title: Hepatocytes enhance effects of lipopolysaccharide on liver nonparenchymal cells through close cell interactions.
abstract: The response to lipopolysaccharide (LPS) in the liver is complex, requiring cell-to-cell interactions between hepatocytes and liver nonparenchymal cells (NPC), in particular, Kupffer cells. Previous studies show that cytokines produced by Kupffer cells stimulated with LPS can, in turn, activate hepatocytes. In the present study, we sought to examine whether the reverse, hepatocyte (HC)-NPC interactions, is important in cytokine production in mixed cell cocultures. LPS-stimulated production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 from NPC was augmented in mixed HC-NPC cocultures, as compared with NPC monocultures. This HC-NPC interaction was not observed when hepatocytes were cocultured with NPC from TLR4-mutant (C3H/HeJ) mice or CD14-deficient mice. The effect was partially lost when hepatocytes from lipopolysaccharide-binding protein (LBP)-deficient mice were cocultured with wild-type mice. These data indicate that functional TLR4 and CD14 are required for NPC production of cytokines and that at least one of the critical components from hepatocytes is LBP. The augmented cytokine production by mixed HC-NPC cocultures was abrogated when the cells were separated by a filter system, indicating that close cell interactions are also required for this interaction. Thus, interaction between hepatocytes and NPC are critical for cytokine secretion by NPC.
authors.affiliation: Department of Surgery Laboratories, Montefiore University Hospital, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA. scottm@upmc.edu
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Scott
authors.forename: Shubing
authors.initials: S
authors.lastname: Liu
authors.forename: Grace L
authors.initials: GL
authors.lastname: Su
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
mesh_terms: D000818:Animals; D002450:Cell Communication; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D022781:Hepatocytes / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D009154:Mutation; D011485:Protein Binding; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha