Infliximab treatment influences the serological expression of matrix metalloproteinase (MMP)-2 and -9 in Crohnʼs disease

Gao, Qiang; Meijer, M.; Schlüter, Ulrike G.; Hogezand, R. A. van; Zon, J. M. Van Der; Berg, Marlies van den; Duijn, Wim van; Lamers, C. B. H. W.; Verspaget, Hein W.

doi:10.1002/ibd.20100

Cited by 45 publications

(45 citation statements)

References 52 publications

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“…It has been demonstrated that TNF-␣ is important in the pathogenesis of inflammatory bowel disease, and inhibition of TNF-␣ results in alteration of MMP2 and MMP9 levels in CD patients (Podolsky, 2002;Gao et al, 2007). Therefore, we detected the expression of TNF-␣ and the effect of mesalamine on TNF-␣-regulated MMP2 and MMP9 in the experimental UC.…”

Section: Resultsmentioning

confidence: 94%

“…Kaiser et al (1999) demonstrated that 5-ASA blocked TNF-␣ activation in mouse colonocytes. This finding indicated that restored balance between MMP2 and MMP9 by 5-ASA in UC might be mediated by reduction of TNF-␣, as demonstrated by Gao and his colleagues that inhibition of TNF-␣ increases MMP2 and decreases MMP9 in patients with Crohn's disease (Gao et al, 2007). In addition, another study demonstrated that stimulation of CaCO-2 cells with TNF-␣ led to a dosedependent increase in expression and secretion of MMP9 (Gan et al, 2001).…”

Section: Mesalamine Restores Angiogenic Balance In Ulcerative Colitismentioning

confidence: 79%

“…We have previously demonstrated increased MMP9 in colon of experimental UC induced by IA in rats and interleukin-10 knockout mice (Tolstanova et al, 2007). It is relevant that a recent clinical study also showed that therapy with infliximab (anti-TNF-␣ monoclonal antibody) increases MMP2 and decreases MMP9 in patients with Crohn's disease (Gao et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Mesalamine Restores Angiogenic Balance in Experimental Ulcerative Colitis by Reducing Expression of Endostatin and Angiostatin: Novel Molecular Mechanism for Therapeutic Action of Mesalamine

Deng¹,

Tolstanova²,

Khomenko³

et al. 2009

J Pharmacol Exp Ther

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Mesalamine (5-aminosalicylate acid, 5-ASA) is an effective treatment for ulcerative colitis (UC). The mechanisms of its actions are not fully understood. Because angiogenesis is critical for healing UC, we examined whether 5-ASA alters the angiogenic balance between angiogenic factors [e.g., vascular endothelial growth factor (VEGF)] and antiangiogenic factors (e.g., endostatin and angiostatin) in the colon in experimental UC. Rats were treated with saline or 5-ASA (100 mg/kg) twice daily and euthanized 3 or 7 days after iodoacetamide-induced UC. Clinical signs (e.g., lethargy, diarrhea) and UC lesions were measured. Expression of VEGF, endostatin, angiostatin, tissue necrosis factor ␣ (TNF-␣), and matrix metalloproteinases (MMPs) 2 and 9 was determined by Western blots, enzymelinked immunosorbent assay, and zymography in the distal colon. 5-ASA treatment reduced lethargy and diarrhea and significantly decreased colonic lesions (by ϳ50%) compared with saline treatment in UC (both, P Ͻ 0.05). 5-ASA did not reverse the increased levels of VEGF, but it significantly reduced expression of endostatin and angiostatin in UC compared with vehicle treatment (both, P Ͻ 0.05). Furthermore, 5-ASA treatment significantly diminished increased activity of TNF-␣ and MMP9 in UC. This is the first demonstration that 5-ASA treatment reverses an imbalance between the angiogenic factor VEGF and antiangiogenic factors endostatin and angiostatin in experimental UC. The effect of 5-ASA in UC may be caused by the down-regulation of expression of endostatin and angiostatin by modulation of MMP2 and MMP9 via inhibition of TNF␣. The inhibition of antiangiogenic factors may represent a novel molecular mechanism of the therapeutic action of 5-ASA.

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Section: Resultsmentioning

confidence: 94%

Section: Mesalamine Restores Angiogenic Balance In Ulcerative Colitismentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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Mesalamine Restores Angiogenic Balance in Experimental Ulcerative Colitis by Reducing Expression of Endostatin and Angiostatin: Novel Molecular Mechanism for Therapeutic Action of Mesalamine

Deng¹,

Tolstanova²,

Khomenko³

et al. 2009

J Pharmacol Exp Ther

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“…PF4 is generally found angiostatic, prothrombotic, acts as inhibitor of immune cell migration elicited by other chemotactic cytokines and is able to induce leukocyte activation. It could be part of a complex mechanism of control of tissue healing and infiltration also involving Matrix Metallo-Proteinases (MMP-2 and 9), highlighted in a recent study addressing as well the characterization of infliximab's mode of action in CD [17]. PF4 is also considered as an acute phase reactant because its level increases with general inflammation, as already observed in plasma of CD patients [18][19][20].…”

Section: Discussionmentioning

confidence: 96%

“…Biomarkers showing a significant evolution in at least 4/10 patients in R were different from those in NR patients, highlighting different modifications in serum composition depending on the response to infliximab. The identification of these markers should provide new information about infliximab's mode of action and could be other components of the complex mechanism leading to infiltration, tissue remodelling and to healing, already known to involve specific MMPs [17]. The expressions of these proteins are, like PF4 and other "CXC" chemokines, also controlled by proinflammatory cytokines and are produced in their final mature and active form(s) by proteolytic processing.…”

Section: Discussionmentioning

confidence: 99%

Proteomics for prediction and characterization of response to infliximab in Crohn's disease: A pilot study

Meuwis

Fillet

Lutteri

et al. 2008

Clinical Biochemistry

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Objectives: Infliximab is the first anti-TNFα accepted by the Food and Drug Administration for use in inflammatory bowel disease treatment. Few clinical, biological and genetic factors tend to predict response in Crohn's disease (CD) patient subcategories, none widely predicting response to infliximab. Design and methods: Twenty CD patients showing clinical response or non response to infliximab were used for serum proteomic profiling on Surface Enhanced Lazer Desorption Ionisation-Time of Flight-Mass Spectrometry (SELDI-TOF-MS), each before and after treatment. Univariate and multivariate data analysis were performed for prediction and characterization of response to infliximab. Results: We obtained a model of classification predicting response to treatment and selected relevant potential biomarkers, among which platelet aggregation factor 4 (PF4). We quantified PF4, sCD40L and IL-6 by ELISA for correlation studies. Conclusions: This first proteomic pilot study on response to infliximab in CD suggests association between platelet metabolism and response to infliximab and requires validation studies on a larger cohort of patients.

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Anti-TNF Antibodies: Lessons from the Past, Roadmap for the Future

Shealy¹,

Visvanathan²

2008

Therapeutic Antibodies

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Tumor necrosis factor alpha (TNF) is an important cell-signaling component of the immune system. Since its discovery over 20 years ago, much has been learned about its functions under normal and disease conditions. Nonclinical studies suggested a role for TNF in chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis, Crohn's disease, and psoriasis, and therefore neutralizing monoclonal antibodies specific to human TNF were developed for clinical evaluation. Treatment with anti-TNF monoclonal antibodies (infliximab, adalimumab, and certolizumab pegol) has been shown to provide substantial benefit to patients through reductions in both localized and systemic expression of markers associated with inflammation. In addition, there are beneficial effects of anti-TNF treatment on markers of bone and cartilage turnover. Further exploration of changes in these markers and their correlation with clinical measures of efficacy will be required to allow accurate prediction of those patients most in need of these treatments. Both the clinical and commercial experience with these anti-TNF antibodies provide a wealth of information regarding their pharmacological effects in humans.

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Infliximab treatment influences the serological expression of matrix metalloproteinase (MMP)-2 and -9 in Crohnʼs disease

Cited by 45 publications

References 52 publications

Mesalamine Restores Angiogenic Balance in Experimental Ulcerative Colitis by Reducing Expression of Endostatin and Angiostatin: Novel Molecular Mechanism for Therapeutic Action of Mesalamine

Mesalamine Restores Angiogenic Balance in Experimental Ulcerative Colitis by Reducing Expression of Endostatin and Angiostatin: Novel Molecular Mechanism for Therapeutic Action of Mesalamine

Proteomics for prediction and characterization of response to infliximab in Crohn's disease: A pilot study

Anti-TNF Antibodies: Lessons from the Past, Roadmap for the Future

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