A murine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling.
The arthritogenic activities of tumor necrosis factor (TNF) and its p55TNF-receptor (R) have been well documented in experimental animal models of arthritis, and in transgenic mice expressing wild-type or mutant transmembrane human TNF proteins in their joints. In this study we show that chronic inflammatory arthritis also develops in transgenic mice made to overexpress a mutant transmembrane from of the murine TNF protein (muTNF delta 1-12) which is known to utilize efficiently both the p55 and the p75TNFR. Cross-breeding of the transgene into a TNF knockout background did not alter development of disease. Analysis of TNF bioactivity in sera from lipopolysaccharide-stimulated mice or ex vivo macrophage cultures demonstrated that the muTNF delta 1-12 protein accumulates on the cell surface and is not processed to bioactive soluble TNF, indicating that transmembrane TNF is by itself sufficient to mediate pathogenesis of arthritis. Furthermore, using TNFR knockout mice, it is shown that development of transmembrane TNF-mediated arthritis requires the presence of the p55TNFR but is significantly delayed in the absence of the p75TNFR, suggesting a positive cooperation between the two TNFR in the arthritogenic process. These results indicate that blocking the activities of both soluble and transmembrane TNF may be required to effectively neutralize the pathogenic potential of this cytokine in arthritis.
Alexopoulou
L
L
Department of Molecular Genetics, Hellenic Pasteur Institute, Athens, Greece.
Pasparakis
M
M
Kollias
G
G
D000818:Animals; D000843:Ankle Joint / Q000473:pathology; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D001168:Arthritis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D016466:CHO Cells; D006224:Cricetinae; D006965:Hyperplasia; D017737:Macrophages, Peritoneal / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology*; D011499:Protein Processing, Post-Translational; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017384:Sequence Deletion; D015398:Signal Transduction / Q000502:physiology; D013583:Synovial Membrane / Q000473:pathology; D019076:Transgenes; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D015703:Antigens, CD; D010446:Peptide Fragments; 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; C109186:tumor necrosis factor (1-12)