Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.

Abstract

Mesenchymal stem cells (MSCs) have been exploited as cellular vectors to treat a wide array of diseases but the mechanisms responsible for their therapeutic effect remain indeterminate. Previously, we reported that MSCs inhibit bleomycin (BLM)-induced inflammation and fibrosis within the lungs of mice. Interrogation of the MSC transcriptome identified interleukin 1 receptor antagonist (IL1RN) as a potential mediator of this effect. Fractionation studies indicated that MSCs are the principal source of IL1RN in murine bone marrow and that its expression is restricted to a unique subpopulation of cells. Moreover, MSC-conditioned media was shown to block proliferation of an IL-1alpha-dependent T cell line and inhibit production of TNF-alpha by activated macrophages in vitro. Studies conducted in mice revealed that MSC administration was more effective than recombinant IL1RN delivered via adenoviral infection or osmotic pumps in inhibiting BLM-induced increases in TNF-alpha, IL-1alpha, and IL1RN mRNA in lung, IL1RN protein in bronchoalveolar lavage (BAL) fluid, and trafficking of lymphocytes and neutrophils into the lung. Therefore, MSCs protect lung tissue from BLM-induced injury by blocking TNF-alpha and IL-1, two fundamental proinflammatory cytokines in lung. Identification of IL1RN-expressing human MSC subpopulations may provide a novel cellular vector for treating chronic inflammatory diseases in humans.

• Authors: Luis A Ortiz, Maria Dutreil, Cheryl Fattman, Amitabh C Pandey, German Torres, Kristina Go, Donald G Phinney
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 104 Issue 26 Pg. 11002-7 (Jun 26 2007) ISSN: 1091-6490 [Electronic] United States
• PMID: 17569781 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1alpha
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Bone Marrow
• Fibrosis
• Inflammation
• Interleukin 1 Receptor Antagonist Protein (biosynthesis, physiology)
• Interleukin-1alpha (antagonists & inhibitors)
• Lung Diseases (pathology)
• Male
• Mesenchymal Stem Cells (metabolism, physiology)
• Mice
• Mice, Inbred BALB C
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)