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Experimental Biology and Medicine 232:607-613 (2007)
© 2007 Society for Experimental Biology and Medicine

ORIGINAL RESEARCH ARTICLE

Peloruside A, an Antimitotic Agent, Specifically Decreases Tumor Necrosis Factor-{alpha} Production by Lipopolysaccharide-Stimulated Murine Macrophages

Kevin P. Crume, John H. Miller and Anne C. La Flamme1

School of Biological Sciences, Victoria University of Wellington, Wellington 6001, New Zealand

To whom requests for reprints should be addressed at 1 School of Biological Sciences, Victoria University of Wellington, P.O. Box 600, Wellington, Wellington 6001, New Zealand. E-mail: Anne.LaFlamme{at}vuw.ac.nz

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.

Key Words: taxol • peloruside • inflammation • macrophage • microtubule-stabilizing agent






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