Therapeutic Effect of Blocking CXCR2 on Neutrophil Recruitment and Dextran Sodium Sulfate-Induced Colitis

Farooq, Shukkur M.; Stillie, RoseMarie; Svensson, Majlis; Svanborg, Catharina; Strieter, Robert M.; Stadnyk, Andrew W.

doi:10.1124/jpet.108.145862

Cited by 90 publications

(94 citation statements)

References 35 publications

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“…As previously found by others (23), there was a significant increase in the number of neutrophils per high-power field (31.4 ± 4.1) in the colons of our DSS-treated 6 + /7 − mice (Figs. 3 B, C, and F) than in the colons of untreated mice, where neutrophils were scarce.…”

Section: Resultssupporting

confidence: 72%

Essential role for mast cell tryptase in acute experimental colitis

Hamilton

Sinnamon

Lyng³

et al. 2010

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

110

102

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Patients with inflammatory bowel disease (IBD) have increased numbers of human tryptase-β (hTryptase-β)-positive mast cells (MCs) in the gastrointestinal tract. The amino acid sequence of mouse mast cell protease (mMCP)-6 is most similar to that of hTryptase-β. We therefore hypothesized that this mMCP, or the related tryptase mMCP-7, might have a prominent proinflammatory role in experimental colitis. The dextran sodium sulfate (DSS) and trinitrobenzene sulfonic acid (TNBS) colitis models were used to evaluate the differences between C57BL/6 (B6) mouse lines that differ in their expression of mMCP-6 and mMCP-7 with regard to weight loss, colon histopathology, and endoscopy scores. Microarray analyses were performed, and confirmatory real-time PCR, ELISA, and/or immunohistochemical analyses were carried out on a number of differentially expressed cytokines, chemokines, and matrix metalloproteinases (MMPs). The mMCP-6-null mice that had been exposed to DSS had significantly less weight loss as well as significantly lower pathology and endoscopy scores than similarly treated mMCP-6-expressing mice. This difference in colitis severity was confirmed endoscopically in the TNBS-treated mice. Evaluation of the distal colon segments revealed that numerous proinflammatory cytokines, chemokines that preferentially attract neutrophils, and MMPs that participate in the remodeling of the ECM were all markedly increased in the colons of DSS-treated WT mice relative to untreated WT mice and DSS-treated mMCP-6-null mice. Collectively, our data show that mMCP-6 (but not mMCP-7) is an essential MC-restricted mediator in chemically induced colitis and that this tryptase acts upstream of many of the factors implicated in IBD.

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Section: Resultssupporting

confidence: 72%

Essential role for mast cell tryptase in acute experimental colitis

Hamilton

Sinnamon

Lyng³

et al. 2010

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

110

102

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“…It has been well documented that blocking the ELR ϩ CXC chemokines/CXCR2 biological axis via CXCR2 neutralizing antibodies or selective CXCR2 antagonists (such as SB225002) or neutralizing antibodies against cognate CXCR2 ligands (such as anti-CXCL1/keratinocyte-derived chemokine antibody) potently inhibited neutrophil migra- tion and infiltration in vitro and in vivo, and significantly ameliorated ulcerative colitis in experimental animals (7,35,(53)(54)(55)(56)(57). Genetic deletion of CXCR2 in colitic mice demonstrated reduced PMN infiltration, limited signs of mucosal damage, and reduced clinical symptoms (35,58). Therefore, the ELR ϩ CXC chemokines/CXCR2 biological axis appears to represent an attractive potential therapeutic target (59).…”

Section: Discussionmentioning

confidence: 99%

“…Murine Neutrophil Isolation from Mouse Bone Marrow-Isolation of murine neutrophils from bone marrow was carried out as reported previously (35). Briefly, the femurs and tibias were removed from euthanized mice and the bone marrow cells were flushed out of the bones with ice-cold Ca 2ϩ -and Mg 2ϩ -free HBSS (HBSS Ϫ ).…”

Section: Methodsmentioning

confidence: 99%

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A Chemokine Receptor CXCR2 Macromolecular Complex Regulates Neutrophil Functions in Inflammatory Diseases

Wang

Farooq

et al. 2012

Journal of Biological Chemistry

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“…CXCL2, signaling through CXCR2, is chemotactic for neutrophils [48]. This chemokine is one of a larger family any number of which may be important in DSS-colitis, as treating mice with a CXCR2 blocking antiserum or a genetic deficiency for CXCR2 reduces DSS colitis [49,50]. IL-4 is regarded as an anti-inflammatory mediator although it is reported elevated in the DSS inflamed colon [51].…”

Section: Discussionmentioning

confidence: 99%

TNFR1 Deficiency Protects Mice from Colitis-Associated Colorectal Cancer Coupled with a Decreased Level of Oxidative Damage in the Colon: Implications for Anti-TNF Therapy of Unremitting Colitis

Stillie¹,

Sapp²,

Stadnyk³

2012

JCT

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It has long been appreciated that there is a direct relationship between the intensity and duration of inflammatory bowel diseases (IBD) and increasing intestinal cancer risk but which elements of the inflammatory response are responsible have not been identified. Anti-TNF drugs have been successful at treating IBD but considering the presumed anti-tumor activity of TNF, it is important to understand whether the treatment impacts on the patients' intestinal cancer risk. We modeled this relationship by "treating mice lacking TNF receptors with a colon cancer causing combination of azoxymethane followed by repeated dextran sulphate sodium exposures (AOM + DSS regime). TNF receptor type1 gene deficient (TNFR1 -/-) and TNFR2 -/-mice experienced similar clinical illnesses and colonic inflammation as C57BL/6 wildtype controls during the AOM + DSS regime. Despite the inflammation, TNFR1-/-mice developed significantly fewer colon tumors than the other strains. The reduced tumor incidence was a product of the combined lack of receptor expression on hematopoietic and nonhematopoietic cells, shown using bone marrow cell chimeras of wildtype and TNFR1 -/-mice. As oxidative damage is a potent contributing factor to tumorigenesis and inflammatory leukocytes make copious amounts of reactive oxygen radicals, we measured oxidative damage in the animals' colons. TNFR1 -/-mice showed less damage compared to the other strains. We subsequently examined mice deficient in their leukocyte NADPH oxidative pathway (Nox2 -/-) for their cancer incidence using the AOM + DSS regime. Nox2 -/-mice became inflamed but had fewer tumors than wildtype mice. We conclude that TNF promotes colon cancer including through promoting oxidative processes utilizing TNFR1 in leukocytes. Moreover, the C57BL/6 strain can be used to dissociate mechanisms of colon inflammation from tumorigenic processes. We interpret our results to mean that IBD patients on TNF antagonist therapies will potentially benefit with reduced colon cancer risk even if they do not respond with reduced inflammation.

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Therapeutic Effect of Blocking CXCR2 on Neutrophil Recruitment and Dextran Sodium Sulfate-Induced Colitis

Cited by 90 publications

References 35 publications

Essential role for mast cell tryptase in acute experimental colitis

Essential role for mast cell tryptase in acute experimental colitis

A Chemokine Receptor CXCR2 Macromolecular Complex Regulates Neutrophil Functions in Inflammatory Diseases

TNFR1 Deficiency Protects Mice from Colitis-Associated Colorectal Cancer Coupled with a Decreased Level of Oxidative Damage in the Colon: Implications for Anti-TNF Therapy of Unremitting Colitis

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