Regulation of mucosal immune responses by recombinant interleukin 10 produced by intestinal epithelial cells in mice

doi:10.1053/gast.2002.33655

Gastroenterology

Volume 122, Issue 7, June 2002, Pages 1829-1841

https://doi.org/10.1053/gast.2002.33655 Get rights and content

Abstract

Background & Aims: Interleukin (IL)-10 is a cytokine with anti-inflammatory properties. The aim of this study was to explore the effect of a site-specific delivery of IL-10 on intestinal immune responses. Methods: Transgenic mice were created in which IL-10 is expressed by the intestinal epithelial cells. Results: Transgenic mice showed a marked increase in the number of intraepithelial lymphocytes in the small intestine. Mucosal lymphocytes of transgenic animals produced fewer T helper type 1 cytokines than wild-type lymphocytes. By contrast, the production of transforming growth factor β was increased. Moreover, the epithelial layer in transgenic mice was significantly enriched for CD4⁺CD25⁺ T cells. Furthermore, transgenic mice had increased numbers of immunoglobulin A–producing B cells in the small intestine. These effects were local because splenic lymphocytes were not affected. Studies in models of inflammatory bowel disease showed that transgenic IL-10 was able to attenuate the acute colitis induced by dextran sodium sulfate administration or by adoptive transfer of CD4⁺CD45RB^high splenocytes, with a modest effect on the chronic intestinal inflammation arising spontaneously in IL-10^−/− mice. Conclusions: These observations provide evidence for an in vivo lymphoepithelial cross talk, by which cytokines locally produced by epithelial cells can regulate immune responses in the intestine without systemic modifications.

GASTROENTEROLOGY 2002;122:1829-1841

Section snippets

Generation of Fabpi/IL-10 transgenic mice

A fragment of the rat Fabpi promoter containing nucleotides −1178 to +28 (a gift of Jeffrey I. Gordon, Washington University, St. Louis, MO)⁴ was cloned upstream of the mouse IL-10 genomic sequence. This IL-10 sequence, a gift of Kevin Moore (DNAX Research Institute, Palo Alto, CA), contains positions 1568–6879 of a 7.2-kilobase Bgl II fragment, in which position 1568 of the IL-10 gene corresponds to nucleotide 16 of the IL-10 complementary DNA (cDNA).²¹ Transgenic mice were made by standard

Intestine-specific expression of IL-10 in transgenic animals

The promoter fragment used to direct IL-10 expression has been extensively characterized previously by analyzing reporter gene expression.⁴ According to these studies, transgene-derived protein should be found exclusively in mature enterocytes but not crypt epithelial cells, with the highest levels of expression in the distal small intestine and lower levels in the remainder of the small intestine and the proximal colon. RT-PCR analysis was performed on samples from various tissues of

Discussion

It is remarkable that large numbers of lymphocytes are located in the intestine, coexisting peaceably with the external environment that is only a single cell layer away. To achieve this, the immunologic tone of the intestinal tract has to be one of suppressed or highly regulated responses. The intestinal epithelial cell has been proposed as a key player in this process. It can take up, process, and present antigens to the mucosal immune system.1, 35, 36 Furthermore, epithelial cells can

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^☆: Address requests for reprints to: Hilde Cheroutre, Ph.D., Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, California 92121. e-mail: [email protected]; fax: (858) 678-4595.

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Basic ResearchRegulation of mucosal immune responses by recombinant interleukin 10 produced by intestinal epithelial cells in mice☆

Abstract

Section snippets

Generation of Fabpi/IL-10 transgenic mice

Intestine-specific expression of IL-10 in transgenic animals

Discussion

Immunol Today

Cell

Immunity

Gastroenterology

Gastroenterology

J Immunol Methods

J Immunol Methods

Gastroenterology

Blood

Immunity

Immunity

Gastroenterology

Immunity

Gastroenterology

The intestinal epithelial cell: processing and presentation of antigen to the mucosal immune system

Immunol Rev

Expression and regulation of the human beta-defensins hBD-1 and hBD-2 in intestinal epithelium

J Immunol

Intestinal lymphoepithelial communication

Adv Exp Med Biol

Use of transgenic mice to map cis-acting elements in the intestinal fatty acid binding protein gene (Fabpi) that control its cell lineage-specific and regional patterns of expression along the duodenal-colonic and crypt-villus axes of the gut epithelium

J Cell Biol

Interleukin-10

Annu Rev Immunol

Interleukin-10 and its receptor

Ther Immunol

IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells

J Immunol

Identification and induction of keratinocyte-derived IL-10

J Immunol

Interleukin-10 and the interleukin-10 receptor

Annu Rev Immunol

Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses

J Clin Invest

An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation

J Exp Med

Control of experimental inflammatory bowel disease by regulatory T cells

Am J Respir Crit Care Med

Altered immune responses in interleukin 10 transgenic mice

J Exp Med

Ligation of intestinal epithelial CD1d induces bioactive IL-10: critical role of the cytoplasmic tail in autocrine signaling

Proc Natl Acad Sci U S A

Interleukin-10: potential benefits and possible risks in clinical infectious diseases

Clin Infect Dis

Basic Research
Regulation of mucosal immune responses by recombinant interleukin 10 produced by intestinal epithelial cells in mice☆