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

Proc Natl Acad Sci U S A. 2007 Jun 26;104(26):11002-7. doi: 10.1073/pnas.0704421104. Epub 2007 Jun 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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