EXPRESSION OF INTERLEUKIN-1-INDUCIBLE GENES AND PRODUCTION OF INTERLEUKIN-1 BY AGING HUMAN FIBROBLASTS

The interleukin 1 (IL-1)-inducible mRNAs for plasminogen activator inhibitor type 2, manganese superoxide dismutase, and urokinase are overexpressed in old (> 70% of life-span completed) but not in young (< 40% of life-span completed) human foreskin fibroblasts. Furthermore, the activity of this superoxide dismutase is greater in old than in young fibroblasts. IL-1-beta-mRNA is detected by Northern blot analysis in old fibroblasts and its expression is further enhanced by a treatment with IL-1-alpha. IL-1-alpha and IL-1-beta-mRNAs are detected in old foreskin and lung fibroblasts by a sensitive reverse transcription-PCR assay. IL-1 mRNA is consistently expressed after fibroblasts have completed 85% of their in vitro life-span; an assay with specific antibodies shows that IL-1-alpha is present in these fibroblasts. Prolonged treatment with IL-1 receptor antagonist decreases the levels of IL-1-alpha and of IL-1-alpha and IL-1-beta-mRNAs. This observation suggests that IL-1 receptor antagonist inhibits an autocrine loop responsible for IL-1 expression. IL-1 mRNA accumulates in young fibroblasts treated with cycloheximide, suggesting that it is transcribed but unstable in these cells; accumulation of IL-1 mRNA in old fibroblasts may be due at least in part to increased stability. IL-1-alpha stimulates DNA synthesis in young fibroblasts but has progressively less effect as the cells age in culture. These data indicate that IL-1 is "constitutively" produced by aging fibroblasts and that IL-1 induces the expression of specific proteins in these cells. The mechanism for this constitutive production of IL-1 is explored in this paper.