Neutrophil elastase up-regulates interleukin-8 via toll-like receptor 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.
Devaney
James M
JM
Respiratory Research, Department of Medicine, RCSI Education and Research Centre, Smurfit Building, Beaumont Hospital, Dublin 9, Ireland.
Greene
Catherine M
CM
Taggart
Clifford C
CC
Carroll
Tomás P
TP
O'Neill
Shane J
SJ
McElvaney
Noel G
NG
D015153:Blotting, Western; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003550:Cystic Fibrosis / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D007834:Lasers; D019272:Leukocyte Elastase / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011485:Protein Binding; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection; D015854:Up-Regulation
D018076:DNA, Complementary; D016209:Interleukin-8; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D012313:RNA; D019272:Leukocyte Elastase