An interleukin 1 beta point mutant demonstrates that jun/fos expression is not sufficient for fibroblast metalloproteinase expression.
Substitution of glycine for arginine at position 127 of the mature human interleukin 1 beta protein generates a mutant IL-1 beta protein (IL-1 beta R----G) which binds cellular IL-1 receptors with high affinity but fails to elicit significant proliferation of T-helper cells (Gehrke, L., Jobling, S. A., Paik, L. S. K., McDonald, B., Rosenwasser, L. J., and Auron, P. E. (1990) J. Biol. Chem. 265, 5922-5925). Although both IL-1 beta and the IL-1 beta R----G mutein stimulate transcription of fibroblast immediate early (fos and jun) and early (IL-1 beta and IL-6) genes, the IL-1 beta R----G mutein, in contrast to the wild-type IL-1 beta protein, induces minimal or no transcription of late genes such as procollagenase and prostromelysin. The effect of the naturally occurring IL-1 receptor antagonist protein (IL-1ra) on fibroblast transcription is distinct from that of the IL-1 beta R----G mutein, for the IL-1ra fails to stimulate not only late (procollagenase and prostromelysin) but also immediate early (fos and jun) gene expression. These data suggest that the IL-I beta R----G mutein triggers an incomplete or defective signal transduction cascade and demonstrate that fibroblast fos and jun expression is not necessarily accompanied by increased transcription of genes containing the AP-1 binding site. These data also suggest that at least two events are required for IL-1-mediated late gene induction in fibroblasts.
Conca
W
W
Department of Medicine, Harvard Medical School, Massachusetts General Hospital, Boston 02114.
Auron
P E
PE
Aoun-Wathne
M
M
Bennett
N
N
Seckinger
P
P
Welgus
H G
HG
Goldring
S R
SR
Eisenberg
S P
SP
Dayer
J M
JM
Krane
S M
SM
D015152:Blotting, Northern; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D007375:Interleukin-1; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D008666:Metalloendopeptidases