TNF and its receptor antibody agonist differ in mediation of cellular responses.
TNF binds to two distinct receptors designated p60 and p80. Because Abs to the p60 receptor (anti-p60) can mimic TNF, we therefore compared the cellular signaling of TNF with that of anti-p60. We demonstrate both qualitative and quantitative differences between TNF and anti-p60. HepG2 cells, which express the p60 receptor, were found to be completely resistant to TNF but highly sensitive to the antiproliferative effects of anti-p60. In contrast, normal fibroblasts were found to be several fold more sensitive to TNF than to anti-p60. Several other epithelial cell lines that also express primarily the p60 receptor showed quantitative differences in mediation of cellular responses by TNF and anti-p60. The blocking of the p60 receptor by TNF had no effect on the response of HepG2 cells to anti-p60, suggesting a difference in their binding sites. Anti-p60, however, inhibited the effect of TNF on fibroblasts. Ab against the p80 receptor had no effect by itself or on the effect of TNF and anti-p60. The difference in the response to TNF and anti-p60 could not be correlated to the differences in the level of expression of p60 receptor on these cells. Furthermore, cycloheximide potentiated the TNF-mediated effect but not that mediated through anti-p60, thus also indicating a difference in the mechanism of action of these two agents. Overall, these results demonstrate that TNF and anti-p60, although both working through the p60 receptor, differ in their cellular signaling.
Totpal
K
K
Department of Clinical Immunology and Biological Therapy, University of Texas M. D. Anderson Cancer Center, Houston 77030.
LaPushin
R
R
Kohno
T
T
Darnay
B G
BG
Aggarwal
B B
BB
D000906:Antibodies / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D008970:Molecular Weight; D012333:RNA, Messenger / Q000235:genetics; D017452:Receptors, IgG / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000906:Antibodies; D012333:RNA, Messenger; D017452:Receptors, IgG; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide