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.
Laboratory of Immunopharmacology of Microbial Products, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.
S
S
Yoshioka
N
N
Ohno
T
T
Miura
Y
Y
Adachi
T
T
Yadomae
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000633:toxicity*; D003115:Colony-Stimulating Factors / Q000097:blood; D016207:Cytokines / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005936:Glucans / Q000008:administration & dosage / Q000633:toxicity*; D007213:Indomethacin / Q000008:administration & dosage / Q000633:toxicity*; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012566:Sizofiran / Q000008:administration & dosage / Q000633:toxicity; D013163:Splenomegaly / Q000139:chemically induced; D047071:beta-Glucans
D000276:Adjuvants, Immunologic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003115:Colony-Stimulating Factors; D016207:Cytokines; D005936:Glucans; D015850:Interleukin-6; D047071:beta-Glucans; D012566:Sizofiran; D007371:Interferon-gamma; C033363:beta-1,3-glucan; D007213:Indomethacin