Interleukin-35 mediates mucosal immune responses that protect against T-cell-dependent colitis.

Abstract

BACKGROUND & AIMS:

The soluble hematopoietin receptor Epstein-Barr virus-induced protein (EBI)-3 is an immune regulator that has been associated with the pathogenesis of inflammatory bowel disease. However, the concept that EBI3 is part of an interleukin (IL)-27 heterodimer that mediates chronic inflammatory and autoimmune diseases has been challenged by the description of IL-35, a bioactive cytokine comprising EBI3 and IL-12 p35. We investigated the roles of IL-27 and IL-35 in chronic inflammation of the intestine.

METHODS:

We analyzed EBI3-deficient mice and IL-27p28-deficient mice with spontaneous or T-cell transfer-induced colitis and compared outcomes with wild-type mice (controls). We constructed vectors that express EBI3 covalently linked to the IL-12p35 chain (recombinant [r]IL-35).

RESULTS:

Intestines of EBI3-deficient mice had increased pathologic features of colitis, compared with IL-27p28-deficient or control mice; they also had shorter survival times, indicating that IL-35, rather than IL-27, protects the intestine from immune responses in mice. The mucosa of EBI3-deficient mice accumulated subsets of activated CD4+ T cells that produced T-helper (Th)1 and Th17 cytokines. Adoptive transfer of these T cells induced colitis in RAG-deficient mice. The rIL-35 significantly reduced the development of several forms of experimental colitis and reduced levels of markers of Th1 and Th17 cells.

CONCLUSIONS:

IL-35 controls the development of T-cell-dependent colitis in mice. It might be developed as a therapeutic target for patients with chronic intestinal inflammation.

• Authors: Stefan Wirtz, Ulrike Billmeier, Tamuna Mchedlidze, Richard S Blumberg, Markus F Neurath
• Journal: Gastroenterology (Gastroenterology) Vol. 141 Issue 5 Pg. 1875-86 (Nov 2011) ISSN: 1528-0012 [Electronic] United States
• PMID: 21820391 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Ebi3 protein, mouse
• Interleukin-12 Subunit p35
• Interleukins
• Minor Histocompatibility Antigens
• Receptors, Cytokine
• interleukin-35, mouse

Topics

• Animals
• Colitis (immunology, metabolism, pathology)
• Disease Models, Animal
• Female
• Immunity, Mucosal (drug effects, physiology)
• Interleukin-12 Subunit p35 (deficiency, genetics)
• Interleukins (metabolism, pharmacology)
• Intestinal Mucosa (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Minor Histocompatibility Antigens
• Phenotype
• Receptors, Cytokine (deficiency, genetics)
• T-Lymphocytes (pathology, physiology)
• Th1 Cells (pathology, physiology)
• Th17 Cells (pathology, physiology)
• Up-Regulation