Immunotoxicity of soluble beta-glucans induced by indomethacin treatment

(1 --> 3)-Beta-D-Glucan (beta-glucan) is a biological response modifier that regulates host immune response. However, the side effects of this drug have not been extensively examined. In this study, we found that the combination of a beta-glucan and a nonsteroidal anti-inflammatory drug, indomethacin, induced lethal toxicity in mice. Lethal toxicity of orally administered indomethacin (multiple administration to ICR mice; once a day for 2 weeks) was 0/8 (2.5 mg kg(-1)) and 5/8 (5 mg kg(-1)) (death/total) over 2 weeks. The toxicity was enhanced to 3/8 and 8/8 in mice treated with a clinical beta-glucan preparation, sonifilan (250 microg/mouse, single i.p. administration on day 0). A similar effect was observed for other beta-glucans, including SSG, grifolan, zymosan A and zymocel. Enhanced lethal toxicity resulted from a single p.o. administration of indomethacin on day 5 to day 9 after multiple beta-glucans administration. Interferon-gamma, interleukin-6 and colony stimulating factor concentrations in sera of indomethacin/beta-glucan-treated mice were significantly elevated. These results strongly suggest that indomethacin/beta-glucan treatment induces lethality in mice by maladjusting the cytokine network.