title: Thrombospondin-1 type 1 repeats in a model of inflammatory bowel disease: transcript profile and therapeutic effects.
abstract: Thrombospondin-1 (TSP-1) is a matricellular protein with regulatory functions in inflammation and cancer. The type 1 repeats (TSR) domains of TSP-1 have been shown to interact with a wide range of proteins that result in the anti-angiogenic and anti-tumor properties of TSP-1. To ascertain possible functions and evaluate potential therapeutic effects of TSRs in inflammatory bowel disease, we conducted clinical, histological and microarray analyses on a mouse model of induced colitis. We used dextran sulfate sodium (DSS) to induce colitis in wild-type (WT) mice for 7 days. Simultaneously, mice were injected with either saline or one form of TSP-1 derived recombinant proteins, containing either (1) the three type 1 repeats of the TSP-1 (3TSR), (2) the second type 1 repeat (TSR2), or (3) TSR2 with the RFK sequence (TSR2+RFK). Total RNA isolated from the mice colons were processed and hybridized to mouse arrays. Array data were validated by real-time qPCR and immunohistochemistry. Histological and disease indices reveal that the mice treated with the TSRs show different patterns of leukocytic infiltration and that 3TSR treatment was the most effective in decreasing inflammation in DSS-induced colitis. Transcriptional profiling revealed differentially expressed (DE) genes, with the 3TSR-treated mice showing the least deviation from the WT-water controls. In conclusion, this study shows that 3TSR treatment is effective in attenuating the inflammatory response to DSS injury. In addition, the transcriptomics work unveils novel genetic data that suggest beneficial application of the TSR domains in inflammatory bowel disease.
authors.affiliation: Department of Biology, Wilkes University, Wilkes-Barre, Pennsylvania, United States of America.
authors.forename: Zenaida P
authors.initials: ZP
authors.lastname: Lopez-Dee
authors.forename: Sridar V
authors.initials: SV
authors.lastname: Chittur
authors.forename: Bhumi
authors.initials: B
authors.lastname: Patel
authors.forename: Rebecca
authors.initials: R
authors.lastname: Stanton
authors.forename: Michelle
authors.initials: M
authors.lastname: Wakeley
authors.forename: Brittany
authors.initials: B
authors.lastname: Lippert
authors.forename: Anastasya
authors.initials: A
authors.lastname: Menaker
authors.forename: Bethany
authors.initials: B
authors.lastname: Eiche
authors.forename: Robert
authors.initials: R
authors.lastname: Terry
authors.forename: Linda S
authors.initials: LS
authors.lastname: Gutierrez
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000276:immunology; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009369:Neoplasms / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D020449:Repetitive Sequences, Amino Acid; D013234:Stem Cells / Q000378:metabolism; D019700:Thrombospondin 1 / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D059467:Transcriptome / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D011994:Recombinant Proteins; D019700:Thrombospondin 1; D016264:Dextran Sulfate