Beta2-integrin-induced p38 MAPK activation is a key mediator in the CD14/TLR4/MD2-dependent uptake of lipopolysaccharide by hepatocytes.
The liver is the main organ that clears circulating lipopolysaccharide (LPS), and hepatocytes are a major cell type involved in LPS uptake. Little is known about the mechanisms for LPS internalization in hepatocytes and what signaling pathways are involved. We show here that LPS uptake is initiated after formation of a multi-receptor complex within lipid rafts. We find that essential components for LPS uptake are CD14, TLR4, MD2, and the beta2-integrin CD11b/CD18. Activation of p38 MAPK is also essential for the initiation of LPS uptake, and interestingly, we show that this activation is not through TLR4 signaling by MyD88 but through activation of TIRAP via CD11b/CD18. However, TLR4/MD2 remain essential components at the cell surface as part of the LPS receptor complex. We therefore suggest novel roles for TLR4/MD2, CD11b/CD18, TIRAP, and p38 MAPK in LPS uptake by hepatocytes.
Scott
Melanie J
MJ
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Billiar
Timothy R
TR
D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D004789:Enzyme Activation; D022781:Hepatocytes / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000096:biosynthesis*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis*; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D048051:p38 Mitogen-Activated Protein Kinases