Proinflammatory effects of pancreatic elastase are mediated through TLR4 and NF-kappaB.
Pancreatic elastase has been implicated in the pathophysiology of severe acute pancreatitis, characterized by systemic inflammatory response, distant organ failure, and high mortality. Here we show that pancreatic elastase activates transcription factors NF-kappaB, AP-1, and NFAT in human myeloid cells (U-937 and THP-1) in culture. Pancreatic elastase also induces TNF-alpha secretion and increased expression of CD11b in THP-1 cells which can be inhibited by neutralizing anti-Toll-like receptor 4 (TLR4) antibodies. NF-kappaB blocking agents (MG-132, PGA1) prevented elastase-induced TNF-alpha secretion from THP-1 cells. Our results suggest that pancreatic elastase-induced proinflammatory effects are mediated by TLR4 and NF-kappaB in human myeloid cells.
Hietaranta
Antti
A
Department of General and Gastroenterological Surgery, Helsinki University Central Hospital, Haartmaninkatu 4, 00029-HUS, Helsinki, Finland. antti.hietaranta@hus.fi
Mustonen
Harri
H
Puolakkainen
Pauli
P
Haapiainen
Reijo
R
Kemppainen
Esko
E
D015153:Blotting, Western; D039481:CD11b Antigen / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation; D008562:Membrane Glycoproteins / Q000378:metabolism*; D022423:Myeloid Cells; D016328:NF-kappa B / Q000378:metabolism*; D010196:Pancreatic Elastase / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013997:Time Factors; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014158:Transcription, Genetic; D014162:Transfection; D020298:U937 Cells
D039481:CD11b Antigen; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D010196:Pancreatic Elastase