The prostaglandin analogs, misoprostol and SC-46275, potently inhibit cytokine release from activated human monocytes.
Inflammatory mediator release is one of the body's responses to tissue injury and inflammation. These mediators, such as interleukin-1 beta (I1-1 beta), tumor necrosis factor (TNF-alpha), and products of arachidonic acid metabolism, are themselves proinflammatory. Purified human monocytes stimulated in vitro with E. coli-derived lipopolysaccharide (LPS) will release these key cytokines along with various other eicosanoid mediators. Monocytes incubated with LPS and the prostaglandin E-1 analog, misoprostol, released significantly lower levels of cytokines compared to monocytes incubated with LPS alone. Eicosanoid release was also affected by misoprostol. SC-46275, a more potent mucosal protective PGE1 analog, also altered the release of cytokines and eicosanoids from human monocytes. However SC-46275 inhibited I1-1 beta release with an IC50 value of 9 microM compared to 75 microM for misoprostol. SC-46275 and misoprostol both inhibited TNF-alpha release. These data suggest there is a potential immunomodulatory role for prostaglandin analogs in the therapeutic treatment of inflammatory diseases such as ulcerative colitis, Crohn's disease, and autoimmune inflammatory diseases of the central nervous system.
Widomski
D
D
Searle Research and Development Skokie, Illinois 60077, USA.
Fretland
D J
DJ
Gasiecki
A F
AF
Collins
P W
PW
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007375:Interleukin-1 / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D016595:Misoprostol / Q000494:pharmacology*; D016260:Monocytes, Activated Killer / Q000378:metabolism*; D000078183:Oxindoles; D011465:Prostaglandins, Synthetic / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D016207:Cytokines; D007211:Indoles; D007375:Interleukin-1; D008070:Lipopolysaccharides; D000078183:Oxindoles; D011465:Prostaglandins, Synthetic; D014409:Tumor Necrosis Factor-alpha; D016595:Misoprostol; C072122:SC-46275; D015847:Interleukin-4; C062866:tenidap; D000527:Alprostadil; D015232:Dinoprostone