Recombinant human MFG-E8 ameliorates colon damage in DSS- and TNBS-induced colitis in mice.
Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the digestive system and typically requires lifelong medical care. Recombinant human MFG-E8 (rhMFG-E8) is a 364-amino acid protein, which promotes apoptotic cell clearance and reduces inflammation. This study investigates the therapeutic effect of rhMFG-E8 on two well-established mouse models of IBD. Acute mucosal injury leading to colitis was caused by exposing C57BL/6 mice to 4% dextran sodium sulfate (DSS) in the drinking water over 7 days, and BALB/c mice to a single intrarectal dose of 2.75 mg of 2,4,6-trinitrobenzene sulfonic acid (TNBS). Upon clinical onset of colitis (day 2 in the DSS model and day 1 in the TNBS model), mice were treated with daily subcutaneous injections of rhMFG-E8 (60 or 120 μg/kg/day) or vehicle (saline) for 6 days. Treatment with rhMFG-E8 significantly attenuated colitis in both models in a dose-dependent way. Treatment of DSS-induced colitis with rhMFG-E8 (120 μg/kg/day) decreased weight loss by 59%, the colitis severity score by 71%, and colon shrinkage by 49% when compared with vehicle. Similarly, treatment of TNBS-induced colitis with rhMFG-E8 (120 μg/kg/day) decreased weight loss by 97%, the colitis severity score by 82%, and colon shrinkage by 62% when compared with vehicle. In both models, the colons of animals receiving rhMFG-E8 showed marked reduction in neutrophil infiltration, cytokine and chemokine expression, and apoptotic cell counts. In conclusion, rhMFG-E8 ameliorates DSS- and TNBS-induced colitis, suggesting that it has the potential to become a novel therapeutic agent for IBD.
Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
Yinzhong
Y
Zhang
1] Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA [2] TheraSource LLC, Manhasset, NY, USA.
Max
M
Brenner
1] Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA [2] TheraSource LLC, Manhasset, NY, USA.
Weng-Lang
WL
Yang
Center for Translational Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
Ping
P
Wang
D000818:Animals; D000954:Antigens, Surface / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D006801:Humans; D015212:Inflammatory Bowel Diseases; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008894:Milk Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
D000954:Antigens, Surface; D016207:Cytokines; C098942:MFGE8 protein, human; D008894:Milk Proteins; D020011:Protective Agents; D011994:Recombinant Proteins; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate