A human IL-1 alpha derivative which lacks prostaglandin E2 inducing activity and inhibits the activity of IL-1 through receptor competition.
In order to segregate multiple activities ascribed to IL-1, various human IL-1 alpha derivatives were produced by recombinant DNA technology. A derivative substituted at the 151st Asp with Tyr(termed to be TN-55) showed unique characteristics. TN-55 lost the PGE2 inducing activity in a human osteosarcoma cell line (MG-63) and growth promoting activity for a human dermal fibroblast cell line (CCD-27Sk), but partially remained LAF activity in mouse thymocyte, cytostatic activity against a human melanoma cell line (A-375) and IL-2 inducing activity in a human T cell line (HSB.2). Although TN-55 bound to the receptor on MG-63 cells with a similar affinity as native IL-1 alpha, TN-55 not only failed in inducing PGE2 production but also antagonized the PGE2 inducing action of IL-1 alpha or IL-1 beta. Thus, TN-55 seems to work as a receptor antagonist. Moreover, TN-55 did not stimulate ACTH secretion in rats in vivo. On the other hand, TN-55 induced PGE2 production in a rabbit dermal fibroblast cell line (RAB-9) and exhibited pyrogenicity in rabbits in vivo. These data suggest that TN-55 has different species-cross reactivity from native IL-1 alpha. In conclusion, multiple biological activities of IL-1 alpha can be segregated by substituting one amino acid. TN-55 may be an ideal IL-1 agonist which lacks inflammatory characteristics of IL-1 (e.g. PGE2-dependent activities) in human but partially retained T lymphocyte stimulating activity and tumor cytostatic activity. In addition, TN-55 may also work as an IL-1 antagonist to block PGE2 production induced by IL-1 through receptor competition.
Yamayoshi
M
M
Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Ohue
M
M
Kawashima
H
H
Kotani
H
H
IIda
M
M
Kawata
S
S
Yamada
M
M
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D015232:Dinoprostone / Q000096:biosynthesis*; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007375:Interleukin-1 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008213:Lymphocyte Activation; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011971:Receptors, Immunologic / Q000187:drug effects* / Q000378:metabolism; D017472:Receptors, Interleukin-1
D007375:Interleukin-1; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D000324:Adrenocorticotropic Hormone; D015232:Dinoprostone