TJN-419 improves dextran sulfate sodium-induced colitis via inhibition of interleukin-12 release.
We investigated the association of interleukin-12 (IL-12) with development of dextran sulfate sodium (DSS)-induced colitis in mice, and examined the effects of TJN-419, a synthetic compound derived from acteoside, on this process. Enhanced IL-12 production in lipopolysaccharide (LPS)-stimulated macrophages was dose-dependently inhibited by addition of TJN-419 to culture medium, and this effect was abolished by pretreatment with PD98059, an inhibitor of extracellular-regulated kinase. We then assessed the effect of TJN-419 or a neutralizing antibody against murine IL-12 in a DSS-induced colitis model in C57 BL/6 mice. Colitis was induced by 5% DSS solution given as drinking water. Treatment with the anti-IL-12 antibody was performed intravenously and TJN-419 was administered orally. We also investigated the effect of TJN-419 on erosion in the rectum in a DSS-induced colitis model in rat. The IL-12 level in the rectum was significantly enhanced and the IL-10 level was significantly decreased in animals with DSS-induced colitis compared with untreated controls. Intravenous injection of the anti-IL-12 antibody and oral administration of TJN-419 inhibited clinical symptoms in DSS-induced colitis. TJN-419 also inhibited the increase in IL-12 and suppressed the area of erosion in the rectum in DSS-induced colitis in rats. These results indicate that IL-12 has a possible role in development of DSS-induced colitis and that TJN-419 is effective for treatment of this disease model via inhibition of IL-12 production.
Sadakane
Chiharu
C
Tsumura & Co., Tsumura Research Laboratories, Ibaraki, Japan.
Koseki
Junichi
J
Inagaki
Yayoi
Y
Hasegawa
Yoshihiro
Y
Shindo
Shoichiro
S
Maruyama
Hirofumi
H
Takeda
Shuichi
S
Takeda
Hiroshi
H
Hattori
Tomohisa
T
D000085:Acetates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing; D002934:Cinnamates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D016264:Dextran Sulfate; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids; D005960:Glucosides / Q000378:metabolism*; D018664:Interleukin-12 / Q000037:antagonists & inhibitors*; D008070:Lipopolysaccharides; D032411:Lippia / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010636:Phenols / Q000378:metabolism*; D010936:Plant Extracts / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012007:Rectum / Q000187:drug effects* / Q000473:pathology; D059808:Polyphenols
D000085:Acetates; D000893:Anti-Inflammatory Agents; D057134:Antibodies, Neutralizing; D002934:Cinnamates; D016264:Dextran Sulfate; D005419:Flavonoids; D005960:Glucosides; D018664:Interleukin-12; D008070:Lipopolysaccharides; D010636:Phenols; D010936:Plant Extracts; C549834:4-(2-(N-(3-pyridylmethyl)carbamoylethenyl)phenoxy)acetate; C058956:acteoside; D059808:Polyphenols; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one