Effect of the anti-tumor necrosis factor-alpha antibody infliximab on the ex vivo mucosal matrix metalloproteinase-proteolytic phenotype in inflammatory bowel disease.
BACKGROUND
Previous studies have shown an upregulation of matrix metalloproteinases (MMPs) in intestinal tissue of patients with inflammatory bowel disease (IBD) and significant clinical improvement after administration of the anti-TNF-a antibody infliximab. The aims of our study were to determine expression and secretion of MMP-1, -2, -3, -9, and their inhibitors TIMP-1, -2 by IBD versus control intestinal mucosa ex vivo and to assess the regulatory capacity by infliximab of the proteolytic phenotype.


METHODS
Intestinal mucosal explants from 20 IBD and 15 control patients were cultured with or without infliximab and/or the T-cell activator pokeweed mitogen (PWM). Explants and culture supernatants were analyzed for MMPs, TIMPs, and TNF-alpha protein, activity and/or mRNA levels. All patients were genotyped for functional TNF-alpha, MMP, and TIMP single nucleotide polymorphism (SNP) loci.


RESULTS
Expression of MMP and TIMP protein/activity in basal medium was higher in IBD versus control explants. Dependent on genotype at SNP loci, infliximab downregulated MMP-1, -3, and -9 relative to TIMP-1 and -2 and also decreased MMP-1 and -3 activities, while PWM enhanced these levels, partly counteracted again by infliximab. The expression of MMP-2 relative to TIMP did not change by treatment with infliximab and/or PWM.


CONCLUSIONS
The high expression of MMPs in patients with IBD suggests a role for these proteinases in the pathogenesis of this disease. Infliximab seems to induce a genotype-associated matrix protective phenotype, which may contribute to the observed therapeutic efficacy of this drug in IBD, particularly at the mucosal surface.
Meijer
Martin J
MJ
Leiden University Medical Center, Department of Gastroenterology-Hepatology, Leiden, The Netherlands.
Mieremet-Ooms
Marij A C
MA
van Duijn
Wim
W
van der Zon
Annie M
AM
Hanemaaijer
Roeland
R
Verheijen
Jan H
JH
van Hogezand
Ruud A
RA
Lamers
Cornelis B H W
CB
Verspaget
Hein W
HW
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D003093:Colitis, Ulcerative / Q000201:enzymology* / Q000235:genetics; D003424:Crohn Disease / Q000201:enzymology* / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D006801:Humans; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000201:enzymology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D046509:Tissue Culture Techniques; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D019714:Tissue Inhibitor of Metalloproteinases; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D020782:Matrix Metalloproteinases