Amelioration of inflammatory arthritis by targeting the pre-ligand assembly domain of tumor necrosis factor receptors.
Tumor necrosis factor (TNF)-alpha has an important role in the pathogenesis of autoimmune and inflammatory diseases such as rheumatoid and septic arthritis. The biological effects of TNF-alpha are mediated by binding to TNF receptors TNFR1 (also known as P60) or TNFR2 (also known as P80). The pre-ligand assembly domain (PLAD) is a portion of the extracellular region of TNFRs that mediates receptor-chain association essential for signaling. We found that soluble versions of PLAD, especially those derived from P60, block the biochemical effects of TNF-alpha in vitro and potently inhibit arthritis in animal models. Thus, targeting the PLAD may have clinical value in the treatment of human arthritis and other disorders involving receptors of the TNFR superfamily.
Deng
Guo-Min
GM
Laboratory of Immunology, Building 10, Room 11N311, 10 Center Drive, MSC 1892, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland 20892, USA.
Zheng
Lixin
L
Chan
Francis Ka-Ming
FK
Lenardo
Michael
M
D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D001665:Binding Sites; D001667:Binding, Competitive; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003094:Collagen; D018899:CpG Islands / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000494:pharmacology; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017434:Protein Structure, Tertiary; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D008024:Ligands; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen; D004247:DNA