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 (greater than 70% of life-span completed) but not in young (less than 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.
Kumar
S
S
Department of Biological Sciences, State University of New York, Albany 12222.
Millis
A J
AJ
Baglioni
C
C
D001483:Base Sequence; D015152:Blotting, Northern; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics* / Q000494:pharmacology*; D008168:Lung; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D015849:Plasminogen Inactivators / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012867:Skin; D013482:Superoxide Dismutase / Q000235:genetics*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
D007375:Interleukin-1; D009838:Oligodeoxyribonucleotides; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013482:Superoxide Dismutase; D014568:Urokinase-Type Plasminogen Activator