Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury.
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.
Ortiz
Luis A
LA
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Dutreil
Maria
M
Fattman
Cheryl
C
Pandey
Amitabh C
AC
Torres
German
G
Go
Kristina
K
Phinney
Donald G
DG
D000818:Animals; D001853:Bone Marrow; D005355:Fibrosis; D007249:Inflammation; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000502:physiology*; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors; D008171:Lung Diseases / Q000473:pathology*; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D014409:Tumor Necrosis Factor-alpha