Gastroenterology

Gastroenterology

Volume 122, Issue 7, June 2002, Pages 2011-2025
Gastroenterology

Basic Research
Leptin: A pivotal mediator of intestinal inflammation in mice,☆☆

https://doi.org/10.1053/gast.2002.33631Get rights and content

Abstract

Background & Aims: In addition to acting as a regulator of food intake and energy expenditure, leptin can also modulate immune and inflammatory responses. The role of leptin in intestinal inflammation is the focus of the present study. Methods: Acute and chronic colitis were induced in leptin-deficient ob/ob or wild-type (WT) mice using dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS). The severity of colitis was evaluated, and possible mechanisms were studied. Results: Leptin directly stimulates intraepithelial lymphocytes (IELs) and lamina propria mononuclear cells (LPMCs). In the DSS acute model, ob/ob mice exhibited a 72% reduction of colitis severity and spontaneous release of proinflammatory cytokines from the colon compared with WT mice. Replacement of leptin in ob/ob mice converted disease resistance to susceptibility, indicating that leptin deficiency, not obesity, accounts for the resistance to acute DSS-induced colitis. During chronic DSS-induced colitis and TNBS-induced colitis, in addition to reduced disease severity, ob/ob mice exhibited a significant attenuation in intestinal inflammation, accompanied by reduced production of cytokines and chemokines. When compared with WT mice, CD8+ IELs of ob/ob mice were reduced in number as well as in their ability to synthesize interferon gamma. In addition, LPMCs of ob/ob mice showed increased apoptosis in untreated as well as DSS- or TNBS-treated mice. Phosphorylation of signal transducer and activator of transcription 3 and induction of cyclooxygenase 2 were absent in the colon of DSS-fed ob/ob mice. Conclusions: These results show that leptin represents a functional link between the endocrine and immune systems.

GASTROENTEROLOGY 2002;122:2011-2025

Section snippets

Reagents

Recombinant murine leptin was purchased from R&D Systems, Inc. (Minneapolis, MN). RPMI and fetal calf serum were obtained from Life Technologies Inc. (Grand Island, NY). Concanavalin A (con A; type IV-S) was from Sigma Chemical Co. (St. Louis, MO).

Mice

Animal protocols were approved by the animal studies committee of the University of Colorado Health Sciences Center. Six- to 8-week-old female leptin-deficient (C57BL/6J ob/ob) mice and their wild-type (WT) lean littermates were obtained from Jackson

Leptin-stimulated LPMCs and IELs in vitro

To evaluate the direct stimulatory effect of leptin on the LPMC and IEL population, the following experiments were conducted. LPMCs were isolated from the colons of healthy C57BL/6 mice and cultured in the absence or presence of leptin (100 ng/mL) or con A (0.5 μg/mL; Figure 1A).

. Direct stimulatory effect of leptin on LPMCs and IELs in vitro. LPMCs and IELs were isolated from the colons of healthy C57BL/6 mice. (A) LPMCs were stimulated for 24 hours in the presence or absence of leptin (100

Discussion

In the present study, leptin was identified as a critical mediator of intestinal inflammation. Leptin-deficient ob/ob mice were found to be resistant to acute and chronic intestinal inflammation induced by DSS as well as to colitis induced by rectal administration of TNBS. In IELs and LPMCs, leptin stimulation resulted in STAT-3 activation. In addition, stimulation of LPMCs with leptin induced IL-18 production, indicating a direct effect of leptin on these cell populations. The resistance to

Acknowledgements

The authors thank Charles A. Dinarello for his support and critical review of the manuscript and Massimo Gadina for the detailed instructions for the immunoprecipitation.

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    Address requests for reprints to: Giamila Fantuzzi, Ph.D., Division of Infectious Diseases, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, B168, Denver, Colorado 80262. e-mail: [email protected]; fax: (303) 315-8054.

    ☆☆

    Supported by the Broad Medical Foundation and the Deutsche Forschungsgemeinschaft DFG SI 749/2-1 (to B.S.).

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