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Human umbilical vein endothelial cell (HU-VEC) senescence in vitro is characterized by the loss of proliferative potential and an increase in cell size. Because HUVEC senescence in one strain (HlOl) has been characterized by the increase in the steady-state mRNA level for the signal-peptideless cytokine, interleukin (IL) la, we have examined young and senescent populations of five additional HUVEC strains (13605, H103, H928, H929, and H930) to determine whether the elevated levels of IL-la mRNA could be observed in all HUVEC strains. Consistent with the data from strain H101, strains H3605 and 1930 also exhibited a low steady-state level of the IL-la mRNA in young populations compared to elevated levels of IL-la mRNA in the senescent populations. However, three strains (H103, H928, and H929) did not exhibit reduced levels of IL-la mRNA in the young populations, and interestingly, strain H928, at times, expressed relatively high IL-la mRNA levels in the young populations. In addition, expression of the steady-state level of plainogen activator inhibitor 1 and cyclooxygenase 2 was elevated in senescent populations of all HUVEC strains examined, whereas young populations exhibited a low level of expression for these genes regardless of the IL-la mRNA level. Further, the level of the IL-la polypeptide was elevated in senescent HUVEC populations relative to young populations that expressed either a high or low level of the IL-la mRNA. We have also demonstrated that the elevated level of IL-la mRNA in the senescent population of strain H3605 may be regulated by mRNA stability; however, this mechanism does not apply to all the HUVEC strains examined in this study. Thus, we suggest that while mRNA levels of the IL-1-response genes for plasminogen activator inhibitor 1 and cyclooxygenase 2 are appropriate markers for HUVEC senescence, HUVEC strain-specific post-transcriptional mechanisms may exist to regulate the function of IL-la as a modifier of HUVEC senescence in vitro.

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In vitro cellular senescence of human umbilical vein endothelial cells (HUVEC) may involve the intracellular activity of the signal peptide-less cytokine interleukin (IL)-1 alpha. To determine whether senescence of other human diploid cells involves the function of IL-1 alpha, we examined the steady-state expression of IL-1 alpha mRNA in IMR-90 fibroblasts. The IL-1 alpha transcript was not elevated in senescent IMR-90 cells. With the exception of the plasminogen activator inhibitor (PAI)-1 transcript, other IL-1 alpha-response gene mRNAs were not induced in senescent IMR-90, although the mRNA for each gene was induced by exogenous IL-1 alpha. The mRNA expression of cell cycle-specific genes demonstrated that Fos and ornithine decarboxylase (ODC) were induced in young and senescent cells in response to both serum and fibroblast growth factor (FGF)-1. Histone (H)3 mRNA was induced by serum in young cells, but not in senescent cells, and FGF-1 failed to induce H3 mRNA in either young or senescent cells. Further, while young IMR-90 populations were able to respond to serum as an initiator of DNA synthesis and cell growth, they did not exhibit a response to exogenous FGF-1. FGF receptor (R)-1 substrates were not tyrosine phosphorylated in either young or senescent IMR-90 cells. These data demonstrate that IL-1 alpha and FGF-1 may have different functions in HUVEC and IMR-90 fibroblast populations including distinct pathways for the regulation of cellular growth and senescence.