Synthetic peptide corresponding to a conserved domain of the retroviral protein p15E blocks IL-1-mediated signal transduction.
We studied the mode of action of the synthetic peptide CKS-17, which is a heptadecapeptide homologous to a highly conserved region of the immunosuppressive retroviral envelope protein p15E, as well as to envelope proteins of the human T cell leukemia virus I and II. Previous studies have established that CKS-17 conjugated to BSA (CKS-17-BSA) inhibited IL-1-mediated tumor toxicity in melanoma cells and proliferation in murine Th clones. We examined the effects of CKS-17-BSA on IL-1 action. CKS-17-BSA did not bind to IL-1, nor did it affect the number of IL-1 receptors, their binding affinity, or their ability to internalize IL-1. However, CKS-17-BSA inhibited production of IL-2 by murine thymoma cells treated with IL-1 or with 12-O-tetradecanoyl phorbol-13 acetate. The potent protein kinase C inhibitor, H7, also inhibited IL-1-mediated responses, while HA1004, a weak inhibitor of protein kinase C, did not. Protein kinase C activity in the cytosolic fraction prepared from thymoma cells was found to be inhibited by CKS-17-BSA in a dose-dependent manner. All of these findings are consistent with the idea that CKS-17-BSA inhibits IL-1-mediated responses by interfering with signal transduction through a protein kinase C pathway.
Gottlieb
R A
RA
Department of Pediatrics, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Lennarz
W J
WJ
Knowles
R D
RD
Cianciolo
G J
GJ
Dinarello
C A
CA
Lachman
L B
LB
Kleinerman
E S
ES
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D003600:Cytosol / Q000201:enzymology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007546:Isoquinolines / Q000494:pharmacology; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011971:Receptors, Immunologic / Q000187:drug effects; D017472:Receptors, Interleukin-1; D012191:Retroviridae Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D012710:Serum Albumin, Bovine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013945:Thymoma / Q000201:enzymology / Q000378:metabolism
D007166:Immunosuppressive Agents; D007375:Interleukin-1; D007376:Interleukin-2; D007546:Isoquinolines; D010446:Peptide Fragments; D010879:Piperazines; D011971:Receptors, Immunologic; D017472:Receptors, Interleukin-1; D012191:Retroviridae Proteins; D012710:Serum Albumin, Bovine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate