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Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies.

Desreumaux P, Dubuquoy L, Nutten S, Peuchmaur M, Englaro W, Schoonjans K, Derijard B, Desvergne B, Wahli W, Chambon P, Leibowitz MD, Colombel JF, Auwerx J - J. Exp. Med. (2001)

Bottom Line: This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor alpha and interleukin 1beta mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor kappaB DNA binding activity, c-Jun NH(2)-terminal kinase, and p38 activities in the colon.When coadministered, a significant synergistic effect of PPARgamma and RXR ligands was observed.In combination, these data demonstrate that activation of the RXR/PPARgamma heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARgamma ligands might hold promise in the clinic due to their synergistic effects.

View Article: PubMed Central - PubMed

Affiliation: Equipe Propre Institut National de la Sante et de la Recherche Medicale 0114 sur la Physiopathologie des Maladies Inflammatoires Intestinales, CHU Lille 59037, France. p.desreumaux@chru-lille.fr

ABSTRACT
The peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARgamma and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARgamma(1/)- and RXRalpha(1/)- mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPARgamma heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARgamma agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARgamma and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor alpha and interleukin 1beta mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor kappaB DNA binding activity, c-Jun NH(2)-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARgamma and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARgamma heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARgamma ligands might hold promise in the clinic due to their synergistic effects.

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Representative histological sections of colon tissues of Balb/c mice. (A) Normal transparietal colon section of a vehicle-treated mouse with an Ameho score of 0 (×250). The different layers are indicated: M, mucosa; SM, submucosa; Mu, muscular layer. (B) Transparietal colon section (Ameho score 6) 2 d after the induction of colitis by TNBS. Thickening of the colon wall, with a predominant inflammatory infiltrate in the lamina propria, and necrosis extending deeply into the muscular and serosal layers are evident (×400). (C) Transparietal colon section (Ameho score 6) 5 d after the induction of colitis by TNBS. Parietal necrosis extending deeply into the muscular layer with the disappearance of cells in the mucosa is visible (×250). (D) Transparietal colon section of a mouse, which received rosiglitazone before TNBS administration. The mouse was killed 2 d after colitis induction. The Ameho score was graded 2. The picture shows a subepithelial edema with a diastasis of the crypts and a moderate inflammatory infiltrate in the mucosa and submucosa (×250). (E) Transparietal colonic section of mice treated with rosiglitazone after administration of TNBS. The pictures show mice killed 5 d after colitis induction. Ulceration extending into the submucosa, associated with a mucosal, submucosal, and muscular inflammatory infiltrate involving <50% of the specimen, is visible (×250). (F and G) Colon sections of mice that received rosiglitazone before TNBS administration. The mice were killed 2 d after colitis induction. In some cases, a total repair of the mucosa was observed (F; ×600) despite the persistence of an in-depth focal necrosis in the submucosal layer (G; ×400).
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Figure 3: Representative histological sections of colon tissues of Balb/c mice. (A) Normal transparietal colon section of a vehicle-treated mouse with an Ameho score of 0 (×250). The different layers are indicated: M, mucosa; SM, submucosa; Mu, muscular layer. (B) Transparietal colon section (Ameho score 6) 2 d after the induction of colitis by TNBS. Thickening of the colon wall, with a predominant inflammatory infiltrate in the lamina propria, and necrosis extending deeply into the muscular and serosal layers are evident (×400). (C) Transparietal colon section (Ameho score 6) 5 d after the induction of colitis by TNBS. Parietal necrosis extending deeply into the muscular layer with the disappearance of cells in the mucosa is visible (×250). (D) Transparietal colon section of a mouse, which received rosiglitazone before TNBS administration. The mouse was killed 2 d after colitis induction. The Ameho score was graded 2. The picture shows a subepithelial edema with a diastasis of the crypts and a moderate inflammatory infiltrate in the mucosa and submucosa (×250). (E) Transparietal colonic section of mice treated with rosiglitazone after administration of TNBS. The pictures show mice killed 5 d after colitis induction. Ulceration extending into the submucosa, associated with a mucosal, submucosal, and muscular inflammatory infiltrate involving <50% of the specimen, is visible (×250). (F and G) Colon sections of mice that received rosiglitazone before TNBS administration. The mice were killed 2 d after colitis induction. In some cases, a total repair of the mucosa was observed (F; ×600) despite the persistence of an in-depth focal necrosis in the submucosal layer (G; ×400).

Mentions: First, we characterized the development of colitis in animals subjected to TNBS injection. Whereas control mice, killed 2 or 5 d after administration of 50% ethanol or a saline solution, had no macroscopic lesions in the colon, a severe colitis was induced as early as 2 d after administration of TNBS, resulting in death in 22 ± 6% of the animals (Fig. 2 A, and Table ). 5 d after induction of colitis, the lesions were more severe with necrosis of the colon leading to mortality in 68 ± 4% of the animals. On a histologic level, no abnormalities were detected in control mice (Fig. 3 A). In sharp contrast, 2 d after the administration of TNBS, colon histology was characterized by large areas of ulceration with a neutrophilic infiltrate, necrosis extending deeply into the muscular layer (Fig. 3B and Fig. C), and enhancement of MPO levels, a marker of neutrophil content (21; Fig. 4). Necrosis of the colon in mice surviving 5 d after TNBS administration involved ∼90% of the specimen, and was so severe that it precluded evaluation of other parameters such as MPO, TNF-α, and IL-1β mRNA levels, and activity of NF-κB.


Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies.

Desreumaux P, Dubuquoy L, Nutten S, Peuchmaur M, Englaro W, Schoonjans K, Derijard B, Desvergne B, Wahli W, Chambon P, Leibowitz MD, Colombel JF, Auwerx J - J. Exp. Med. (2001)

Representative histological sections of colon tissues of Balb/c mice. (A) Normal transparietal colon section of a vehicle-treated mouse with an Ameho score of 0 (×250). The different layers are indicated: M, mucosa; SM, submucosa; Mu, muscular layer. (B) Transparietal colon section (Ameho score 6) 2 d after the induction of colitis by TNBS. Thickening of the colon wall, with a predominant inflammatory infiltrate in the lamina propria, and necrosis extending deeply into the muscular and serosal layers are evident (×400). (C) Transparietal colon section (Ameho score 6) 5 d after the induction of colitis by TNBS. Parietal necrosis extending deeply into the muscular layer with the disappearance of cells in the mucosa is visible (×250). (D) Transparietal colon section of a mouse, which received rosiglitazone before TNBS administration. The mouse was killed 2 d after colitis induction. The Ameho score was graded 2. The picture shows a subepithelial edema with a diastasis of the crypts and a moderate inflammatory infiltrate in the mucosa and submucosa (×250). (E) Transparietal colonic section of mice treated with rosiglitazone after administration of TNBS. The pictures show mice killed 5 d after colitis induction. Ulceration extending into the submucosa, associated with a mucosal, submucosal, and muscular inflammatory infiltrate involving <50% of the specimen, is visible (×250). (F and G) Colon sections of mice that received rosiglitazone before TNBS administration. The mice were killed 2 d after colitis induction. In some cases, a total repair of the mucosa was observed (F; ×600) despite the persistence of an in-depth focal necrosis in the submucosal layer (G; ×400).
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Related In: Results  -  Collection

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Figure 3: Representative histological sections of colon tissues of Balb/c mice. (A) Normal transparietal colon section of a vehicle-treated mouse with an Ameho score of 0 (×250). The different layers are indicated: M, mucosa; SM, submucosa; Mu, muscular layer. (B) Transparietal colon section (Ameho score 6) 2 d after the induction of colitis by TNBS. Thickening of the colon wall, with a predominant inflammatory infiltrate in the lamina propria, and necrosis extending deeply into the muscular and serosal layers are evident (×400). (C) Transparietal colon section (Ameho score 6) 5 d after the induction of colitis by TNBS. Parietal necrosis extending deeply into the muscular layer with the disappearance of cells in the mucosa is visible (×250). (D) Transparietal colon section of a mouse, which received rosiglitazone before TNBS administration. The mouse was killed 2 d after colitis induction. The Ameho score was graded 2. The picture shows a subepithelial edema with a diastasis of the crypts and a moderate inflammatory infiltrate in the mucosa and submucosa (×250). (E) Transparietal colonic section of mice treated with rosiglitazone after administration of TNBS. The pictures show mice killed 5 d after colitis induction. Ulceration extending into the submucosa, associated with a mucosal, submucosal, and muscular inflammatory infiltrate involving <50% of the specimen, is visible (×250). (F and G) Colon sections of mice that received rosiglitazone before TNBS administration. The mice were killed 2 d after colitis induction. In some cases, a total repair of the mucosa was observed (F; ×600) despite the persistence of an in-depth focal necrosis in the submucosal layer (G; ×400).
Mentions: First, we characterized the development of colitis in animals subjected to TNBS injection. Whereas control mice, killed 2 or 5 d after administration of 50% ethanol or a saline solution, had no macroscopic lesions in the colon, a severe colitis was induced as early as 2 d after administration of TNBS, resulting in death in 22 ± 6% of the animals (Fig. 2 A, and Table ). 5 d after induction of colitis, the lesions were more severe with necrosis of the colon leading to mortality in 68 ± 4% of the animals. On a histologic level, no abnormalities were detected in control mice (Fig. 3 A). In sharp contrast, 2 d after the administration of TNBS, colon histology was characterized by large areas of ulceration with a neutrophilic infiltrate, necrosis extending deeply into the muscular layer (Fig. 3B and Fig. C), and enhancement of MPO levels, a marker of neutrophil content (21; Fig. 4). Necrosis of the colon in mice surviving 5 d after TNBS administration involved ∼90% of the specimen, and was so severe that it precluded evaluation of other parameters such as MPO, TNF-α, and IL-1β mRNA levels, and activity of NF-κB.

Bottom Line: This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor alpha and interleukin 1beta mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor kappaB DNA binding activity, c-Jun NH(2)-terminal kinase, and p38 activities in the colon.When coadministered, a significant synergistic effect of PPARgamma and RXR ligands was observed.In combination, these data demonstrate that activation of the RXR/PPARgamma heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARgamma ligands might hold promise in the clinic due to their synergistic effects.

View Article: PubMed Central - PubMed

Affiliation: Equipe Propre Institut National de la Sante et de la Recherche Medicale 0114 sur la Physiopathologie des Maladies Inflammatoires Intestinales, CHU Lille 59037, France. p.desreumaux@chru-lille.fr

ABSTRACT
The peroxisome proliferator-activated receptor gamma (PPARgamma) is highly expressed in the colon mucosa and its activation has been reported to protect against colitis. We studied the involvement of PPARgamma and its heterodimeric partner, the retinoid X receptor (RXR) in intestinal inflammatory responses. PPARgamma(1/)- and RXRalpha(1/)- mice both displayed a significantly enhanced susceptibility to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis compared with their wild-type littermates. A role for the RXR/PPARgamma heterodimer in the protection against colon inflammation was explored by the use of selective RXR and PPARgamma agonists. TNBS-induced colitis was significantly reduced by the administration of both PPARgamma and RXR agonists. This beneficial effect was reflected by increased survival rates, an improvement of macroscopic and histologic scores, a decrease in tumor necrosis factor alpha and interleukin 1beta mRNA levels, a diminished myeloperoxidase concentration, and reduction of nuclear factor kappaB DNA binding activity, c-Jun NH(2)-terminal kinase, and p38 activities in the colon. When coadministered, a significant synergistic effect of PPARgamma and RXR ligands was observed. In combination, these data demonstrate that activation of the RXR/PPARgamma heterodimer protects against colon inflammation and suggest that combination therapy with both RXR and PPARgamma ligands might hold promise in the clinic due to their synergistic effects.

Show MeSH
Related in: MedlinePlus