Interleukin-6 production by peritoneal mesothelial cells and its regulation by inflammatory factors in rats administered carbon tetrachloride intraperitoneally

Abstract We previously reported that a high level of interleukin-6 (IL-6), which is protective against CCl 4 -induced hepatotoxicity, is produced in the peritoneal cavity in the early period after ip carbon tetrachloride (CCl 4 ) administration. The objective of this study was to identify the tissues and cells involved in IL-6 production and clarify the mechanisms underlying its regulation. IL-6 mRNA levels increased significantly in the serous membranes of the mesentery and peritoneum, but not in the parenchymal organs including liver, kidney and spleen, 3 h after ip CCl 4 administration. Peritoneal mesothelial cells (PMCs), a major cell population in serous membranes, were isolated from rat peritoneal walls by trypsin digestion and cultured with peritoneal exudate fluid (PEF) from CCl 4 -administered rats. PMCs produced a high level of IL-6 in the presence of PEF recovered 0.5 h after ip CCl 4 administration. Analyses of PEF revealed that the levels of prostaglandin E 2 (PGE 2 ), histamine, IL-1α, IL-1β and tumor necrosis factor-α (TNF-α) increased immediately after ip CCl 4 administration. These inflammatory factors, except for histamine, stimulated IL-6 production to varying degrees, in the following order: IL-1α > IL-1β > TNF-α ≫ PGE 2 . In summary, the present study indicates that the high level of IL-6 observed in the rat peritoneal cavity after ip CCl 4 administration is at least partially produced by PMCs stimulated cooperatively with IL-1α, IL-1β, TNF-α and PGE 2 . These inflammatory factors may be released from tissues or cells either stimulated or injured directly by CCl 4 .