15-deoxyspergualin prevents mucosal injury by inhibiting production of TNF-alpha and down-regulating expression of MD-1 in a murine model of TNBS-induced colitis.
The immunosuppressive drug 15-deoxyspergualin (DSG) is currently being used in clinical trials to prolong graft survival and reverse graft rejection. Here we evaluated whether DSG has a potential for ameliorating diseases characterized by mucosal inflammation. Using a murine model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis, we were able to demonstrate that DSG reduced the severity of colitis. Therefore, colitic mice pretreated with DSG showed a striking improvement of the wasting disease compared with colitic mice, as assessed by weight loss as well as clinical, macroscopic and microscopic analysis. Also, we observed the significant change occurred in the CD19(+) B cell subset, which was decreased 15% in DSG pretreated colitic mice compared with colitic mice. However, DSG pretreatment does not influence the apoptotic population of T and B cells. Compared with colitic mice, down-regulation of TNF-alpha production was observed in DSG pretreated colitic mice. In addition, DSG pretreated colitic mice significantly reduced expression of MD-1 compared with colitic mice on B cells and dendritic cells (DCs). Therefore, pretreatment with DSG resulted in a significant histologic improvement, protecting against mucosal ulcerations and reduced inflammatory response by modulating expression of MD-1, which plays a very important role in immune response on B cells and DCs. Also, this improvement was paralleled by a reduction in TNF-alpha levels. Collectively, current results demonstrate that DSG may be an effective agent for the treatment of diseases characterized by mucosal inflammation.
Lee
Jienny
J
Transplantation Research Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul, 135-710, South Korea.
Kim
Myung-Sunny
MS
Kim
Eun-Young
EY
Park
Hae-Jung
HJ
Chang
Chi-Young
CY
Jung
Da-Yeon
DY
Kwon
Choon-Hyuck
CH
Joh
Jae-Won
JW
Kim
Sung-Joo
SJ
D000285:Administration, Rectal; D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D051193:Toll-Like Receptors / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000008:administration & dosage / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D018941:Antigens, CD19; D000954:Antigens, Surface; D006146:Guanidines; D007166:Immunosuppressive Agents; C113553:Ly86 protein, mouse; D008562:Membrane Glycoproteins; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D014302:Trinitrobenzenesulfonic Acid; C037258:gusperimus