Ursodeoxycholic acid inhibits colonic mucosal cytokine release and prevents colitis in a mouse model of disease

JB Ward, OB Kelly, S Smith, Murtaza Tambuwala, CT Taylor, FE Murray, C Jefferies, SJ Keely

    Research output: Chapter in Book/Report/Conference proceedingConference contribution

    Abstract

    Toll-like receptors (TLR) promote cytokine release from intestinal epithelia, thereby driving inflammation. Although ursodeoxycholic acid (UDCA) is well known to exert anti-inflammatory effects in the liver, its potential for treating intestinal inflammation has not been well-studied. Here, we investigated UDCA effects on TLR-driven colonic mucosal cytokine release and induction of inflammation in a mouse model of colitis. Resected human colonic mucosa and T84 colonic epithelial cells were treated with specific TLR agonists (TLR3: Polyinosinic-polycytidylic acid, 25 μg/ml; TLR4: lipopolysaccharide (LPS), 100 ng/ml), in the presence or absence of UDCA. Released cytokines were measured by ELISA and luciferase reporter assays were performed in HEK293T cells. Dextran sodium sulphate (DSS) colitis was induced by administering DSS (2.5 %) in the drinking water of male C57BL/6 mice, along with daily intraperitoneal injections of UDCA (30 or 100 mg/kg) or vehicle for 5 days. Colitis severity was recorded as disease activity index (DAI) and by histological inflammation score. Results were analysed by ANOVA using Tukey multiple comparisons test and are expressed as the mean ± standard error of the mean. In T84 cells, UDCA (200 μM) attenuated TLR3-stimulated tumour necrosis factor α (TNFα) release from 32.9 ± 4.1 to 23.8 ± 3.7 pg/ml; interleukin-8 (IL-8) release from 1197.5 ± 110.1 to 923.8 ± 110.3 pg/ml and IL-1β release from 2.0 ± 0.2 to 1.6 ± 0.2 pg/ml (n = 4, p <0.05). Apical LPS (6 hours) induced basolateral IL-8 secretion from human colonic mucosa from 435 ± 46 in unstimulated controls to 959 ± 22 pg/ml and caused a 3 fold increase in secretion of Regulated on Activation, Normal T cell Expressed and Secreted (RANTES); increases that were abolished by UDCA (250 μM) (n = 3, p <0.001). Using NFκB and P125 luciferase reporter assays we determined that UDCA (200 μM) exerts its anti-inflammatory effects at the level of TANK-binding kinase 1 (TBK1) (n = 5, p <0.01). In the DSS model of colitis, UDCA (30 mg/kg and 100 mg/kg) significantly reduced disease severity from a DAI of 10.0 ± 0.3 in mice treated with DSS alone to 7.2 ± 0.7 and 5.8 ± 0.5, respectively (n = 6 - 12, p <0.001). Furthermore, histologically the inflammation score was also significantly reduced in UDCA (100 mg/kg)-treated animals to 24.3 ± 4.4, compared to 37.3 ± 0.8 in mice treated with DSS alone (n = 4 - 6, p <0.05). In conclusion, our data show that UDCA prevents inflammation in a mouse model of colitis and that the protective effects of UDCA may be due to inhibition of TLR-induced proinflammatory cytokine release. These findings suggest that UDCA represents a good target for developing new therapeutic approaches to treat IBD.
    LanguageEnglish
    Title of host publicationUnknown Host Publication
    Number of pages1
    Publication statusPublished - 5 Mar 2013
    Event37th Congress of IUPS - (Birmingham, UK)
    Duration: 5 Mar 2013 → …

    Conference

    Conference37th Congress of IUPS
    Period5/03/13 → …

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    Ursodeoxycholic Acid
    Colitis
    Cytokines
    Dextran Sulfate
    Toll-Like Receptors
    Inflammation
    Luciferases
    Interleukin-8
    Lipopolysaccharides
    Mucous Membrane
    Anti-Inflammatory Agents
    Poly I-C
    Intestinal Mucosa
    Intraperitoneal Injections
    Inbred C57BL Mouse
    Drinking Water
    Analysis of Variance
    Phosphotransferases
    Tumor Necrosis Factor-alpha

    Cite this

    Ward, JB., Kelly, OB., Smith, S., Tambuwala, M., Taylor, CT., Murray, FE., ... Keely, SJ. (2013). Ursodeoxycholic acid inhibits colonic mucosal cytokine release and prevents colitis in a mouse model of disease. In Unknown Host Publication
    Ward, JB ; Kelly, OB ; Smith, S ; Tambuwala, Murtaza ; Taylor, CT ; Murray, FE ; Jefferies, C ; Keely, SJ. / Ursodeoxycholic acid inhibits colonic mucosal cytokine release and prevents colitis in a mouse model of disease. Unknown Host Publication. 2013.
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    title = "Ursodeoxycholic acid inhibits colonic mucosal cytokine release and prevents colitis in a mouse model of disease",
    abstract = "Toll-like receptors (TLR) promote cytokine release from intestinal epithelia, thereby driving inflammation. Although ursodeoxycholic acid (UDCA) is well known to exert anti-inflammatory effects in the liver, its potential for treating intestinal inflammation has not been well-studied. Here, we investigated UDCA effects on TLR-driven colonic mucosal cytokine release and induction of inflammation in a mouse model of colitis. Resected human colonic mucosa and T84 colonic epithelial cells were treated with specific TLR agonists (TLR3: Polyinosinic-polycytidylic acid, 25 μg/ml; TLR4: lipopolysaccharide (LPS), 100 ng/ml), in the presence or absence of UDCA. Released cytokines were measured by ELISA and luciferase reporter assays were performed in HEK293T cells. Dextran sodium sulphate (DSS) colitis was induced by administering DSS (2.5 {\%}) in the drinking water of male C57BL/6 mice, along with daily intraperitoneal injections of UDCA (30 or 100 mg/kg) or vehicle for 5 days. Colitis severity was recorded as disease activity index (DAI) and by histological inflammation score. Results were analysed by ANOVA using Tukey multiple comparisons test and are expressed as the mean ± standard error of the mean. In T84 cells, UDCA (200 μM) attenuated TLR3-stimulated tumour necrosis factor α (TNFα) release from 32.9 ± 4.1 to 23.8 ± 3.7 pg/ml; interleukin-8 (IL-8) release from 1197.5 ± 110.1 to 923.8 ± 110.3 pg/ml and IL-1β release from 2.0 ± 0.2 to 1.6 ± 0.2 pg/ml (n = 4, p <0.05). Apical LPS (6 hours) induced basolateral IL-8 secretion from human colonic mucosa from 435 ± 46 in unstimulated controls to 959 ± 22 pg/ml and caused a 3 fold increase in secretion of Regulated on Activation, Normal T cell Expressed and Secreted (RANTES); increases that were abolished by UDCA (250 μM) (n = 3, p <0.001). Using NFκB and P125 luciferase reporter assays we determined that UDCA (200 μM) exerts its anti-inflammatory effects at the level of TANK-binding kinase 1 (TBK1) (n = 5, p <0.01). In the DSS model of colitis, UDCA (30 mg/kg and 100 mg/kg) significantly reduced disease severity from a DAI of 10.0 ± 0.3 in mice treated with DSS alone to 7.2 ± 0.7 and 5.8 ± 0.5, respectively (n = 6 - 12, p <0.001). Furthermore, histologically the inflammation score was also significantly reduced in UDCA (100 mg/kg)-treated animals to 24.3 ± 4.4, compared to 37.3 ± 0.8 in mice treated with DSS alone (n = 4 - 6, p <0.05). In conclusion, our data show that UDCA prevents inflammation in a mouse model of colitis and that the protective effects of UDCA may be due to inhibition of TLR-induced proinflammatory cytokine release. These findings suggest that UDCA represents a good target for developing new therapeutic approaches to treat IBD.",
    author = "JB Ward and OB Kelly and S Smith and Murtaza Tambuwala and CT Taylor and FE Murray and C Jefferies and SJ Keely",
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    Ward, JB, Kelly, OB, Smith, S, Tambuwala, M, Taylor, CT, Murray, FE, Jefferies, C & Keely, SJ 2013, Ursodeoxycholic acid inhibits colonic mucosal cytokine release and prevents colitis in a mouse model of disease. in Unknown Host Publication. 37th Congress of IUPS, 5/03/13.

    Ursodeoxycholic acid inhibits colonic mucosal cytokine release and prevents colitis in a mouse model of disease. / Ward, JB; Kelly, OB; Smith, S; Tambuwala, Murtaza; Taylor, CT; Murray, FE; Jefferies, C; Keely, SJ.

    Unknown Host Publication. 2013.

    Research output: Chapter in Book/Report/Conference proceedingConference contribution

    TY - GEN

    T1 - Ursodeoxycholic acid inhibits colonic mucosal cytokine release and prevents colitis in a mouse model of disease

    AU - Ward, JB

    AU - Kelly, OB

    AU - Smith, S

    AU - Tambuwala, Murtaza

    AU - Taylor, CT

    AU - Murray, FE

    AU - Jefferies, C

    AU - Keely, SJ

    PY - 2013/3/5

    Y1 - 2013/3/5

    N2 - Toll-like receptors (TLR) promote cytokine release from intestinal epithelia, thereby driving inflammation. Although ursodeoxycholic acid (UDCA) is well known to exert anti-inflammatory effects in the liver, its potential for treating intestinal inflammation has not been well-studied. Here, we investigated UDCA effects on TLR-driven colonic mucosal cytokine release and induction of inflammation in a mouse model of colitis. Resected human colonic mucosa and T84 colonic epithelial cells were treated with specific TLR agonists (TLR3: Polyinosinic-polycytidylic acid, 25 μg/ml; TLR4: lipopolysaccharide (LPS), 100 ng/ml), in the presence or absence of UDCA. Released cytokines were measured by ELISA and luciferase reporter assays were performed in HEK293T cells. Dextran sodium sulphate (DSS) colitis was induced by administering DSS (2.5 %) in the drinking water of male C57BL/6 mice, along with daily intraperitoneal injections of UDCA (30 or 100 mg/kg) or vehicle for 5 days. Colitis severity was recorded as disease activity index (DAI) and by histological inflammation score. Results were analysed by ANOVA using Tukey multiple comparisons test and are expressed as the mean ± standard error of the mean. In T84 cells, UDCA (200 μM) attenuated TLR3-stimulated tumour necrosis factor α (TNFα) release from 32.9 ± 4.1 to 23.8 ± 3.7 pg/ml; interleukin-8 (IL-8) release from 1197.5 ± 110.1 to 923.8 ± 110.3 pg/ml and IL-1β release from 2.0 ± 0.2 to 1.6 ± 0.2 pg/ml (n = 4, p <0.05). Apical LPS (6 hours) induced basolateral IL-8 secretion from human colonic mucosa from 435 ± 46 in unstimulated controls to 959 ± 22 pg/ml and caused a 3 fold increase in secretion of Regulated on Activation, Normal T cell Expressed and Secreted (RANTES); increases that were abolished by UDCA (250 μM) (n = 3, p <0.001). Using NFκB and P125 luciferase reporter assays we determined that UDCA (200 μM) exerts its anti-inflammatory effects at the level of TANK-binding kinase 1 (TBK1) (n = 5, p <0.01). In the DSS model of colitis, UDCA (30 mg/kg and 100 mg/kg) significantly reduced disease severity from a DAI of 10.0 ± 0.3 in mice treated with DSS alone to 7.2 ± 0.7 and 5.8 ± 0.5, respectively (n = 6 - 12, p <0.001). Furthermore, histologically the inflammation score was also significantly reduced in UDCA (100 mg/kg)-treated animals to 24.3 ± 4.4, compared to 37.3 ± 0.8 in mice treated with DSS alone (n = 4 - 6, p <0.05). In conclusion, our data show that UDCA prevents inflammation in a mouse model of colitis and that the protective effects of UDCA may be due to inhibition of TLR-induced proinflammatory cytokine release. These findings suggest that UDCA represents a good target for developing new therapeutic approaches to treat IBD.

    AB - Toll-like receptors (TLR) promote cytokine release from intestinal epithelia, thereby driving inflammation. Although ursodeoxycholic acid (UDCA) is well known to exert anti-inflammatory effects in the liver, its potential for treating intestinal inflammation has not been well-studied. Here, we investigated UDCA effects on TLR-driven colonic mucosal cytokine release and induction of inflammation in a mouse model of colitis. Resected human colonic mucosa and T84 colonic epithelial cells were treated with specific TLR agonists (TLR3: Polyinosinic-polycytidylic acid, 25 μg/ml; TLR4: lipopolysaccharide (LPS), 100 ng/ml), in the presence or absence of UDCA. Released cytokines were measured by ELISA and luciferase reporter assays were performed in HEK293T cells. Dextran sodium sulphate (DSS) colitis was induced by administering DSS (2.5 %) in the drinking water of male C57BL/6 mice, along with daily intraperitoneal injections of UDCA (30 or 100 mg/kg) or vehicle for 5 days. Colitis severity was recorded as disease activity index (DAI) and by histological inflammation score. Results were analysed by ANOVA using Tukey multiple comparisons test and are expressed as the mean ± standard error of the mean. In T84 cells, UDCA (200 μM) attenuated TLR3-stimulated tumour necrosis factor α (TNFα) release from 32.9 ± 4.1 to 23.8 ± 3.7 pg/ml; interleukin-8 (IL-8) release from 1197.5 ± 110.1 to 923.8 ± 110.3 pg/ml and IL-1β release from 2.0 ± 0.2 to 1.6 ± 0.2 pg/ml (n = 4, p <0.05). Apical LPS (6 hours) induced basolateral IL-8 secretion from human colonic mucosa from 435 ± 46 in unstimulated controls to 959 ± 22 pg/ml and caused a 3 fold increase in secretion of Regulated on Activation, Normal T cell Expressed and Secreted (RANTES); increases that were abolished by UDCA (250 μM) (n = 3, p <0.001). Using NFκB and P125 luciferase reporter assays we determined that UDCA (200 μM) exerts its anti-inflammatory effects at the level of TANK-binding kinase 1 (TBK1) (n = 5, p <0.01). In the DSS model of colitis, UDCA (30 mg/kg and 100 mg/kg) significantly reduced disease severity from a DAI of 10.0 ± 0.3 in mice treated with DSS alone to 7.2 ± 0.7 and 5.8 ± 0.5, respectively (n = 6 - 12, p <0.001). Furthermore, histologically the inflammation score was also significantly reduced in UDCA (100 mg/kg)-treated animals to 24.3 ± 4.4, compared to 37.3 ± 0.8 in mice treated with DSS alone (n = 4 - 6, p <0.05). In conclusion, our data show that UDCA prevents inflammation in a mouse model of colitis and that the protective effects of UDCA may be due to inhibition of TLR-induced proinflammatory cytokine release. These findings suggest that UDCA represents a good target for developing new therapeutic approaches to treat IBD.

    M3 - Conference contribution

    BT - Unknown Host Publication

    ER -

    Ward JB, Kelly OB, Smith S, Tambuwala M, Taylor CT, Murray FE et al. Ursodeoxycholic acid inhibits colonic mucosal cytokine release and prevents colitis in a mouse model of disease. In Unknown Host Publication. 2013