Journal Article

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

Meijer, Martin J.W., Lamers, Cornelis B.H.W., Schlüter, Ulrike G., van den Berg, Marlies, Gao, Qiang, van Duijn, Wim, van Hogezand, Ruud A., Verspaget, Hein W., van der Zon, Johanna M.

2007

Overview

Matrix metalloproteinases (MMPs) are actively involved in the pathogenesis of Crohn's disease (CD). We assessed the effect of the anti-tumor necrosis factor-α (TNF-α) monoclonal antibody infliximab on the in vitro and in vivo expression of MMP-2 and MMP-9 in CD.MethodsInfliximab-treated fistulizing (n = 10) or active disease (n = 7) CD patients, from an in-house study, and fistulizing CD patients (n = 42) and active CD patients (n = 24) from 2 placebo controlled studies were evaluated for serum MMP levels and clinical response. Biopsies were evaluated immunohistochemically for the MMPs. Whole blood cultures stimulated with lipopolysaccharide (LPS)/infliximab were evaluated for MMP mRNA and protein levels.ResultsSerum MMP-2 levels in CD patients increased during follow-up, similarly in responders and nonresponders, by infliximab. Immunohistochemistry showed no clear MMP-2 change in biopsies. Serum MMP-9 levels, however, showed a consistent pattern of decrease in most CD patients, particularly in those responding, and MMP-9-positive polymorphonuclear leukocytes in biopsies also decreased by infliximab. LPS stimulation of whole blood increased the MMP-9 levels in plasma significantly in CD patients and controls, but infliximab had no effect on the secretion. Long-term LPS stimulation raised leukocyte MMP-9 mRNA levels 16-fold and infliximab inhibited this induction by 80%.ConclusionsInfliximab treatment increases MMP-2 and decreases MMP-9 in serum of patients with CD, the latter also in the intestine, which extends and confirms our previous ex vivo explants observations. However, these changes were not strictly associated with the response to treatment. The enhanced leukocyte MMP-9 expression in CD seems to be regulated by TNF-α.

• Publisher: Oxford University Press,Wiley Subscription Services, Inc., A Wiley Company
• Subject: Adolescent / Adult / Aged / Anti-Inflammatory Agents - therapeutic use / Antibodies, Monoclonal - therapeutic use / Biomarkers - blood / Biopsy / Crohn Disease - blood / Crohn Disease - drug therapy / Crohn Disease - enzymology / Crohn's disease / Enzyme-Linked Immunosorbent Assay / Follow-Up Studies / Gene Expression - drug effects / Humans / Immunohistochemistry / Infliximab / Leukocytes / Matrix Metalloproteinase 2 - blood / Matrix Metalloproteinase 2 - genetics / Matrix Metalloproteinase 9 - blood / Matrix Metalloproteinase 9 - genetics / matrix metalloproteinases / Middle Aged / Neutrophils - enzymology / Reverse Transcriptase Polymerase Chain Reaction / RNA, Messenger - genetics / Treatment Outcome / Tumor necrosis factor-TNF