title: TGF-β1 limits the onset of innate lung inflammation by promoting mast cell-derived IL-6.
abstract: TGF-β1 is an important suppressive mediator of inflammation, but it can also drive fibrosis and remodeling in the lung. In response to intratracheal LPS, neutrophils migrate into the lung, and TGF-β1 was suggested to protect against the ensuing injury. However, the mechanisms for this protective role remain unknown. Using a model of acute lung injury, we demonstrate that TGF-β1 decreases neutrophil numbers during the onset of injury. This was due to increased apoptosis rather than reduced migration. We demonstrate that TGF-β1 does not directly regulate neutrophil apoptosis but instead functions through IL-6 to promote neutrophil clearance. rIL-6 is sufficient to promote neutrophil apoptosis and reduce neutrophilia in bronchoalveolar lavage fluid, while IL-6 increases rapidly following LPS-induced injury. Mast cells are a critical source of IL-6, because mast cell-deficient mice exhibit increased neutrophil numbers that are reduced by reconstitution with wild-type, but not IL-6(-/-), mast cells. Although IL-6 diminishes neutrophilia in mast cell-deficient mice, TGF-β1 is ineffective, suggesting that these effects were mast cell dependent. Taken together, our findings establish a novel pathway through which TGF-β1, likely derived from resident regulatory T cells, controls the severity and magnitude of early innate inflammation by promoting IL-6 from mast cells.
authors: Division of Allergy/Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
authors: Kirthana
authors: K
authors: Ganeshan
authors: Laura K
authors: LK
authors: Johnston
authors: Paul J
authors: PJ
authors: Bryce
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D005260:Female; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000009:adverse effects; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D011014:Pneumonia / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D053773:Transforming Growth Factor beta1
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