Inhibition of phosphoinositide 3-kinase ameliorates dextran sodium sulfate-induced colitis in mice.

Abstract

The critical role of phosphoinositide 3-kinase gamma (PI3Kgamma) in inflammatory cell activation and recruitment makes it an attractive target for immunomodulatory therapy. 5-Quinoxilin-6-methylene-1,3-thiazolidine-2,4-dione (AS605240), a potent PI3Kgamma inhibitor, has been reported to ameliorate chronic inflammatory disorders including rheumatoid arthritis, systemic lupus erythematosus, and atherosclerosis. However, its in vivo effect on intestinal inflammation remains unknown. Here we evaluated the protective and therapeutic potentials of AS605240 in mice with dextran sodium sulfate (DSS)-induced acute and chronic colitis. Our results showed that AS605240 improved survival rate, disease activity index, and histological damage score in mice administered DSS in both preventive and therapeutic studies. AS605240 treatment also significantly inhibited the increase in myeloperoxidase levels, macrophage infiltration, and CD4(+) T-cell number in the colon of DSS-fed mice. The DSS-induced overproduction of colonic proinflammatory cytokines including interleukin (IL)-1beta, tumor necrosis factor-alpha, and interferon-gamma was significantly suppressed in mice undergoing AS605240 therapy, whereas colonic anti-inflammatory cytokines such as IL-4 were up-regulated. The down-regulation of the phospho-Akt level in immunological cells from the inflamed colon tissue and spleen of AS605240-treated mice was detected both by immunohistochemical analysis and Western blotting. These findings demonstrate that AS605240 may represent a promising novel agent for the treatment of inflammatory bowel disease by suppressing leukocyte infiltration as well as by immunoregulating the imbalance between proinflammatory and anti-inflammatory cytokines.

• Authors: Xiao-dong Peng, Xiao-hua Wu, Li-juan Chen, Zhen-ling Wang, Xiao-hong Hu, Li-fang Song, Chun-mei He, You-fu Luo, Zhi-zhi Chen, Ke Jin, Hong-gang Lin, Xiao-lei Li, Yong-sheng Wang, Yu-quan Wei
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 332 Issue 1 Pg. 46-56 (Jan 2010) ISSN: 1521-0103 [Electronic] United States
• PMID: 19828878 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione
• Cytokines
• Enzyme Inhibitors
• Phosphoinositide-3 Kinase Inhibitors
• Quinoxalines
• Thiazolidinediones
• Dextran Sulfate

Topics

• Acute Disease
• Animals
• Blotting, Western
• CD4 Lymphocyte Count
• CD4-Positive T-Lymphocytes (cytology)
• Chronic Disease
• Colitis (chemically induced, enzymology, immunology, pathology, prevention & control)
• Colon (drug effects, enzymology, immunology, pathology)
• Cytokines (biosynthesis, immunology)
• Dextran Sulfate
• Disease Models, Animal
• Enzyme Inhibitors (administration & dosage, pharmacology, therapeutic use)
• Flow Cytometry
• Fluorescent Antibody Technique
• Immunohistochemistry
• Intestinal Mucosa (drug effects, enzymology, immunology, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Organ Size
• Phosphoinositide-3 Kinase Inhibitors
• Quinoxalines (administration & dosage, pharmacology, therapeutic use)
• Severity of Illness Index
• Spleen (drug effects, immunology)
• Thiazolidinediones (administration & dosage, pharmacology, therapeutic use)