Endotoxin stimulates hepatocyte interleukin-6 production.
BACKGROUND
Interleukin-6 (IL-6) is a multifunctional cytokine which mediates many aspects of the acute phase response. Although known to be produced by macrophages and other proinflammatory cells, IL-6 is also released by many types of epithelial cells. The present studies were performed to determine if endotoxin and proinflammatory cytokines stimulate the release of IL-6 from native murine hepatocytes.


METHODS
Cultured hepatocytes were treated with various concentrations of lipopolysaccharide (LPS), interleukin-1 (IL-1), or tumor necrosis factor (TNF), in the presence or absence of the IL-1 receptor antagonist (IL-1 RA), an anti-TNF antibody, or dexamethasone. Culture supernatants were assayed for murine IL-6 using an ELISA. The cellular source of IL-6 was investigated using immunohistochemical staining.


RESULTS
Hepatocyte IL-6 production was significantly increased following treatment with LPS, IL-1, and TNF. Combinations of LPS and these cytokines were synergistic in stimulating IL-6 release. Dexamethasone, but not IL-1 RA or an anti-TNF antibody, inhibited hepatocyte production of IL-6 in response to LPS. Immunohistochemical staining revealed that the hepatocytes, and not contaminating nonparenchymal cells, were the principal source of the IL-6 produced in these cultures.


CONCLUSIONS
Murine hepatocytes release significant amounts of IL-6 when exposed to endotoxin or proinflammatory cytokines. LPS appears to stimulate hepatocyte IL-6 production directly, and this effect does not appear to be mediated by IL-1 or TNF.
Panesar
N
N
Department of Surgery, DVA Medical Center, St. Louis, Missouri, USA.
Tolman
K
K
Mazuski
J E
JE
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007150:Immunohistochemistry; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D012795:Sialoglycoproteins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
D000906:Antibodies; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone