Portal de Periódicos da CAPES

IL-1α mediates cellular cross-talk in the airway epithelial mesenchymal trophic unit

2016; Taylor & Francis; Volume: 4; Issue: 3 Linguagem: Inglês

10.1080/21688370.2016.1206378

2168-8370

Alison R Hill, Jessica Donaldson, Cornelia Blume, Natalie P. Smithers, Liku B. Tezera, Kamran Tariq, Patrick Dennison, Hitasha Rupani, Matthew Edwards, Peter Howarth, Christopher Grainge, Donna E. Davies, Emily J. Swindle,

IL-33, ST2, and ILC Pathways

The bronchial epithelium and underlying fibroblasts form an epithelial mesenchymal trophic unit (EMTU) which controls the airway microenvironment. We hypothesized that cell-cell communication within the EMTU propagates and amplifies the innate immune response to respiratory viral infections.EMTU co-culture models incorporating polarized (16HBE14o-) or differentiated primary human bronchial epithelial cells (HBECs) and fibroblasts were challenged with double-stranded RNA (dsRNA) or rhinovirus.In the polarized EMTU model, dsRNA affected ionic but not macromolecular permeability or cell viability. Compared with epithelial monocultures, dsRNA-stimulated pro-inflammatory mediator release was synergistically enhanced in the basolateral compartment of the EMTU model, with the exception of IL-1α which was unaffected by the presence of fibroblasts. Blockade of IL-1 signaling with IL-1 receptor antagonist (IL-1Ra) completely abrogated dsRNA-induced basolateral release of mediators except CXCL10. Fibroblasts were the main responders to epithelial-derived IL-1 since exogenous IL-1α induced pro-inflammatory mediator release from fibroblast but not epithelial monocultures. Our findings were confirmed in a differentiated EMTU model where rhinovirus infection of primary HBECs and fibroblasts resulted in synergistic induction of basolateral IL-6 that was significantly abrogated by IL-1Ra. This study provides the first direct evidence of integrated IL-1 signaling within the EMTU to propagate inflammatory responses to viral infection.