Neutrophil elastase up-regulates interleukin-8 via toll-like receptor 4

• Published in: FEBS letters 2003-06, Vol.544 (1), p.129-132
• Main Authors: Devaney, James M, Greene, Catherine M, Taggart, Clifford C, Carroll, Tomás P, O’Neill, Shane J, McElvaney, Noel G
• Format: Article
• Language: English
• Subjects: Blotting, Western; Cell Line; Cell Membrane - metabolism; Cells, Cultured; CF, cystic fibrosis; Cystic fibrosis; Cystic Fibrosis - metabolism; DNA, Complementary - metabolism; ELISA, enzyme-linked immunosorbent assay; Genes, Reporter; HBE, human bronchial epithelia(l); HEK, human embryonic kidney; Humans; Interleukin-8 - metabolism; IRAK, interleukin-1 receptor-associated kinase; Lasers; Leukocyte Elastase - metabolism; Membrane Glycoproteins - metabolism; NE, neutrophil elastase; Neutrophil elastase; Protein Binding; Receptors, Cell Surface - metabolism; RNA - metabolism; RNA, Messenger - metabolism; TLR, toll-like receptor; Toll-Like Receptor 4; Toll-Like Receptors; Transfection; Up-Regulation
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/S0014-5793(03)00482-4

Cystic fibrosis is characterised in the lungs by high levels of neutrophil elastase (NE). NE induces interleukin-8 (IL-8) expression via an IL-1 receptor-associated kinase signalling pathway. Here, we show that these events involve the cell surface membrane bound toll-like receptor 4 (TLR4). We demonstrate that human embryonic kidney (HEK)293 cells transfected with a TLR4 cDNA (HEK-TLR4) express TLR4 mRNA and protein and induce IL-8 promoter activity in response to NE. Treatment of both HEK-TLR4 and human bronchial epithelial cells with NE decreases TLR4 protein expression. Furthermore, a TLR4 neutralising antibody abrogates NE-induced IL-8 production, and induces tolerance to a secondary lipopolysaccharide stimulus. These data implicate TLR4 in NE induced IL-8 expression in bronchial epithelium.