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 studi ed on mouse fibroblasts, taking advantage of TNF-R55-deficient mice ge nerated by gene targeting (Tnfr1 degrees-mice), and selectivity of hum an TNF-alpha for mouse TNF-R55. Radioligand binding assays showed that both TNF receptors were expressed on wild-type mouse fibroblasts, whe reas normal levels of TNF-R75 were expressed on mouse fibroblasts isol ated from Tnfr1 degrees-mice. It was found that TNF-R55 controlled fou r major TNF-induced fibroblast functions: (1) adhesion to leukocyte ce ll lines as well as ICAM-1, VCAM-1, CD44, and MHC class I up-regulatio n; (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-def icient fibroblasts, did not have any effect in these functions. In gen eral, mouse TNF-alpha (recognizing both mouse TNF receptors) had a hig her sp. act. than human TNF-alpha (recognizing only mouse TNF-R55) in wild-type fibroblasts, whereas both mouse and human TNF-alpha had simi lar cytotoxic activities in WEHI 164 cells.