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.