Inhibition of interleukin 1 synthesis by tenidap: a new drug for arthritis.
Tenidap is a new antiarthritic drug of novel chemical structure. This study shows the effects of tenidap on the in vitro synthesis of interleukin 1 (IL-1). IL-1 production by murine peritoneal macrophages was induced either by stimulation with lipopolysaccharide (LPS) or by phagocytosis of zymosan. With either stimulus, tenidap inhibited IL-1 production as measured by a quantitative competitive IL-1 receptor binding assay. Approximately 20 ng/mL of IL-1 was produced by 10(6) macrophages in response to LPS and about half that amount was produced in response to zymosan. Fifty percent inhibition of IL-1 production by tenidap was found at 3 microM for both stimuli. Using goat anti-IL-1 alpha and Western blot analysis, the appearance of intracellular 34 kDa pro-IL-1 alpha was inhibited by tenidap down to 3 microM. Tenidap decreased [35S]Met incorporation into cellular protein at 30 microM but not at 10 or 3 microM, indicating selectivity for IL-1 inhibition relative to total protein synthesis. Because tenidap inhibited IL-1 induction by both zymosan and LPS, it must act subsequently to receptor triggering. As the appearance of IL-1 was inhibited both intracellularly and extracellularly, the primary drug effect cannot be on secretion.
Otterness
I G
IG
Department of Immunology and Infectious Diseases, Pfizer Inc., Groton, CT 06340.
Bliven
M L
ML
Downs
J T
JT
Natoli
E J
EJ
Hanson
D C
DC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D003600:Cytosol / Q000276:immunology; D015232:Dinoprostone / Q000096:biosynthesis; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007375:Interleukin-1 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D000078183:Oxindoles; D014176:Protein Biosynthesis; D013189:SRS-A / Q000096:biosynthesis; D015054:Zymosan / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007211:Indoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D000078183:Oxindoles; D013189:SRS-A; D015054:Zymosan; C062866:tenidap; D015232:Dinoprostone