Changes in matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinases (TIMP) expression profile in Crohn's disease after immunosuppressive treatment correlate with histological score and calprotectin values.
BACKGROUND
Matrix metalloproteinases (MMPs) constitute a family of enzymes capable of degrading various extracellular matrices (ECM) and basement membrane components playing a role in ECM turnover. They activate and degrade signaling molecules, such as cytokines and chemokines. MMPs are involved in inflammation and have been implicated in tissue degradation and repair occurring in inflammatory bowel disease. The aim of this study was to investigate the MMP profile of intestinal Crohn's disease (CD) patients before and after immunosuppressive treatment (anti-TNF-alpha agents or corticosteroids and conventional immunosuppressants azathioprine or methotrexate) to learn more about the therapeutic pathways for immunosuppressive agents.


METHODS
Expression of MMP-1, MMP-7, MMP-9, MMP-10, and MMP-26 and tissue inhibitors of metalloproteinases (TIMP)-1 and TIMP-3 was studied by immunohistochemistry in pretreatment and post-treatment tissue samples. Semiquantitative immunohistochemical scores were tested for correlations with fecal and serum inflammation markers as well as endoscopic and clinical disease activity scores.


RESULTS
Neutrophil MMP-9 (p = 0.039) and MMP-26 (p = 0.030) and stromal TIMP-1 (p = 0.041) and TIMP-3 (p = 0.029) decreased along with treatment. However, expression of TIMP-3 by enterocytes tended to increase. Total histological score demonstrated positive correlation with neutrophil MMP-9 (p = 0.000), MMP-26 (p = 0.014), and macrophage TIMP-1 (p = 0.001). Calprotectin followed a similar pattern with stromal MMP-26 (p = 0.011), TIMP-1 (p = 0.000), and TIMP-3 (p = 0.001). Crohn's disease endoscopic index of severity (CDEIS) value correlated positively with macrophage TIMP-1 (p = 0.007) and stromal TIMP-3 (p = 0.005). Epithelial TIMP-3 presented with negative correlations with CDEIS (p = 0.006) and C-reactive protein values (p = 0.004).


CONCLUSIONS
Our results suggest that immunosuppressive drugs modulate disease activity in CD by downregulation of MMP-9 and MMP-26 positive neutrophils and stromal TIMP-1 and TIMP-3.
Mäkitalo
Laura
L
Department of Dermatology, Helsinki University Central Hospital and Biomedicum Helsinki, University of Helsinki, Meilahdentie 2, 00250, Helsinki, Finland.
Sipponen
Taina
T
Kärkkäinen
Päivi
P
Kolho
Kaija-Leena
KL
Saarialho-Kere
Ulpu
U
D000328:Adult; D003424:Crohn Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D004847:Epithelial Cells / Q000201:enzymology / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008875:Middle Aged; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*; D055815:Young Adult
D007166:Immunosuppressive Agents; D039841:Leukocyte L1 Antigen Complex; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases