title: Peloruside A, an antimitotic agent, specifically decreases tumor necrosis factor-alpha production by lipopolysaccharide-stimulated murine macrophages.
abstract: Peloruside A (peloruside) is a naturally occurring compound isolated from a New Zealand marine sponge that, like the anticancer drug paclitaxel, stabilizes microtubules and inhibits mitosis. Paclitaxel is known to induce a proinflammatory response in murine macrophages; whereas, peloruside has never been tested for its immunomodulatory effects in these cells. Although the antimitotic effects of the two drugs appear to be similar, we found that peloruside, unlike paclitaxel, does not induce murine macrophages to produce the proinflammatory mediators interleukin-12p40 (IL-12p40), tumor necrosis factor-alpha (TNF-alpha), and nitric oxide. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay confirmed that the absence of cytokine production was not caused by cytotoxicity in these nondividing cells. Additionally, there was no effect on unstimulated splenocytes; whereas, both compounds inhibited proliferation after concanalavin A (Con A) stimulation. Finally, there was a significant decrease in TNF-alpha and nitric oxide but not IL-12p40 when macrophages were cultured with lipopolysaccharide (LPS) and either paclitaxel or peloruside. These results suggest that peloruside may prove to be an effective anti-inflammatory treatment, since it does not induce the production of proinflammatory mediators yet can downregulate TNF-alpha and nitric oxide production by LPS-stimulated macrophages, as well as inhibit lymphocyte proliferation.
authors.affiliation: School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand.
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Crume
authors.forename: John H
authors.initials: JH
authors.lastname: Miller
authors.forename: Anne C
authors.initials: AC
authors.lastname: La Flamme
mesh_terms: D000818:Animals; D050256:Antimitotic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D007783:Lactones / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis; D017239:Paclitaxel / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D050256:Antimitotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D053762:Interleukin-12 Subunit p40; D007783:Lactones; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; C414085:peloruside A; D009569:Nitric Oxide; D017239:Paclitaxel