A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

Woodruff, Trent M.; Arumugam, Thiruma V.; Shiels, Ian A.; Reid, Robert C.; Fairlie, David P.; Taylor, Stephen M.

doi:10.4049/jimmunol.171.10.5514

Cited by 109 publications

(103 citation statements)

References 49 publications

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“…This is in pace with reductions observed in other studies. For example, in an animal model of colitis, the treatment with a dose of infliximab, which is similar to the one used in our study, promoted a 45% decrease in local (colonic) levels of TNF-a and a 50% reduction in blood levels of the cytokine (Woodruff et al 2003). Furthermore, infliximab treatment effectively inhibited the expression of the proinflammatory cytokines, IL-6, and IL-1b, while the antiinflammatory cytokine IL-10 was not affected by the treatment.…”

Section: Discussionmentioning

confidence: 99%

Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet

Barbuio

Milanski

Bértolo

et al. 2007

Journal of Endocrinology

137

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Non-alcoholic fatty liver disease, induced by nutritional factors, is one of the leading causes of hepatic dysfunction in the modern world. The activation of proinflammatory signaling in the liver, which is induced by systemic and locally produced cytokines, and the development of hepatic insulin resistance are two important factors associated with the progression from steatosis to steatohepatitis, a pre-cirrhotic condition. The objective of the present study was to evaluate the effect of inhibition of tumour necrosis factor (TNF)-a, using the monoclonal antibody infliximab, on the expression of cytokines, induction of steatosis and fibrosis, and insulin signal transduction in the liver of Wistar rats fed a high-fat diet. Ten days of treatment with infliximab significantly reduced the expression of the proinflammatory markers, TNF-a, IL-6, IL-1b, and SOCS-3, in the liver of rats fed a high-fat diet. This was accompanied by reduced fat deposition and fibrosis and by improved insulin signal transduction through insulin receptor (IR)/IR substrate/Akt/FOXO1 and JAK2/STAT3 pathways. In conclusion, short-term inhibition of TNF-a with infliximab reduces inflammation and steatosis/fibrosis, while improving insulin signal transduction in an animal model treated with a high-fat diet.

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Section: Discussionmentioning

confidence: 99%

Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet

Barbuio

Milanski

Bértolo

et al. 2007

Journal of Endocrinology

137

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“…Examples are that C5a anaphylatoxin can induce the release of TNF-␣, IL-6, and IL-1 from inflamed colonic tissue (44 -46) and the generation of IL-8, IL-6, TNF-␣, IL-10, and IL-1 from retinal pigment epithelial cells (47). Moreover, recent studies have shown that C5a receptor antagonists protect against disease in a rat model of IBD (48).…”

Section: Discussionmentioning

confidence: 99%

Decay-Accelerating Factor Deficiency Increases Susceptibility to Dextran Sulfate Sodium-Induced Colitis: Role for Complement in Inflammatory Bowel Disease

Lin¹,

Spencer

Hatala³

et al. 2004

The Journal of Immunology

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Decay-accelerating factor (DAF or CD55) is expressed on colonic epithelial cells but its function in the mucosa is unknown. In humans, a proportion of DAF-deficient (Cromer INAB) patients develop inflammatory bowel disease (IBD). To evaluate how DAF deficiency may contribute to gut inflammation and thus could play a role in IBD pathogenesis, we compared the severity of dextran sulfate sodium-induced colitis in Daf1 gene-targeted and control mice. Seven days after consuming 3% dextran sulfate sodium in their drinking water, Daf1−/− mice suffered markedly greater weight loss (−24.7 ± 7.5% vs −14.2% ± 4.9%), exhibited uniformly bloody diarrhea as compared with soft stool in control mice, developed shortened colons, and had larger spleens. Histological examination of distal colons showed massively increased neutrophilic and mononuclear cell infiltration, greater epithelial cell destruction, and increased ulcerations. Cytokine production in organ cultures of colonic explants showed increased levels of IL-12 and IL-6. Fourteen days after switching back to regular water, in contrast to the Daf1+/+ controls which showed little stool abnormality, all Daf1−/− mice continued to have diarrhea. Organ culture cytokine measurements at this time point, i.e., the end of the recovery phase, showed markedly increased levels of IL-10 (6-fold), IL-12 (4-fold), and IL-6 (2-fold), as well as TNF-α (>10-fold) compared with the controls. Our findings argue that, as shown for IL-10 in IL-10−/− mice and IL-2 in IL-2−/− mice, DAF control of complement additionally is important in regulating gut homeostasis and consequently its activity may participate in protecting against IBD.

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“…Every time rhabdomyolysis was induced, a similar number of sham (glycerol)-injected rats that had been subjected to the same procedures before and after injection was used to serve as control groups. After glycerol injection, rats were immediately treated with saline (sham treatment) or with a single dose of infliximab (5 mg/kg ip, Centocor BV, Leiden, Holland) (40). In a separate series of experiments, using the same model, rats were treated with a single intraperitoneal dose of the RIP1 inhibitor necrostatin-1 (1.65 mg/kg, Sigma-Aldrich, St. Louis, MO) (16) or infliximab (5 mg/kg, Centocor BV), or their combination at the same doses used alone.…”

Section: Methodsmentioning

confidence: 99%

TNF-α-mediated cardiorenal injury after rhabdomyolysis in rats

Homsi

Andreazzi

Faria

et al. 2015

American Journal of Physiology-Renal Physiology

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Homsi E, Andreazzi DD, Lopes de Faria JB, Janino P. TNF-␣-mediated cardiorenal injury after rhabdomyolysis in rats. Am J Physiol Renal Physiol 308: F1259 -F1267, 2015. First published November 12, 2014 doi:10.1152/ajprenal.00311.2014.-The TNF-␣ serum level increases after rhabdomyolysis and is involved in the subsequent cardiorenal injury. In the present study, we investigated the TNF-␣-dependent cell signaling pathways implicated in cellular injury in these organs. Rhabdomyolysis was induced by intramuscular glycerol injection in rats. Renal function, cardiac and renal pathology, and activation of caspases were evaluated during the first 24 h after glycerol injection. TNF-␣ blockade with infliximab reduced tubular necrosis and cardiorenal apoptosis. Cellular Fas-associated protein with death domain-like IL-1␤-converting enzyme inhibitory protein (cFLIP), an inhibitor of caspase-8, was overexpressed in the kidney but not in the heart. The inhibitory effect of cFLIP blunted caspase-8 activation in the kidney. In this condition, the cellular response to the TNF-␣ stimulus was driven to receptor-interacting protein-1 (RIP1)-mediated necroptosis. Treatment with RIP1 inhibitor (necrostatin-1) isolated or in combination with infliximab showed a similar reduction in tubular necrosis, underscoring the importance of TNF-␣-mediated tubular necroptosis in this model. TNF-␣ played a positive regulatory role in the transcription of proapoptotic Bax and p53-upregulated modulator of apoptosis (PUMA) proteins. Infliximab treatment reduced caspase-9-mediated apoptosis in both organs. Treatment with a caspase-8 inhibitor showed that caspase-8 participated in the process of apoptosis only in the heart, upstream of caspase-9 activation. TNF-␣-mediated necroptosis is the predominant form of tubular injury observed in the glycerol model. TNF-␣ up regulates Bax and PUMA proapoptotic proteins, resulting in activation of the intrinsic pathway of apoptosis in the kidney and heart. acute kidney injury; apoptosis; necroptosis; cardiac injury; tumor necrosis factor-␣; rhabdomyolysis RHABDOMYOLYSIS elicits a systemic inflammatory response that may contribute to distant organ injuries (3,35,42). Acute kidney injury (AKI) is the most well-known distant organ injury frequently observed after severe rhabdomyolysis (2,19). A large amount of evidence supports the role of renal ischemia and myoglobinuria as the main mechanisms involved in the renal injury after rhabdomyolysis (9, 41). Apart from these mechanisms, Shulman et al. (34) showed many years ago that treatment with anti-TNF-␣-neutralizing antibody conferred renal protection to rats subjected to rhabdomyolysis.More recently, Kelly (12) showed an increased serum level and cardiac expression of TNF-␣ after renal ischemia-reperfusion injury (IRI) in rats. Cardiac function was depressed after renal IRI, and the author detected a significant increase in cardiomyocyte apoptosis 48 h after renal IRI. Treatment with anti-TNF-␣ polyclonal antibody simultaneously with renal IRI significantly atten...

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A Potent Human C5a Receptor Antagonist Protects against Disease Pathology in a Rat Model of Inflammatory Bowel Disease

Cited by 109 publications

References 49 publications

Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet

Infliximab reverses steatosis and improves insulin signal transduction in liver of rats fed a high-fat diet

Decay-Accelerating Factor Deficiency Increases Susceptibility to Dextran Sulfate Sodium-Induced Colitis: Role for Complement in Inflammatory Bowel Disease

TNF-α-mediated cardiorenal injury after rhabdomyolysis in rats

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