title: Mycophenolate mofetil promotes down-regulation of expanded B cells and production of TNF-alpha in an experimental murine model of colitis.
abstract: 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.
authors.affiliation: Transplantation Research Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Republic of Korea.
authors.forename: Jienny
authors.initials: J
authors.lastname: Lee
authors.forename: Myung-Sunny
authors.initials: MS
authors.lastname: Kim
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kim
authors.forename: Hae-Jung
authors.initials: HJ
authors.lastname: Park
authors.forename: Chi-Young
authors.initials: CY
authors.lastname: Chang
authors.forename: Ki-Soo
authors.initials: KS
authors.lastname: Park
authors.forename: Da-Yeon
authors.initials: DY
authors.lastname: Jung
authors.forename: Choon-Hyuck
authors.initials: CH
authors.lastname: Kwon
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Joh
authors.forename: Sung-Joo
authors.initials: SJ
authors.lastname: Kim
mesh_terms: 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*
chemical_list: 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