Effect of anti-inflammatory agents on ricin-induced macrophage toxicity.
The toxicity of ricin in susceptible cells is well characterized biochemically, but the pathophysiological implications of its toxicity and the immune response to ricin challenge in the lung are unknown. Incubating macrophage cell line with ricin (1 pM-10 nM) for 4 hours markedly inhibited 3H-leucine incorporation (acid insoluble) into protein (> 95%, at 1 nM) without affecting the acid-soluble radioactivity. In spite of increased uptake of total thymidine (141 +/- 13.5%) and total uridine (135 +/- 17.2%), DNA synthesis in ricin-treated cells was progressively inhibited although RNA synthesis was not affected. Fluocinolone (an anti-inflammatory glucocorticoid) pretreatment increased the ricin-induced inhibition of protein synthesis. The synergistic effect of fluocinolone on ricin-induced protein synthesis inhibition was due to an increased binding (167%, p < 0.01) and internalization (134 +/- 12%, p < 0.025) of ricin. Partial protection from ricin-induced inhibition of protein synthesis by indomethacin (nonsteroidal, anti-inflammatory agent) was due to decreased binding and internalization of ricin. These results show that macrophages are sensitive to ricin and that pharmacologically active drugs may regulate ricin's toxicity, perhaps by controlling synthesis and release of certain mediators of fast death.
Naseem
S M
SM
Toxinology Division, United States Army Medical Research, Fort Detrick, Frederick, MD 21702-5011.
Pace
J G
JG
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D005446:Fluocinolone Acetonide / Q000031:analogs & derivatives / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007457:Iodine Radioisotopes; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis; D012276:Ricin / Q000633:toxicity*
D000893:Anti-Inflammatory Agents; D007457:Iodine Radioisotopes; D005446:Fluocinolone Acetonide; D012313:RNA; D004247:DNA; D012276:Ricin; C035394:fluocinolone; D007213:Indomethacin