Abstract
The interleukin-1 family member IL-33 participates in both innate and adaptive T helper-2 immune cell responses in models of lung disease. The IL-6-type cytokine Oncostatin M (OSM) elevates lung inflammation, Th2-skewed cytokines, alternatively activated (M2) macrophages, and eosinophils in C57Bl/6 mice in vivo. Since OSM induces IL-33 expression, we here test the IL-33 function in OSM-mediated lung inflammation using IL-33-/- mice. Adenoviral OSM (AdOSM) markedly induced IL-33 mRNA and protein levels in wild-type animals while IL-33 was undetectable in IL-33-/- animals. AdOSM treatment showed recruitment of neutrophils, eosinophils, and elevated inflammatory chemokines (KC, eotaxin-1, MIP1a, and MIP1b), Th2 cytokines (IL-4/IL-5), and arginase-1 (M2 macrophage marker) whereas these responses were markedly diminished in IL-33-/- mice. AdOSM-induced IL-33 was unaffected by IL-6-/- deficiency. AdOSM also induced IL-33R+ ILC2 cells in the lung, while IL-6 (AdIL-6) overexpression did not. Flow-sorted ILC2 responded in vitro to IL-33 (but not OSM or IL-6 stimulation). Matrix remodelling genes col3A1, MMP-13, and TIMP-1 were also decreased in IL-33-/- mice. In vitro, IL-33 upregulated expression of OSM in the RAW264.7 macrophage cell line and in bone marrow-derived macrophages. Taken together, IL-33 is a critical mediator of OSM-driven, Th2-skewed, and M2-like responses in mouse lung inflammation and contributes in part through activation of ILC2 cells.
Highlights
The interleukin-1-type cytokine IL-33 acts as an “alarmin” or damage signal that facilitates the recruitment of inflammatory cells in T helper-2 (Th2) immune cell models of lung disease [1]
We have recently shown that the gp130/IL-6-family cytokine Oncostatin M (OSM) can upregulate the nuclear expression of IL-33 in alveolar epithelial cells in the mouse lung [14]
We have previously shown that pulmonary overexpression of OSM upregulates expression of IL-33 in the lungs of C57Bl/6 and BALB/c mice in alveolar epithelial cells in vivo and in mouse lung epithelial cell lines in vitro [14]
Summary
The interleukin-1-type cytokine IL-33 acts as an “alarmin” or damage signal that facilitates the recruitment of inflammatory cells in T helper-2 (Th2) immune cell models of lung disease [1]. Transgenic overexpression of soluble IL-33 in mice results in lethal inflammation and autoimmunity [6], and elevated levels of IL-33 are found in mouse models of allergic airway inflammation and in severe asthma in human patients [7, 8]. We have recently shown that the gp130/IL-6-family cytokine Oncostatin M (OSM) can upregulate the nuclear expression of IL-33 in alveolar epithelial cells in the mouse lung [14]. The OSM receptor is composed of a heterodimeric gp130-OSMRβ complex [15] that is expressed by lung stromal cells, and among gp130 cytokines, OSM is a potent inducer of gp130 signaling that leads to expression of proinflammatory target genes and extracellular matrix remodelling [16, 17]. The results show that IL-33 is required for OSM-induced inflammatory functions in the mouse lung
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