Rapid development of colitis in NSAID-treated IL-10-deficient mice.

Abstract

BACKGROUND & AIMS:

Interleukin (IL)-10 is an anti-inflammatory and immune regulatory cytokine. IL-10-deficient mice (IL-10(-/-)) develop chronic inflammatory bowel disease (IBD), indicating that endogenous IL-10 is a central regulator of the mucosal immune response. Prostaglandins are lipid mediators that may be important mediators of intestinal inflammation. In this study we assessed the role of prostaglandins in the regulation of mucosal inflammation in the IL-10(-/-) mouse model of IBD.

METHODS:

Prostaglandin (PG) synthesis was inhibited with nonselective or cyclooxygenase (COX)-isoform selective inhibitors. Severity of inflammation was assessed histologically. Cytokine production was assessed by ribonuclease protection analysis and enzyme-linked immunosorbent assay. PGE(2) levels were assessed by enzyme immunoassay. COX-1 and COX-2 expression was assessed by Western blot analysis.

RESULTS:

Nonsteroidal anti-inflammatory drug (NSAID) treatment of wild-type mice had minimal effect on the colon. In contrast, NSAID treatment of 4-week-old IL-10(-/-) mice resulted in rapid development of colitis characterized by infiltration of the lamina propria with macrophages and interferon gamma-producing CD4(+) T cells. Colitis persisted after withdrawal of the NSAID. NSAID treatment decreased colonic PGE(2) levels by 75%. Treatment of IL-10(-/-) mice with sulindac sulfone (which does not inhibit PG production) did not induce colitis whereas the NSAID sulindac induced severe colitis. COX-1- or COX-2-selective inhibitors used alone did not induce IBD in IL-10(-/-) mice. However, the combination of COX-1- and COX-2-selective inhibitors did induce colitis.

CONCLUSIONS:

NSAID treatment of IL-10(-/-) mice results in the rapid development of severe, chronic IBD. Endogenous PGs are important inhibitors of the development of intestinal inflammation in IL-10(-/-) mice.

• Authors: Daniel J Berg, Juan Zhang, Joel V Weinstock, Hanan F Ismail, Keith A Earle, Hector Alila, Rifat Pamukcu, Steven Moore, Richard G Lynch
• Journal: Gastroenterology (Gastroenterology) Vol. 123 Issue 5 Pg. 1527-42 (Nov 2002) ISSN: 0016-5085 [Print] United States
• PMID: 12404228 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Cyclooxygenase Inhibitors
• Cytokines
• Prostaglandins
• Receptors, Prostaglandin E
• Interleukin-10
• Sulindac
• Interferon-gamma
• Prostaglandin-Endoperoxide Synthases
• sulindac sulfone
• Dinoprostone

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Colitis (chemically induced, metabolism, pathology)
• Colon (drug effects, metabolism, pathology)
• Cyclooxygenase Inhibitors (pharmacology)
• Cytokines (biosynthesis)
• Dinoprostone (metabolism)
• Disease Progression
• Interferon-gamma (biosynthesis)
• Interleukin-10 (deficiency, genetics)
• Longitudinal Studies
• Mice
• Mice, Inbred C57BL
• Mice, Knockout (genetics)
• Osmolar Concentration
• Phenotype
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Prostaglandins (physiology)
• Receptors, Prostaglandin E (agonists)
• Sulindac (analogs & derivatives, pharmacology)
• T-Lymphocytes (metabolism)
• Time Factors