title: Abrogation of skin disease in LUPUS-prone MRL/FASlpr mice by means of a novel tylophorine analog.
abstract: OBJECTIVE
  To test the therapeutic effect of DCB-3503, a synthetic compound derived from a natural product that inhibits NF-kappaB, on end-organ disease in the MRL-Fas(lpr) murine model of systemic lupus erythematosus (SLE).
  
  
  METHODS
  Eight-week-old female MRL/Fas(lpr) mice were treated intraperitoneally with a low (2 mg/kg) or high (6 mg/kg) dose of DCB-3503 for 10 weeks. Control groups were administered vehicle treatment alone (negative control) or 25 mg/kg cyclophosphamide (positive control). Mice were bled before (8 weeks) and during (13 weeks) treatment, and when they were killed (20 weeks), and serum samples were analyzed for total IgM and IgG levels and autoantibody titers. When the mice were killed, spleen and lymph nodes (axillary, brachial, and cervical) were examined by flow cytometric analysis. The presence of skin and renal disease was determined by histopathologic analysis.
  
  
  RESULTS
  DCB-3503 reduced anti-double-stranded DNA and antichromatin autoantibodies and nearly abrogated inflammatory skin disease in MRL/Fas(lpr) mice; however, it had little effect on histologic kidney disease. Treated mice did not have hematologic or hepatic toxicity. These data indicate that end-organ disease in MRL/Fas(lpr) mice responds differentially to NF-kappaB inhibitor.
  
  
  CONCLUSIONS
  DCB-3503 causes significant abrogation of skin disease in MRL/Fas(lpr) mice and may potentially be beneficial in the treatment of inflammatory skin disease in SLE.
authors.affiliation: Yale School of Medicine, Yale University, New Haven, Connecticut, USA.
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Choi
authors.forename: Wenli
authors.initials: W
authors.lastname: Gao
authors.forename: Jared
authors.initials: J
authors.lastname: Odegard
authors.forename: Her-Shyong
authors.initials: HS
authors.lastname: Shiah
authors.forename: Michael
authors.initials: M
authors.lastname: Kashgarian
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: McNiff
authors.forename: David C
authors.initials: DC
authors.lastname: Baker
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
authors.forename: Joseph
authors.initials: J
authors.lastname: Craft
mesh_terms: D000470:Alkaloids / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D001323:Autoantibodies / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007212:Indolizines / Q000009:adverse effects / Q000494:pharmacology*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D008181:Lupus Nephritis / Q000188:drug therapy / Q000473:pathology; D008206:Lymphatic Diseases / Q000188:drug therapy / Q000517:prevention & control; D051379:Mice; D019463:Mice, Inbred MRL lpr; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010616:Phenanthrenes / Q000009:adverse effects / Q000494:pharmacology*; D012871:Skin Diseases / Q000188:drug therapy* / Q000209:etiology / Q000517:prevention & control; D013163:Splenomegaly / Q000188:drug therapy / Q000517:prevention & control
chemical_list: D000470:Alkaloids; D001323:Autoantibodies; C509364:DCB 3503; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007212:Indolizines; D016328:NF-kappa B; D010616:Phenanthrenes; D004247:DNA; C004218:tylophorine