Analysis of intestinal haem-oxygenase-1 (HO-1) in clinical and experimental colitis.
Haem-oxygenase-1 (HO-1) has been shown to exert anti-inflammatory, anti-apoptotic and anti-proliferative effects. We investigated HO-1 expression in patients with inflammatory bowel disease (IBD) and could demonstrate a scattered expression of HO-1 in the intestinal epithelium of severely inflamed colonic mucosa of patients with IBD compared to control specimens such as diverticulitis, suggesting dysregulated expression in IBD. To further analyse potential mechanisms of HO-1 induction in the intestine we employed an in vitro epithelial cell apoptosis model and an experimental colitis model. In vitro induction of HO-1 by the HO-1 inducer cobalt protoporphyrin (CoPP) resulted in a dose-dependent down-regulation of caspase-3 activation in HT-29 cells, indicating an anti-apoptotic function of HO-1 in the intestine. In vivo, preventive HO-1 induction by CoPP in acute dextran sodium sulphate (DSS)-induced colitis led to a significant down-regulation of colonic inflammation (P < 0.01) with a concomitant reduction in interferon (IFN)-gamma - but unaffected interleukin (IL)-10-secretion by isolated mesenteric lymph nodes (P < 0.01). Additionally, TUNEL staining of colonic sections demonstrated fewer apoptotic epithelial cells in the colon of CoPP treated animals. No beneficial effects were observed if HO-1 was induced by CoPP after the onset of acute colitis or in chronic DSS-induced colitis. In conclusion, the data suggest a protective role of HO-1 if it is induced before the onset of inflammation. However, as shown by the lack of effects in established acute or in chronic colitis, the induction of HO-1 may not be a promising approach for the treatment of IBD.
Paul
G
G
Department of Internal Medicine I, University of Regensburg, Germany.
Bataille
F
F
Obermeier
F
F
Bock
J
J
Klebl
F
F
Strauch
U
U
Lochbaum
D
D
Rümmele
P
P
Farkas
S
S
Schölmerich
J
J
Fleck
M
M
Rogler
G
G
Herfarth
H
H
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D053148:Caspase 3; D020169:Caspases / Q000276:immunology; D045744:Cell Line, Tumor; D002908:Chronic Disease; D003093:Colitis, Ulcerative / Q000276:immunology; D003106:Colon / Q000276:immunology; D003424:Crohn Disease / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006419:Heme Oxygenase (Decyclizing) / Q000032:analysis / Q000276:immunology*; D051547:Heme Oxygenase-1; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D011524:Protoporphyrins / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
D008565:Membrane Proteins; D011524:Protoporphyrins; C007095:cobaltiprotoporphyrin; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases