HUMAN HEPATOCYTES EXPRESS AN ARRAY OF PROINFLAMMATORY CYTOKINES AFTERAGONIST STIMULATION OR BACTERIAL INVASION

Inflammatory cells infiltrate the liver in response to microbial infec tion or hepatic injury. To assess the potential role hepatocytes may p lay in initiating or amplifying the acute inflammatory response in the liver, we used three human hepatocyte cell lines and primary human he patocyte cultures to characterize the repertoire of cytokines that can be expressed and regulated in hepatocytes in response to agonist stim ulation or bacterial infection. As reported herein, a proinflammatory cytokine gene program that includes C-X-C and C-C chemokines [interleu kin-8 (IL-8), growth related (GRO)-alpha, GRO-beta, GRO-gamma, epithel ial neutrophil activating peptide-78 (ENA-78), and RANTES] and the cyt okines tumor necrosis factor-alpha (TNF-alpha) and macrophage colony s timulating factor was upregulated in human hepatocytes after stimulati on with IL-1 alpha or TNF-alpha or bacterial invasion. In contrast, ex pression of hematopoietic/lymphoid growth factors by the same cells wa s either downregulated (erythropoietin and stem cell factor) or unchan ged (IL-7 and IL-15) in response to the identical stimuli. Hepatocytes did not express cytokines that often are associated with the regulati on of antigen-specific immune responses (IL-2, IL-4, IL-5, IL-10, IL-1 2p40, IL-13, and interferon-gamma) or genes for several other proinfla mmatory cytokines [IL-1 alpha, IL-6, monocyte chemotactic protein-1 (M CP-1), and MCP-S] or hematopoietic growth factors (granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, IL-3, and IL-11). Together, these studies suggest that hepatocytes can both initiate and amplify acute inflammatory responses in the liver t hrough the regulated expression and secretion of a specific array of p roinflammatory cytokines.