title: Three TNFR-binding domains of PGRN act independently in inhibition of TNF-alpha binding and activity.
abstract: PGRN was previously reported to bind to TNF receptors (TNFR) and is therapeutic against inflammatory arthritis. Here we present further evidences demonstrating the PGRN inhibition of TNF-alpha binding and activity, and clarifying the distinct mechanisms underlying TNF-alpha inhibition between PGRN and classic TNF-alpha-binding inhibitors. In addition, we present evidences indicating that three TNFR binding domains of PGRN act independently in binding to TNFR. Furthermore, changing the order of three TNFR-binding domains in Atsttrin, a PGRN-derived molecule composed of these TNFR-binding domains, does not affect its anti-inflammatory and anti-TNF activities in both collagen-induced inflammatory arthritis and human TNF-alpha transgenic mouse model. Taken together, these findings provide the additional molecular basis underlying PGRN/TNFR interaction and PGRN-mediated anti-inflammatory activity in various inflammatory diseases and conditions.
authors.affiliation: Department of Orthopaedic Surgery, New York University School of Medicine, 301 East 17th Street, New York, NY 10003.
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Department of Orthopaedic Surgery, New York University School of Medicine, 301 East 17th Street, New York, NY 10003.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Orthopaedic Surgery, New York University School of Medicine, 301 East 17th Street, New York, NY 10003.
authors.forename: Jyoti Joshi
authors.initials: JJ
authors.lastname: Mundra
authors.affiliation: Department of Orthopaedic Surgery, New York University School of Medicine, 301 East 17th Street, New York, NY 10003.
authors.forename: Elena
authors.initials: E
authors.lastname: Gonzalez-Gugel
authors.affiliation: Department of Orthopaedic Surgery, New York University School of Medicine, 301 East 17th Street, New York, NY 10003.
authors.forename: Jinlong
authors.initials: J
authors.lastname: Jian
authors.affiliation: Department of Orthopaedic Surgery, New York University School of Medicine, 301 East 17th Street, New York, NY 10003.
authors.forename: Sardar M Z
authors.initials: SM
authors.lastname: Uddin
authors.affiliation: Department of Orthopaedic Surgery, New York University School of Medicine, 301 East 17th Street, New York, NY 10003.
authors.forename: Chuanju
authors.initials: C
authors.lastname: Liu
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000517:prevention & control; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D000077153:Progranulins; D011485:Protein Binding / Q000187:drug effects; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D020798:Two-Hybrid System Techniques; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D000077153:Progranulins; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1