Transcriptomic analysis of intestinal fibrosis-associated gene expression in response to medical therapy in Crohn's disease.
BACKGROUND
Glucocorticoids and monoclonal antibodies to tumor necrosis factor reduce inflammation in Crohn's disease (CD). Rapid luminal healing, however, may promote intestinal stricture formation. The aim of this study was to examine fibrosis-associated gene expression in the intestine of patients with CD and correlate expression levels with prior medical therapies.


METHODS
In all, 37 patients with stricturing CD and 18 non-CD controls underwent a transmural biopsy at the time of elective intestinal resection. Quantitative real-time polymerase chain reaction (PCR) was conducted to determine differential mRNA expression of TGF-beta(1), Smad-7, CTGF, collagen-1alpha, fibronectin, BMP-7, and MIF. Intestinal fibroblasts were treated in vitro with dexamethasone.


RESULTS
Relative to control, strictured CD intestinal tissue expressed increased TGF-beta(1), CTGF, collagen-1alpha, and BMP-7 (all P < 0.05). TGF-beta(1) gene expression positively correlated with the expression of its downstream targets (all P < 0.001). Preoperative infliximab exposure was not associated with increased expression in any of the target genes nor did the number of infliximab infusions correlate with gene expression. The number of cycles of corticosteroid treatment preoperatively was positively associated with CTGF (r = 0.486, P = 0.016) and MIF (r = 0.524, P = 0.009) expression. Intestinal fibroblasts treated in vitro with dexamethasone upregulated CTGF expression (P = 0.023).


CONCLUSIONS
Exposure to infliximab does not appear to induce a profibrotic transcriptional response in the CD intestine. Previous corticosteroid treatment is associated with increased expression of CTGF and MIF. Treating intestinal fibroblasts in vitro with steroids upregulates CTGF expression.
Burke
John P
JP
Department of Surgery, Mater Misericordiae University Hospital, University College Dublin, Ireland.
Ferrante
Marc
M
Dejaegher
Karen
K
Watson
R William G
RW
Docherty
Neil G
NG
De Hertogh
Gert
G
Vermeire
Severine
S
Rutgeerts
Paul
P
D'Hoore
Andre
A
Penninckx
Freddy
F
Geboes
Karel
K
Van Assche
Gert
G
O'Connell
P Ronan
PR
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D055513:Connective Tissue Growth Factor / Q000235:genetics; D003424:Crohn Disease / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005353:Fibronectins / Q000235:genetics; D005355:Fibrosis / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D000069285:Infliximab; D007422:Intestines / Q000473:pathology*; D019746:Intramolecular Oxidoreductases / Q000235:genetics; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051906:Smad7 Protein / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics
D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D015415:Biomarkers; D055419:Bone Morphogenetic Protein 7; C526317:CCN2 protein, human; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D005353:Fibronectins; D008263:Macrophage Migration-Inhibitory Factors; D012333:RNA, Messenger; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; D000069285:Infliximab; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human