Overexpression of translocator protein in inflammatory bowel disease: potential diagnostic and treatment value.
BACKGROUND
Inflammatory bowel diseases (IBDs), such as ulcerative colitis and Crohn's disease, are chronic inflammatory disorders that increase the risk for colorectal cancer. The mitochondrial translocator protein (TSPO) is a high-affinity drug- and cholesterol-binding protein expressed in the colon and its expression is increased in colon cancers. The aim of this study was to investigate TSPO expression in IBD biopsies and to establish an animal model of IBD to examine the role of TSPO. In addition, we evaluated the potential use of TSPO drug ligands in diagnosing and treating IBD.


METHODS
TSPO expression in IBD biopsies was evaluated using immunohistochemistry. IBD was induced in a rat experimental model via treatment with dextran sodium sulfate (DSS). Colon morphology, TSPO expression, and proinflammatory cytokine production were evaluated in addition to the effect of TSPO drug ligands on disease pathology.


RESULTS
TSPO protein levels were elevated in the enterocytes of IBD biopsies. TSPO expression was localized to the enterocyte mitochondria. DSS treatment induced a time-dependent phenotype mimicking IBD with tissue injury and subsequent tissue regeneration. Coadministration of DSS and the TSPO drug ligands PK 11195 or Ro5-4864 increased both the rate of colon ulceration and regeneration, whereas administration of the TSPO drug ligand flunitrazepam partially prevented this pathology. These data correlated with changes in proinflammatory cytokine plasma levels, as well as increased cytokine production and secretion from the colon.


CONCLUSIONS
TSPO may serve as a marker of the IBD repair process, and TSPO drug ligands should be further evaluated for IBD treatment.
Ostuni
Mariano A
MA
Unité INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Université Paris 7 Denis Diderot, Paris, France. mariano.ostuni@inserm.fr
Issop
Leeyah
L
Péranzi
Gabriel
G
Walker
Francine
F
Fasseu
Magali
M
Elbim
Carole
C
Papadopoulos
Vassilios
V
Lacapere
Jean-Jacques
JJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001570:Benzodiazepinones / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D020895:Enterocytes / Q000378:metabolism*; D005445:Flunitrazepam / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D015212:Inflammatory Bowel Diseases / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D001570:Benzodiazepinones; D002352:Carrier Proteins; D016207:Cytokines; D018757:GABA Modulators; D000960:Hypolipidemic Agents; D007546:Isoquinolines; D012333:RNA, Messenger; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C499229:TSPO protein, human; C069997:Tspo protein, rat; C028513:4'-chlorodiazepam; D005445:Flunitrazepam; D016264:Dextran Sulfate; C037850:PK 11195