The Open Gastroenterology Journal

2008, 2 : 64-72
Published online 2008 December 05. DOI: 10.2174/1874259900802010064
Publisher ID: TOGASJ-2-64

Modulation of Dextran Sulphate Sodium-Induced Colonic Inflammation by Local Supplementation of Leptin

Corinne Nazaret , Sandra Guilmeau , Yassine Sakar , Francine Walker , Robert Ducroc , Thomas Aparicio , Thérèse Lehy , Christine Linard and André Bado
INSERM, U773 - CRB3/E02, UFR de Médecine Paris 7 - Denis Diderot, 16, rue Henri Huchard, 75018 Paris, France.

ABSTRACT

Background & Aims:

Leptin is overproduced in gastrointestinal mucosa during inflammatory processes, suggesting that mucosal cells represent sources of secreted leptin active in the lumen. The effects of leptin, acting apically from colonic epithelial cells, were analysed on dextran sulphate sodium-induced colonic inflammation in rats.

Methods:

We determined the effects of intracolonic leptin on the phosphorylation of STAT3, MAPkinase and on colon mucosa-derived inflammation-related genes (IL-8, IL1β, TNFα, COX-2). Colitis was induced by administering dextran sodium sulphate. The effects of intracolonic leptin on DSS colitis was evaluated based on disease symptoms, cytokine expression and PPAR α, γ.

Results:

In vivo, intracolonic leptin rapidly stimulated STAT-3 and p42-MAPK phosphorylation. We also detected a 3- fold increase in COX-2 induction, and a dose-dependent increase in mucosal PGE2 content (EC50 0.89 nM). Intracolonic leptin reduced the severity of DSS-induced colitis, whereas intraperitoneal leptin exacerbated colitis. Intracolonic leptin decreased DSS-induced inflammatory IL-8 (-75%; P<0.01 vs DSS) and IL-1β (-60%; P<0.01 vs DSS); it also prevented a DSS-induced decrease in the levels of mucosa PPARα mRNA and increased the levels of PPARγ mRNA two-fold (P<0.01 vs DSS).

Conclusion:

Leptin activates its apical receptor and this mechanism coupled to the activation of STAT-3 and MAPKinase signalling pathways may have a beneficial effect on the integrity of the epithelium upon mucosa injury. These data shed further light on the role of gastrointestinal luminally acting leptin in the modulation of intestinal inflammation.

Keywords:

Leptin, local action, dextran sulfate sodium, inflammation, colon, PPARs.