A HUMAN IL-1-ALPHA DERIVATIVE WHICH LACKS PROSTAGLANDIN-E2 INDUCING ACTIVITY AND INHIBITS THE ACTIVITY OF IL-1 THROUGH RECEPTOR COMPETITION

  • 1 September 1990
    • journal article
    • research article
    • Vol. 9  (3) , 405-413
Abstract
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 retained LAF activity in mouse thymocyte, cytostatic activity against a human melanoma celline(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 acitvities of IL-1.alpha. can be segregated by substituing one amino acid. TN-55 may be an idealIL-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.