In vitro and in vivo effects of gliotoxin, a fungal metabolite: efficacy against dextran sodium sulfate-induced colitis in rats.
Gliotoxin is a fungal metabolite that has immunosuppressive properties. First, we determined if gliotoxin could inhibit cytokine production from macrophage and colonic epithelial cell lines, as well as whether it inhibited nuclear factor-kappa B in these same cell types. Second, we evaluated whether gliotoxin could reduce dextran sodium sulfate-induced colitis in rats. A disease activity index, myeloperoxidase activity, and cytokine levels were evaluated on either day 7 or 21. In both cell lines, gliotoxin dose dependently inhibited cytokine production and nuclear factor-kappa B. On day 21, gliotoxin significantly reduced disease activity (diarrhea and bloody stools) in rats. On day 7, gliotoxin treatment significantly improved various indices of colitis, including colonic cytokine levels. Decreased food consumption and weight gain was evident with a larger dose of gliotoxin. In summary, gliotoxin, a nuclear factor-kappa B inhibitor, effectively reduced dextran sodium sulfate-induced colitis in rats. However, gliotoxin exhibited a narrow therapeutic to toxicity ratio in these rats.
Fitzpatrick
L R
LR
GI Inflammation Research Laboratory, Otsuka America Pharmaceutical Inc, Rockville, Maryland, USA.
Wang
J
J
Le
T
T
D000818:Animals; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy*; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000276:immunology; D005912:Gliotoxin / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D007375:Interleukin-1 / Q000096:biosynthesis; D053583:Interleukin-1beta; D008264:Macrophages / Q000276:immunology; D008297:Male; D016328:NF-kappa B / Q000096:biosynthesis; D010446:Peptide Fragments / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D007166:Immunosuppressive Agents; D007375:Interleukin-1; D053583:Interleukin-1beta; D016328:NF-kappa B; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C052994:interleukin-1beta (163-171); D005912:Gliotoxin; D016264:Dextran Sulfate