Differential responses of fibroblasts from wild-type and TNF-R55-deficient mice to mouse and human TNF-alpha activation.
The role of the two TNF receptor types, TNF-R55 and TNF-R75, was studied on mouse fibroblasts, taking advantage of TNF-R55-deficient mice generated by gene targeting (Tnfr1 degree-mice), and selectivity of human TNF-alpha for mouse TNF-R55. Radioligand binding assays showed that both TNF receptors were expressed on wild-type mouse fibroblasts, whereas normal levels of TNF-R75 were expressed on mouse fibroblasts isolated from Tnfr1 degree-mice. It was found that TNF-R55 controlled four major TNF-induced fibroblast functions: (1) adhesion to leukocyte cell lines as well as ICAM-1, VCAM-1, CD44, and MHC class I up-regulation; (2) secretion of other cytokines as demonstrated by stimulated IL-6 and granulocyte-macrophage-CSF releases; (3) cell proliferation; and (4) NF-kappa B activation. Stimulation through TNF-R75, in TNF-R55-deficient fibroblasts, did not have any effect in these functions. In general, mouse TNF-alpha (recognizing both mouse TNF receptors) had a higher sp. act. than human TNF-alpha (recognizing only mouse TNF-R55) in wild-type fibroblasts, whereas both mouse and human TNF-alpha had similar cytotoxic activities in WEHI 164 cells.
Mackay
F
F
Central Nervous System Department, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Rothe
J
J
Bluethmann
H
H
Loetscher
H
H
Lesslauer
W
W
D000818:Animals; D015703:Antigens, CD; D001483:Base Sequence; D002352:Carrier Proteins / Q000096:biosynthesis; D002448:Cell Adhesion / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002455:Cell Division / Q000276:immunology; D002460:Cell Line; D005260:Female; D005347:Fibroblasts / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D018960:Hyaluronan Receptors; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D016201:Receptors, Lymphocyte Homing / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D015854:Up-Regulation
D015703:Antigens, CD; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D015395:Histocompatibility Antigens Class I; D018960:Hyaluronan Receptors; D015850:Interleukin-6; D011956:Receptors, Cell Surface; D016201:Receptors, Lymphocyte Homing; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor