title: The JNK inhibitor XG-102 protects against TNBS-induced colitis.
abstract: The c-Jun N-terminal kinase (JNK)-inhibiting peptide D-JNKI-1, syn. XG-102 was tested for its therapeutic potential in acute inflammatory bowel disease (IBD) in mice. Rectal instillation of the chemical irritant trinitrobenzene sulfonic acid (TNBS) provoked a dramatic acute inflammation in the colon of 7-9 weeks old mice. Coincident subcutaneous application of 100 µg/kg XG-102 significantly reduced the loss of body weight, rectal bleeding and diarrhoea. After 72 h, the end of the study, the colon was removed and immuno-histochemically analysed. XG-102 significantly reduced (i) pathological changes such as ulceration or crypt deformation, (ii) immune cell pathology such as infiltration and presence of CD3- and CD68-positive cells, (iii) the production of tumor necrosis factor (TNF)-α in colon tissue cultures from TNBS-treated mice, (iv) expression of Bim, Bax, FasL, p53, and activation of caspase 3, (v) complexation of JNK2 and Bim, and (vi) expression and activation of the JNK substrate and transcription factor c-Jun. A single application of subcutaneous XG-102 was at least as effective or even better depending on the outcome parameter as the daily oral application of sulfasalazine used for treatment of IBD.The successful and substantial reduction of the severe, TNBS-evoked intestinal damages and clinical symptoms render the JNK-inhibiting peptide XG-102 a powerful therapeutic principle of IBD.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Kirstin
authors.initials: K
authors.lastname: Reinecke
authors.forename: Sevgi
authors.initials: S
authors.lastname: Eminel
authors.forename: Franziska
authors.initials: F
authors.lastname: Dierck
authors.forename: Wibke
authors.initials: W
authors.lastname: Roessner
authors.forename: Sabine
authors.initials: S
authors.lastname: Kersting
authors.forename: Ansgar Michael
authors.initials: AM
authors.lastname: Chromik
authors.forename: Olga
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Ale
authors.initials: A
authors.lastname: Laukevicience
authors.forename: Ivo
authors.initials: I
authors.lastname: Leuschner
authors.forename: Vicki
authors.initials: V
authors.lastname: Waetzig
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Thomas
authors.initials: T
authors.lastname: Herdegen
authors.forename: Christian
authors.initials: C
authors.lastname: Sina
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western; D017252:CD3 Complex / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D053222:Fas Ligand Protein / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D017252:CD3 Complex; D053148:Caspase 3; D053222:Fas Ligand Protein; D048031:JNK Mitogen-Activated Protein Kinases; D008565:Membrane Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C000606775:BCL2L11 protein, human; C494827:Bax protein, mouse; C000606776:Bcl2l11 protein, mouse; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C505658:Fasl protein, mouse; C478085:D-JNKI-1