Gliotoxin, an inhibitor of nuclear factor-kappa B, attenuates peptidoglycan-polysaccharide-induced colitis in rats.
Gliotoxin is a fungal metabolite that has immunosuppressive properties. First, we determined if gliotoxin could inhibit bacterial peptidoglycan-polysaccharide-stimulated tumor necrosis factor-alpha production, as well as nuclear factor-kappa B (NF-kappaB), in a rat macrophage (NR8383) cell line. Next, the apoptosis-inducing potential of gliotoxin was also evaluated in this cell line. Finally, we evaluated whether gliotoxin could reduce peptidoglycan-polysaccharide-induced colitis in rats. Gliotoxin (2 mg/kg/day) was dosed from day 14 after the initial intramural colonic injection of peptidoglycan-polysaccharide until day 21. A gross colonic injury score, myeloperoxidase activity, and cytokine levels were all evaluated on day 21. Gliotoxin dose dependently inhibited cytokine production, as well as NF-kappaB, and also induced apoptosis in the NR8383 cell line. On day 21, gliotoxin significantly reduced gross colonic injury (adhesions, nodules, mucosal lesions) in rats. Gliotoxin-treated rats also had partially normalized biochemical indices of colitis, such as colonic cytokine levels. The colonic level of NF-kappaB was also partially normalized in gliotoxin treated rats. Gliotoxin also exhibited an antiarthritis effect in peptidoglycan-polysaccharide-treated rats. In summary, gliotoxin effectively attenuated the chronic reactivation phase of peptidoglycan-polysaccharide-induced colitis. This anticolitis effect may be related to the inhibition of NF-kappaB in Lewis rats.
Fitzpatrick
Leo R
LR
Gastrointestinal Research Laboratory, Maryland Research Laboratories, Otsuka Maryland Research Institute, Rockville, Maryland 20850, USA.
Wang
Jian
J
Le
Truc
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D003092:Colitis / Q000188:drug therapy* / Q000209:etiology*; D005260:Female; D005912:Gliotoxin / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism; D008264:Macrophages; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010457:Peptidoglycan; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D007166:Immunosuppressive Agents; D007375:Interleukin-1; D016328:NF-kappa B; D010457:Peptidoglycan; D014409:Tumor Necrosis Factor-alpha; D005912:Gliotoxin