Activated Immunocompetent Cells in Rat Colitis Mucosa Induced by Dextran Sulfate Sodium and Not Complete but Partial Suppression of Colitis by FK506

Takizawa, Hajime; Shintani, Nahoko; Natsui, Masaaki; Sasakawa, Tetsuya; Nakakubo, Hiroshi; Nakajima, Tsunetaka; Asakura, Hitoshi

doi:10.1159/000201253

Cited by 45 publications

(35 citation statements)

References 7 publications

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“…MPO activity is a useful index for evaluating neutrophil infiltration in colonic tissues after induction of colitis (Takizawa et al, 1995). Using a standard enzymatic procedure, we observed that MPO levels in the colon tissue of vehicle-treated DSS mice were 3.3-fold greater than those in the colon tissue of control healthy mice (p ϭ 0.001) (Fig.…”

Section: As605240 Treatment Extends Lifespan In a Mouse Model Of Dss-mentioning

confidence: 89%

Inhibition of Phosphoinositide 3-Kinase Ameliorates Dextran Sodium Sulfate-Induced Colitis in Mice

Peng

Wu²,

Chen³

et al. 2009

J Pharmacol Exp Ther

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The critical role of phosphoinositide 3-kinase ␥ (PI3K␥) in inflammatory cell activation and recruitment makes it an attractive target for immunomodulatory therapy. 5-Quinoxilin-6-methylene-1,3-thiazolidine-2,4-dione (AS605240), a potent PI3K␥ inhibitor, has been reported to ameliorate chronic inflammatory disorders including rheumatoid arthritis, systemic lupus erythematosus, and atherosclerosis. However, its in vivo effect on intestinal inflammation remains unknown. Here we evaluated the protective and therapeutic potentials of AS605240 in mice with dextran sodium sulfate (DSS)-induced acute and chronic colitis. Our results showed that AS605240 improved survival rate, disease activity index, and histological damage score in mice administered DSS in both preventive and therapeutic studies. AS605240 treatment also significantly inhibited the increase in myeloperoxidase levels, macrophage infiltration, and CD4ϩ T-cell number in the colon of DSS-fed mice. The DSS-induced overproduction of colonic proinflammatory cytokines including interleukin (IL)-1␤, tumor necrosis factor-␣, and interferon-␥ was significantly suppressed in mice undergoing AS605240 therapy, whereas colonic anti-inflammatory cytokines such as IL-4 were up-regulated. The downregulation of the phospho-Akt level in immunological cells from the inflamed colon tissue and spleen of AS605240-treated mice was detected both by immunohistochemical analysis and Western blotting. These findings demonstrate that AS605240 may represent a promising novel agent for the treatment of inflammatory bowel disease by suppressing leukocyte infiltration as well as by immunoregulating the imbalance between proinflammatory and anti-inflammatory cytokines.The intestinal bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, are characterized by chronic relapsing inflammatory disorders of the gastrointestinal tract. Despite extensive efforts, the etiology and pathogenesis of IBDs remain unclear and effective therapies with limited side effects are still lacking (Bouma and Strober, 2003;Baert et al., 2004). Therefore, development of new effective and well tolerated drugs for IBD therapy is necessary.Chemokines, as detected in the inflamed colon of humans and in murine IBD models, are responsible for recruitment of leukocytes into the lamina propria (LP) of the intestine, which in most cases results in focal crypt damage and epithelial ulceration, the markers in the pathogenesis of IBD (MacDermott et al., 1998;Danese and Gasbarrini, 2005). Many studies have convincingly demonstrated that antagonists targeted against chemokine or receptor function can effectively inhibit acute and chronic inflammation via prevention of leukocyte chemotaxis and activation in animal models of IBD (Onuffer and Horuk, 2002). Recent studies have illustrated the fact that PI3K␥ acts as a key downstream signaling component that relays chemokine receptor signals (Curnock et al., 2002;Rü ckle et al., 2006).

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Section: As605240 Treatment Extends Lifespan In a Mouse Model Of Dss-mentioning

confidence: 89%

Inhibition of Phosphoinositide 3-Kinase Ameliorates Dextran Sodium Sulfate-Induced Colitis in Mice

Peng

Wu²,

Chen³

et al. 2009

J Pharmacol Exp Ther

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“…Although disease can be induced by acute administration of DSS in severe combined immunodeficient mice (48), other studies provide evidence that cyclosporin and FK506 are protective in the short-term acute DSS model, suggesting that T cells participate in disease development (49,50). Furthermore, specific T cell subsets exert protective effects after acute administration of DSS (51).…”

Section: Discussionmentioning

confidence: 99%

IL-1β-converting enzyme (caspase-1) in intestinal inflammation

Siegmund

Lehr

Fantuzzi

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

384

293

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IL-1␤-converting enzyme (ICE; caspase-1) is the intracellular protease that cleaves the precursors of IL-1␤ and IL-18 into active cytokines. In the present study, the effect of ICE deficiency was evaluated during experimental colitis in mice. In acute dextran sulfate sodium-induced colitis, ICE-deficient (ICE KO) mice exhibited a greater than 50% decrease of the clinical scores weight loss, diarrhea, rectal bleeding, and colon length, whereas daily treatment with IL-1 receptor antagonist revealed a modest reduction in colitis severity. To further characterize the function of ICE and its role in intestinal inflammation, chronic colitis was induced over a 30-day time period. During this chronic time course, ICE KO mice exhibited a near complete protection, as reflected by significantly reduced clinical scores and almost absent histological signs of colitis. Consistently, colon shortening occurred only in dextran sulfate sodium-exposed wild-type mice but not in ICE KO mice. Protection was accompanied by reduced spontaneous release of the proinflammatory cytokines IL-18, IL-1␤, and IFN-␥ from total colon cultures. In addition, flow cytometric analysis of isolated mesenteric lymph node cells revealed evidence of reduced cell activation in ICE KO mice as evaluated by surface expression of CD3 CD69 and CD4 CD25. We conclude that inhibition of ICE represents a novel anti-inflammatory strategy for intestinal inflammation.

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“…To allow inference of pharmacological effect from occult blood discharge, occult blood level and number of days from first drug administration were used to establish an occult blood index, which was calculated thus: occult blood index ¼ Culture of colonic mucosa DSS-induced colitis rats treated for 6 days with IgG were killed on the day after final administration and the colon from the rectum to the sigmoid colon was removed. According to the method of Takizawa et al [18], the colons were cut open and the mucosa gently stripped off. The stripped mucosa was transferred to 15 ml polypropylene tubes (Falcon; Becton Dickinson, Franklin Lakes, NJ), where it was washed in a medium of RPMI 1640 (Flow Labs, Irvine, UK) containing 100 U/ml penicillin and 100 mg/ml streptomycin through a process of centrifugation at 400 g, aspiration of the supernatant and addition of clean RPMI 1640.…”

Section: Calculation Of Occult Blood Indexmentioning

confidence: 99%

Intravenous immunoglobulin (IVIG) treatment of experimental colitis induced by dextran sulfate sodium in rats

Shintani

Nakajima

Nakakubo

et al. 1997

Clinical and Experimental Immunology

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SUMMARYWe investigated the therapeutic effect and immunological action mechanism of IgG in experimental colitis induced by 3% dextran sulfate sodium in rats. Intravenous injection of homologous (rat) IgG (400 mg/kg per day) caused a significant suppression of occult blood discharge and ulcerative lesions in the colon, while no suppressive effect was observed in the case of heterologous (human) IgG. The positive effect of rat IgG on the lesions was also clearly shown by the histological examinations. Generation of proinflammatory cytokines, i.e. tumour necrosis factor-alpha (TNF-a) and IL-1a, in the lesions was found to be inhibited by administration of rat IgG. Little or no suppressive action was exerted by human IgG. Careful examination of recruited T cells and macrophages, both of which are thought to play important roles in the development of ulcerative colitis, indicated that rat IgG, but not its human counterpart, decreased the number of immunocompetent cells in colonic mucosa. Meanwhile, in an in vitro study, both forms of IgG were shown to suppress production of TNF-a and IL-1a from lamina propria mononuclear cells isolated from rat colon. These findings suggest that, mainly by suppressing recruitment of immunocompetent cells into the lesions, homologous IgG may reduce the occurrence of colitis.

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Activated Immunocompetent Cells in Rat Colitis Mucosa Induced by Dextran Sulfate Sodium and Not Complete but Partial Suppression of Colitis by FK506

Cited by 45 publications

References 7 publications

Inhibition of Phosphoinositide 3-Kinase Ameliorates Dextran Sodium Sulfate-Induced Colitis in Mice

Inhibition of Phosphoinositide 3-Kinase Ameliorates Dextran Sodium Sulfate-Induced Colitis in Mice

IL-1β-converting enzyme (caspase-1) in intestinal inflammation

Intravenous immunoglobulin (IVIG) treatment of experimental colitis induced by dextran sulfate sodium in rats

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