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

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.