Abrogation of skin disease in LUPUS-prone MRL/FASlpr mice by means of a novel tylophorine analog.
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.
Choi
Jin-Young
JY
Yale School of Medicine, Yale University, New Haven, Connecticut, USA.
Gao
Wenli
W
Odegard
Jared
J
Shiah
Her-Shyong
HS
Kashgarian
Michael
M
McNiff
Jennifer M
JM
Baker
David C
DC
Cheng
Yung-Chi
YC
Craft
Joseph
J
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
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