title: Reduction in arthritis severity and modulation of immune function in tissue factor cytoplasmic domain mutant mice.
abstract: Tissue factor (TF), a transmembrane receptor for plasma factor VII(a), is the main initiator of the coagulation cascade. It has also been implicated in noncoagulant processes, including inflammation. The function of the TF cytoplasmic domain was studied in mice in which 18 of the 20 cytoplasmic amino acids were deleted. This mutation (TF(deltaCT/deltaCT)) is not associated with alterations in blood coagulation. Arthritis was induced by intra-articular injection of methylated bovine serum albumin (mBSA) in mice preimmunized with mBSA. Arthritis severity was significantly reduced in TF(deltaCT/deltaCT) mice compared to wild-type mice, including reductions in synovitis, synovial exudate, cartilage degradation, and bone damage. A marked reduction in synovial interleukin (IL)-1beta and IL-6 mRNA was also observed. Serum anti-mBSA IgG1, but not IgG2a, was increased in mutant mice. Cutaneous delayed-type hypersensitivity and antigen-induced T-cell proliferation were reduced in TF(deltaCT/deltaCT) compared to wild-type mice. A significant down-regulation of lipopolysaccharide-induced IL-1, tumor necrosis factor, IL-6, macrophage migration inhibitory factor, and matrix metalloproteinase-13 mRNA was observed in immunized, but not in naive TF(deltaCT/deltaCT) macrophages ex vivo. These data suggest a significant role for the cytoplasmic domain of TF in the regulation of the immunoinflammatory responses, a murine arthritis model, and macrophage function.
authors.affiliation: Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
authors.forename: Yuan H
authors.initials: YH
authors.lastname: Yang
authors.forename: Pam
authors.initials: P
authors.lastname: Hall
authors.forename: Georgia
authors.initials: G
authors.lastname: Milenkovski
authors.forename: Laveena
authors.initials: L
authors.lastname: Sharma
authors.forename: Paul
authors.initials: P
authors.lastname: Hutchinson
authors.forename: Els
authors.initials: E
authors.lastname: Melis
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Peter
authors.initials: P
authors.lastname: Tipping
authors.forename: Eric
authors.initials: E
authors.lastname: Morand
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D003593:Cytoplasm / Q000737:chemistry; D005786:Gene Expression Regulation / Q000276:immunology; D007270:Injections, Intra-Articular; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000633:toxicity; D013925:Thromboplastin / Q000235:genetics*
chemical_list: C029180:methylated bovine serum albumin; D012710:Serum Albumin, Bovine; D013925:Thromboplastin