue fragments in vitro and 11betaHSD1 and 11betaHSD2 mRNA abundance was quantified using real-time RT-PCR one week after administration of TNBS and 10 days after drinking the DSS solution. RESULTS: In both models of inflammatory bowel disease we observed down-regulation of corticosterone oxidation to 11-dehydrocorticosterone by 64% (TNBS) and 53% (DSS) and reciprocal stimulation of reduction of 11-dehydrocorticosterone to corticosterone by 83% and 54%, respectively. A similar pattern was observed at the level of mRNA; 11betaHSD1 mRNA was significantly higher (TNBS: increase by 660%; DSS: increase by 760%) and 11betaHSD2 mRNA lower (TNBS: decrease by 85%; DSS: decrease by 60%) during inflammation. CONCLUSIONS: Colitis induces local glucocorticoid activation from 11-oxo steroids and decreases glucocorticoid inactivation; i.e. inflammation increases local tissue ratio of active and inactive glucocorticoids. The results indicate that the changes in local metabolism of glucocorticoids could contribute to the control of an overshoot of inflammation processes in the colon.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 1 genetika   metabolismus   MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 genetika   metabolismus   MeSH
• Crohnova nemoc chemicky indukované   enzymologie   MeSH
• kortikosteron analogy a deriváty   metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA genetika   MeSH
• modely nemocí na zvířatech MeSH
• potkani Wistar MeSH
• síran dextranu MeSH
• ulcerózní kolitida chemicky indukované   enzymologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 1 MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• 11-dehydrocorticosterone MeSH Prohlížeč
• kortikosteron MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA MeSH
• síran dextranu MeSH