Matrix metalloproteinase pattern in celiac duodenal mucosa.
Matrix metalloproteinases (MMPs) are a family of endopeptidases playing a key role in tissue remodelling in both physiological and pathological conditions. Since little information is available about their role in celiac disease (CD), our aims were to quantify their expression/activity and to investigate their relation to proinflammatory cytokines in this condition. Duodenal biopsies from untreated, treated celiac patients and controls were used to quantify the expression of MMP-1, MMP-2, MMP-3, MMP-9, MMP-12, MMP-14, their inhibitor TIMP-1, IFN-gamma and TNF-alpha by using real-time reverse transcription-polymerase chain reaction and the gelatin/casein/elastin activities by gel zymography, and to isolate lamina propria mononuclear cells (LPMCs). These cells and myofibroblasts isolated from jejunal specimens were incubated in the absence or presence of IFN-gamma and TNF-alpha. MMP-1 and MMP-12 mRNA levels were significantly increased in active CD compared to treated (P<0.01 and P<0.0005, respectively) and normal mucosa (P<0.01 and P<0.0005, respectively), and this was paralleled by an upregulation of caseinolytic and elastolytic activities. Furthermore, MMP-12 levels significantly (P<0.05) correlated with those of IFN-gamma and the degree of villous flattening. MMP-2 turned out to be significantly (P<0.05) reduced in untreated and treated celiacs compared to controls. In active CD, transcripts of TIMP-1 were higher than in treated and controls (P<0.005 and P<0.05, respectively), such as those of IFN-gamma (P<0.05), whereas TNF-alpha levels were suppressed (P=0.0001). In physiological condition, myofibroblasts represent the main source of MMP-2, whereas LPMCs produce almost all MMPs only after cytokine stimulation. Conversely, cells isolated from active patients constitutively express MMPs without any increase after cytokine stimulation, while those from treated patients are in a resting condition. In conclusion, our results show the presence of a peculiar MMP pattern in active CD strongly dominated by MMP-12, correlating either with IFN-gamma or the degree of mucosal damage.
Ciccocioppo
Rachele
R
Gastroenterology Unit, IRCCS Policlinico San Matteo, University of Pavia, Italy.
Di Sabatino
Antonio
A
Bauer
Michael
M
Della Riccia
Daniela N
DN
Bizzini
Francesca
F
Biagi
Federico
F
Cifone
Maria G
MG
Corazza
Gino R
GR
Schuppan
Detlef
D
D000293:Adolescent; D000328:Adult; D000368:Aged; D002446:Celiac Disease / Q000201:enzymology* / Q000473:pathology; D004386:Duodenum / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology* / Q000473:pathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
C439524:TNF protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D020782:Matrix Metalloproteinases