Synthetic alleles at position 121 define a functional domain of human interleukin-1 beta.
The non-conservative substitution of the tyrosine residue at position 121 of human interleukin-1 beta (IL-1 beta) generates protein mutants showing strong reduction of the capacity to induce (a) prostaglandin E2 (PGE2) release from fibroblasts and smooth muscle cells, (b) murine T-cells proliferation and (c) activation of interleukin-6 (IL-6) gene expression. It is generally accepted that these functions are mediated by the type-I interleukin-1 receptor (IL-1RI). However, the mutant proteins maintain the binding affinity to the types-I and II IL-1 receptors, which is the same as the control IL-1 beta, suggesting that this amino acid substitution does not alter the structure of the molecule, except locally. Thus we have identified a new functional site of IL-1 beta different from the known receptor binding region, responsible for fundamental IL-1 beta functions. Moreover, we show that the same mutants maintain at least two hypothalamic functions, that is, the in vitro short-term PGE2 release from rat hypothalamus and the induction of fever in rabbits. This result suggests that there is yet another site of the molecule responsible for the hypothalamic functions, implying that multiple active sites on the IL-1 beta molecule, possibly binding to more than one receptor chain, trigger different signals.
Ambrosetti
D C
DC
Department of Molecular Biology, Immunobiological Research Institute, Siena, Italy.
Palla
E
E
Mirtella
A
A
Galeotti
C
C
Solito
E
E
Navarra
P
P
Parente
L
L
Melli
M
M
D000483:Alleles; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism; D005334:Fever / Q000209:etiology; D005786:Gene Expression Regulation; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007375:Interleukin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D017354:Point Mutation; D011817:Rabbits; D051381:Rats; D017472:Receptors, Interleukin-1 / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000737:chemistry
D007375:Interleukin-1; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D014443:Tyrosine; D015232:Dinoprostone