IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis

Interleukin 17A (IL-17A) and complement (C′) activation have each been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We have reported that IL-17A induces epithelial injury via TGF-β in murine bronchiolitis obliterans; that TGF-β and the C′ cascade present signaling interactions in mediating epithelial injury; and that the blockade of C′ receptors mitigates lung fibrosis. In the present study, we investigated the role of IL-17A in regulating C′ in lung fibrosis. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that IL-17A (100 ng/ml; 24 h; n = 5 donor lungs) induces C′ components (C′ factor B, C3, and GPCR kinase isoform 5), cytokines (IL8, -6, and -1B), and cytokine ligands (CXCL1, -2, -3, -5, -6, and -16). IL-17A induces protein and mRNA regulation of C′ components and the synthesis of active C′ 3a (C3a) in normal primary human alveolar type II epithelial cells (AECs). Wild-type mice subjected to IL-17A neutralization and IL-1...