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Activation of TGF ‐ β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease

View Article: PubMed Central - PubMed

ABSTRACT

The etiology and mechanisms for inflammatory bowel disease (IBD) are incompletely known. Determination of new, clinically important mechanisms for intestinal inflammation is imperative for developing effective therapies to treat IBD. We sought to define a widespread mechanism for colon mucosal inflammation via the activation of TGF‐β activated Kinase 1 (TAK1), a central regulator of cellular inflammatory actions. Activation of TAK1 and the downstream inflammatory signaling mediators was determined in pediatric patients with ulcerative colitis (UC) or Crohn's disease (CD) as well as in DSS‐induced and spontaneous IBD in mice. The role of TAK1 in facilitating intestinal inflammation in murine models of IBD was investigated by using (5Z)‐7‐Oxozeaenol, a highly selective pharmacological inhibitor of TAK1. We found hyper‐activation of TAK1 in patients with UC or CD and in murine models of IBD. Pharmacological inhibition of TAK1 prevented loss in body weight, disease activity, microscopic histopathology, infiltration of inflammatory cells in the colon mucosa, and elevated proinflammatory cytokine production in two murine models of IBD. We demonstrated that at the early phase of the disease activation of TAK1 is restricted in the epithelial cells. However, at a more advanced stage of the disease, TAK1 activation predominantly occurs in nonepithelial cells, especially in macrophages. These findings elucidate the activation of TAK1 as crucial in promoting intestinal inflammation. Thus, the TAK1 activation pathway may represent a suitable target to design new therapies for treating IBD in humans.

No MeSH data available.


Pharmacological inhibition of TAK1 prevents expression of inflammatory signaling mediators and cytokine in acute IBD. Male and female C57BL/6 mice (n = 12–15 per group) were on 3% DSS for 7 days. Mice were treated with TAK1 inhibitor Oxo or vehicle (DMSO + mineral oil) (5 mg/kg) and sacrificed as illustrated in (A). (A) Colon tissue homogenates were analyzed by immunoblot analysis using anti‐phospho TAK1 (p‐TAK1), total TAK1 (TAK1); anti‐phospho JNK (p‐JNK), total JNK (JNK); anti‐phospho p38 MAPK (p‐p38), total p38 MAPK (p38); anti‐phospho IκBα and β‐actin antibodies. (B) Expression of IL‐6, TNF‐α and IL‐12 in colon homogenates were analyzed by ELISA. Data presented as mean ± SEM.
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phy213181-fig-0004: Pharmacological inhibition of TAK1 prevents expression of inflammatory signaling mediators and cytokine in acute IBD. Male and female C57BL/6 mice (n = 12–15 per group) were on 3% DSS for 7 days. Mice were treated with TAK1 inhibitor Oxo or vehicle (DMSO + mineral oil) (5 mg/kg) and sacrificed as illustrated in (A). (A) Colon tissue homogenates were analyzed by immunoblot analysis using anti‐phospho TAK1 (p‐TAK1), total TAK1 (TAK1); anti‐phospho JNK (p‐JNK), total JNK (JNK); anti‐phospho p38 MAPK (p‐p38), total p38 MAPK (p38); anti‐phospho IκBα and β‐actin antibodies. (B) Expression of IL‐6, TNF‐α and IL‐12 in colon homogenates were analyzed by ELISA. Data presented as mean ± SEM.

Mentions: The efficacy of Oxo in restricting activation of inflammation‐inducing signaling mediators was determined. Substantial increases in the phosphorylation of TAK1, JNK, p38 MAPK, and IκBα in the colonic tissues were observed in vehicle‐treated mice exposed to DSS (Fig. 4A). However, treatment with Oxo markedly reduced phosphorylation of all signaling intermediators investigated in these studies (Fig. 4A). Since proinflammatory cytokines promote intestinal inflammation, effects of TAK1 inhibition on cytokine synthesis were evaluated. Elevated expression of IL‐6, TNF‐α, and IL‐12 were not affected by the treatment with vehicle (Fig. 4B). However, treatment with Oxo significantly inhibited expression of IL‐6 (P = 0.0001), TNF‐α (P = 0.01), and IL‐12 (P = 0.005) induced by DSS exposure (Fig. 4B).


Activation of TGF ‐ β activated kinase 1 promotes colon mucosal pathogenesis in inflammatory bowel disease
Pharmacological inhibition of TAK1 prevents expression of inflammatory signaling mediators and cytokine in acute IBD. Male and female C57BL/6 mice (n = 12–15 per group) were on 3% DSS for 7 days. Mice were treated with TAK1 inhibitor Oxo or vehicle (DMSO + mineral oil) (5 mg/kg) and sacrificed as illustrated in (A). (A) Colon tissue homogenates were analyzed by immunoblot analysis using anti‐phospho TAK1 (p‐TAK1), total TAK1 (TAK1); anti‐phospho JNK (p‐JNK), total JNK (JNK); anti‐phospho p38 MAPK (p‐p38), total p38 MAPK (p38); anti‐phospho IκBα and β‐actin antibodies. (B) Expression of IL‐6, TNF‐α and IL‐12 in colon homogenates were analyzed by ELISA. Data presented as mean ± SEM.
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phy213181-fig-0004: Pharmacological inhibition of TAK1 prevents expression of inflammatory signaling mediators and cytokine in acute IBD. Male and female C57BL/6 mice (n = 12–15 per group) were on 3% DSS for 7 days. Mice were treated with TAK1 inhibitor Oxo or vehicle (DMSO + mineral oil) (5 mg/kg) and sacrificed as illustrated in (A). (A) Colon tissue homogenates were analyzed by immunoblot analysis using anti‐phospho TAK1 (p‐TAK1), total TAK1 (TAK1); anti‐phospho JNK (p‐JNK), total JNK (JNK); anti‐phospho p38 MAPK (p‐p38), total p38 MAPK (p38); anti‐phospho IκBα and β‐actin antibodies. (B) Expression of IL‐6, TNF‐α and IL‐12 in colon homogenates were analyzed by ELISA. Data presented as mean ± SEM.
Mentions: The efficacy of Oxo in restricting activation of inflammation‐inducing signaling mediators was determined. Substantial increases in the phosphorylation of TAK1, JNK, p38 MAPK, and IκBα in the colonic tissues were observed in vehicle‐treated mice exposed to DSS (Fig. 4A). However, treatment with Oxo markedly reduced phosphorylation of all signaling intermediators investigated in these studies (Fig. 4A). Since proinflammatory cytokines promote intestinal inflammation, effects of TAK1 inhibition on cytokine synthesis were evaluated. Elevated expression of IL‐6, TNF‐α, and IL‐12 were not affected by the treatment with vehicle (Fig. 4B). However, treatment with Oxo significantly inhibited expression of IL‐6 (P = 0.0001), TNF‐α (P = 0.01), and IL‐12 (P = 0.005) induced by DSS exposure (Fig. 4B).

View Article: PubMed Central - PubMed

ABSTRACT

The etiology and mechanisms for inflammatory bowel disease (IBD) are incompletely known. Determination of new, clinically important mechanisms for intestinal inflammation is imperative for developing effective therapies to treat IBD. We sought to define a widespread mechanism for colon mucosal inflammation via the activation of TGF‐β activated Kinase 1 (TAK1), a central regulator of cellular inflammatory actions. Activation of TAK1 and the downstream inflammatory signaling mediators was determined in pediatric patients with ulcerative colitis (UC) or Crohn's disease (CD) as well as in DSS‐induced and spontaneous IBD in mice. The role of TAK1 in facilitating intestinal inflammation in murine models of IBD was investigated by using (5Z)‐7‐Oxozeaenol, a highly selective pharmacological inhibitor of TAK1. We found hyper‐activation of TAK1 in patients with UC or CD and in murine models of IBD. Pharmacological inhibition of TAK1 prevented loss in body weight, disease activity, microscopic histopathology, infiltration of inflammatory cells in the colon mucosa, and elevated proinflammatory cytokine production in two murine models of IBD. We demonstrated that at the early phase of the disease activation of TAK1 is restricted in the epithelial cells. However, at a more advanced stage of the disease, TAK1 activation predominantly occurs in nonepithelial cells, especially in macrophages. These findings elucidate the activation of TAK1 as crucial in promoting intestinal inflammation. Thus, the TAK1 activation pathway may represent a suitable target to design new therapies for treating IBD in humans.

No MeSH data available.