Cathepsins B, L and D in inflammatory bowel disease macrophages and potential therapeutic effects of cathepsin inhibition in vivo.
The cathepsins D (CTSD), B (CTSB) and L (CTSL) are important for the intracellular degradation of proteins. Increased cathepsin expression is associated with inflammatory diseases. We have shown previously an induction of CTSD expression in intestinal macrophages (IMAC) in inflamed mucosa of patients with inflammatory bowel disease (IBD). Here we investigated the regulation of CTSB and CTSL in IMAC during IBD and effects of CTSD and CTSB/CTSL inhibition in vivo. Human IMAC were isolated from normal and inflamed mucosa. Reverse transcription-polymerase chain reaction (RT-PCR) was performed for CTSB and CTSL mRNA. Immunostaining was used to confirm PCR results. Cathepsin inhibition was investigated in the dextran-sulphate-sodium (DSS) colitis model in mice with application of pepstatin A (CTSD inhibitor), CA-074 (CTSB inhibitor) and Z-Phe-Tyr-aldehyde (CTSL inhibitor). CTSL mRNA was significantly up-regulated in IMAC isolated from IBD mucosa. Up-regulated protein expression was found mainly in areas of mucosal damage by immunostaining. Inhibition of CTSD in mouse DSS colitis was followed by an amelioration of the disease. Inhibitor-treated mice showed a significant lower histological score (HS) and less colon reduction in comparison to controls. Similarly, simultaneous inhibition of CTSB/CTSL was followed by a significant amelioration of colitis. Expression of tissue-degrading cathepsins is increased in IMAC in IBD. Inhibition of CTSD as well as CTSB/CTSL is followed by an amelioration of experimental colitis. The prevention of mucosal damage by cathepsin inhibition could represent a new approach for the therapy of IBD.
Menzel
K
K
Department of Internal Medicine I, University of Regensburg, Regensburg, Germany.
Hausmann
M
M
Obermeier
F
F
Schreiter
K
K
Dunger
N
N
Bataille
F
F
Falk
W
W
Scholmerich
J
J
Herfarth
H
H
Rogler
G
G
D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D002402:Cathepsin D / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D003092:Colitis / Q000188:drug therapy / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D015853:Cysteine Proteinase Inhibitors / Q000627:therapeutic use; D004151:Dipeptides / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000201:enzymology*; D007413:Intestinal Mucosa / Q000201:enzymology; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; C101290:N-(benzyloxycarbonyl)-phenylalanyl-tyrosinal; D012333:RNA, Messenger; C068250:N-(3-propylcarbamoyloxirane-2-carbonyl)-isoleucyl-proline; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D002402:Cathepsin D