Mycophenolate mofetil promotes down-regulation of expanded B cells and production of TNF-alpha in an experimental murine model of colitis.
In this study, we used a murine intestinal inflammation model that mimics immunologic characteristics of human Crohn's disease (CD) to investigate the anti-inflammatory effects of mycophenolate mofetil (MMF) on intestinal injury and tissue inflammation. When these colitic mice were pretreated with MMF, we observed a significant decrease in mortality rates and body weight loss as well as an improvement in both wasting and histopathologic signs of colonic inflammation, relative to untreated colitic mice. To determine the mechanisms of action of MMF, we compared various immunological characteristics of the untreated and MMF-pretreated colitic mice. MMF-pretreated colitic mice showed an 18% decrease in the proportion of CD19+ B cells compared with untreated colitic mice 3 days. As a result, MMF pretreatment increases proportion of apoptotic T and B cells, especially CD19+ B cells. Also, down-regulation of Th1 cytokines (TNF-alpha, IFN-gamma) and augmentation of CD4+CD45RB(low) regulatory T (Treg) cells were observed in MMF-pretreated colitic mice compared with untreated colitic mice. Furthermore, mycophenolic acid (MPA) reduced TNF-alpha-stimulated NF-kappaB activation in HT-29 colon epithelial cells. Also, MMF-pretreated colitic mice significantly reduced expression of MD-1 compared with untreated colitic mice on B cells and dendritic cells (DCs). These studies show that MMF pretreatment can improve experimental colitis by down-regulation of expanded B cells population through apoptosis and augmentation of Treg cells. Through these mechanisms, MMF might also be an effective agent for the treatment of other 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, Republic of Korea.
Kim
Myung-Sunny
MS
Kim
Eun-Young
EY
Park
Hae-Jung
HJ
Chang
Chi-Young
CY
Park
Ki-Soo
KS
Jung
Da-Yeon
DY
Kwon
Choon-Hyuck
CH
Joh
Jae-Won
JW
Kim
Sung-Joo
SJ
D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D000954:Antigens, Surface / Q000096:biosynthesis; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D016328:NF-kappa B / Q000187:drug effects / Q000502:physiology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D018941:Antigens, CD19; D000954:Antigens, Surface; C113553:Ly86 protein, mouse; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D014302:Trinitrobenzenesulfonic Acid; D009173:Mycophenolic Acid