DIMINISHED RESPONSIVENESS OF SENESCENT NORMAL HUMAN FIBROBLASTS TO TNF-DEPENDENT PROLIFERATION AND INTERLEUKIN PRODUCTION IS NOT DUE TO ITSEFFECT ON THE RECEPTORS OR ON THE ACTIVATION OF A NUCLEAR FACTOR NF-KAPPA-B

The limited life span in culture of normal human diploid fibroblasts ( HDF) has provided a model of cellular senescence, The short-term growt h of these cells in culture is regulated by a number of different cyto kines, including tumor necrosis factor (TNF), interleukin-l (IL-1), an d fibroblast growth factor (FGF), However, the effect of senescence on the responsiveness of HDF to these cytokines is not known, In the pre sent report, we examined the effects of TNF on foreskin-derived HDF at different passage levels. We compared the response of HDF cells at po pulation doubling (PD) 23 (young) with that of cells at PD 70 (senesce nt), Young cells proliferated in response to TNF in a dose-dependent m anner, Under these conditions TNF had no effect on senescent HDF, The decrease in TNF responsiveness was found to be dependent on PD. The la ck of response of senescent HDF was not unique to TNF, since FGF and I L-1 were also ineffective, In contrast to senescent HDF, TNF-dependent proliferation of young HDF could be further potentiated by IL-1 and F GF, suggesting an independent signaling mechanism, On exposure to TNF, senescent HDF produced 1L-6 and 1L-8, but to a much lower degree than that produced by young HDF. The diminished responsiveness of senescen t HDF to TNF does not appear to be due to the difference in either rec eptor number or affinity, since senescent cells had two- to threefold higher number of TNF receptors than young HDF but the same affinity, T NF induced the activation of a nuclear transcriptional factor, NF-KB, equally in both young and senescent cells, which indicates the lack of a defect in the early events of TNF signal transduction in senescent fibroblasts, Overall, our results indicate that there is an age-depend ent decline in TNF-induced proliferation and in the production of inte rleukins by fibroblasts; this unresponsiveness appears not to be due t o TNF receptors or NF-KB activation, These results may have importance in understanding the diminished immune response, inflammation, and wo und healing associated with aging. (C) 1995 Academic Press, Inc.