RRC ID 58149
Author Takagi T, Naito Y, Mizushima K, Hirai Y, Kamada K, Uchiyama K, Handa O, Ishikawa T, Itoh Y.
Title 15-Deoxy-Δ12,14-prostaglandin J2 ameliorates dextran sulfate sodium-induced colitis in mice through heme oxygenase-1 induction.
Journal Arch Biochem Biophys
Abstract The prostaglandin D2 metabolite, 15-deoxy-Δ12,14-Prostaglandin J2 (15d-PGJ2), exerts an anti-inflammatory effect through peroxisome proliferator-activated receptor γ (PPARγ)-dependent and -independent anti-inflammatory actions. In the present study, we focused on heme oxygenase-1 (HO-1) induced by 15d-PGJ2, and evaluated the effects of enema treatment with 15d-PGJ2 in the development of intestinal inflammation using a murine colitis model. Acute colitis was induced with dextran sulfate sodium (DSS) in male C57BL/6 mice (8 weeks old) and NF-E2-related factor-2 (Nrf2) deficient mice. Mice were rectally administered 15d-PGJ2 (1 μM, 0.2 mL: 66.9 ng) daily during DSS administration. Intestinal expression of HO-1 mRNA and protein after rectal administration of 15d-PGJ2 was evaluated by real-time PCR and western blotting, respectively. A disease activity index (DAI) was determined on a daily basis for each animal, and consisted of a calculated score based on changes in body weight, stool consistency, and intestinal bleeding. Tissue-associated myeloperoxidase (MPO) activity as an index of neutrophil infiltration and mRNA expression levels of TNF-α, IFN-γ, and IL-17A were measured in the colonic mucosa. In addition, we evaluated the effects of co-treatment with a HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), or a specific PPARγ antagonist, GW9662. As a result, rectal administration of 15d-PGJ2 markedly induced HO-1 protein and mRNA expression in the colonic mucosa. Treatment with 15d-PGJ2 ameliorated the increase in DAI score and MPO activity and the mRNA expression levels of TNF-α, IFN-γ, and IL-17A after DSS administration. These effects of 15d-PGJ2 against intestinal inflammation were negated by co-treatment with ZnPP, but not with GW9662. In Nrf2 deficient mice, the rectal administration of 15d-PGJ2 did not affect colonic HO-1 expression and activity of DSS-induced colitis. These results demonstrate that 15d-PGJ2 inhibits development of intestinal inflammation in mice via PPAR-independent and Nrf2-HO-1-dependent mechanisms.
Volume 677
Pages 108183
Published 2019-11-30
DOI 10.1016/j.abb.2019.108183
PII S0003-9861(19)30220-6
PMID 31704099
MeSH Administration, Rectal Animals Anti-Inflammatory Agents / administration & dosage Anti-Inflammatory Agents / therapeutic use* Colitis / chemically induced Colitis / drug therapy* Colon / cytology Colon / pathology Dextran Sulfate Heme Oxygenase-1 / metabolism* Inflammation / drug therapy* Male Membrane Proteins / metabolism* Mice, Inbred C57BL NF-E2-Related Factor 2 / metabolism Prostaglandin D2 / administration & dosage Prostaglandin D2 / analogs & derivatives* Prostaglandin D2 / therapeutic use
IF 3.391
Times Cited 0
Mice RBRC01390