Fitzpatrick, Leo R. and Deml, Ludwig and Hofmann, Claudia and Small, Jeffrey S. and Groeppel, Manfred and Hamm, Svetlana and Lemstra, Sylvia and Leban, Johann and Ammendola, Aldo (2010) 4SC-101, a Novel Immunosuppressive Drug, Inhibits IL-17 and Attenuates Colitis in Two Murine Models of Inflammatory Bowel Disease. INFLAMMATORY BOWEL DISEASES, 16 (10). pp. 1763-1777. ISSN 1078-0998, 1536-4844
Full text not available from this repository. (Request a copy)Abstract
Background: Dihydroorotate dehydrogenase (DHODH) is a key enzyme involved in pyrimidine biosynthesis. DHODH is a known target for the treatment of autoimmune diseases. 4SC-101 is a novel immunosuppressive drug that inhibits DHODH. A goal of our study was to examine the in vitro effects of 4SC-101 on IL-17 production by mononuclear cells. In addition, we evaluated the efficacy of 4SC-101 against acute TNBS (2,4,6-tritrobenzene sulfonic acid) and chronic dextran sodium sulfate (DSS)-induced colitis in mice. Methods: Peripheral blood mononuclear cells (PBMCs) from healthy human donors were used to evaluate cellular proliferation and cytokine (IL-17, TNF-alpha) production. The oral effects of 4SC-101 (100 or 200 mg/kg) were examined following induction of chronic colitis by the administration of 3% DSS (4 cycles) to Balb/c mice. Morphometric and histological indices of colitis were evaluated as indicators of drug efficacy. 4SC-101 was also administered for 6 days after the intracolonic administration of TNBS (20 mg in 50% ethanol) to female Balb/c mice. The colons were analyzed for overall macroscopic damage, ulceration, total length, distal segment weight, MPO activity, and histological pathology as indicators for the effectiveness of 4SC-101. Results: In vitro, 4SC-101 is a potent inhibitor of human DHODH, inhibits lymphocyte proliferation, and uniquely blocks phytohemagglutinin-stimulated IL-17 production by lymphocytes. In vivo, oral administration of 4SC-101 effectively improved both chronic DSS and acute TNBS colitis in mice. In these colitis models the overall efficacy profile of 4SC-101 was similar to that of dexamethasone. Conclusions: 4SC-101 is a novel immunosuppressive drug with excellent potential for the treatment of intestinal inflammation. (Inflamm Bowel Dis 2010; 16: 1763-1777)
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TNBS-INDUCED COLITIS; TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; CROHNS-DISEASE; IN-VITRO; LEFLUNOMIDE; MICE; INTERLEUKIN-17; HETERODIMER; EXPRESSION; 4SC-101; colitis; IL-17; mice |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin I |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 13 Jul 2020 05:49 |
| Last Modified: | 13 Jul 2020 05:49 |
| URI: | https://pred.uni-regensburg.de/id/eprint/24078 |
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