title: Angiopoietin-like 4 Mediates Colonic Inflammation by Regulating Chemokine Transcript Stability via Tristetraprolin.
abstract: Many gastrointestinal diseases exhibit a protracted and aggravated inflammatory response that can lead to hypercytokinaemia, culminating in extensive tissue damage. Recently, angiopoietin-like 4 (ANGPTL4) has been implicated in many inflammation-associated diseases. However, how ANGPTL4 regulates colonic inflammation remains unclear. Herein, we show that ANGPTL4 deficiency in mice (ANGPTL4-/-) exacerbated colonic inflammation induced by dextran sulfate sodium (DSS) or stearic acid. Microbiota was similar between the two genotypes prior DSS challenge. A microarray gene expression profile of the colon from DSS-treated ANGPTL4-/-mice was enriched for genes involved in leukocyte migration and infiltration, and showed a close association to inflamed ulcerative colitis (UC), whereas the profile from ANGPTL4+/+littermates resembled that of non-inflamed UC biopsies. Bone marrow transplantation demonstrates the intrinsic role of colonic ANGPTL4 in regulating leukocyte infiltration during DSS-induced inflammation. Using immortalized human colon epithelial cells, we revealed that the ANGPTL4-mediated upregulation of tristetraprolin expression operates through CREB and NF-κB transcription factors, which in turn, regulates the stability of chemokines. Together, our findings suggest that ANGPTL4 protects against acute colonic inflammation and that its absence exacerbates the severity of inflammation. Our findings emphasize the importance of ANGPTL4 as a novel target for therapy in regulating and attenuating inflammation.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.|Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16, Stockholm 17177, Sweden.
authors.forename: Terri
authors.initials: T
authors.lastname: Phua
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.|Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Drive, Singapore 639798, Singapore.
authors.forename: Ming Keat
authors.initials: MK
authors.lastname: Sng
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Eddie Han Pin
authors.initials: EH
authors.lastname: Tan
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Dickson Shao Liang
authors.initials: DS
authors.lastname: Chee
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Yinliang
authors.initials: Y
authors.lastname: Li
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Jonathan Wei Kiat
authors.initials: JW
authors.lastname: Wee
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Teo
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Jeremy Soon Kiat
authors.initials: JS
authors.lastname: Chan
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Maegan Miang Kee
authors.initials: MM
authors.lastname: Lim
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Drive, Singapore 639798, Singapore.
authors.forename: Chek Kun
authors.initials: CK
authors.lastname: Tan
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Nobels väg 16, Stockholm 17177, Sweden.
authors.forename: Velmurugesan
authors.initials: V
authors.lastname: Arulampalam
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore.|Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Drive, Singapore 639798, Singapore.|Institute of Molecular Cell Biology, 61 Biopolis Drive, Proteos, Agency for Science Technology &Research, Singapore 138673, Singapore.|KK Research Centre, KK Women's and Children Hospital, 100 Bukit Timah Road, Singapore 229899, Singapore.
authors.forename: Nguan Soon
authors.initials: NS
authors.lastname: Tan
mesh_terms: D000075803:Angiopoietin-Like Protein 4 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D018925:Chemokines / Q000235:genetics* / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000235:genetics / Q000378:metabolism; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020871:RNA Stability; D013229:Stearic Acids; D000074084:THP-1 Cells; D051816:Tristetraprolin / Q000235:genetics* / Q000378:metabolism
chemical_list: D000075803:Angiopoietin-Like Protein 4; D018925:Chemokines; D013229:Stearic Acids; D051816:Tristetraprolin; C031183:stearic acid; D016264:Dextran Sulfate