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The physiological function of interleukin-6 within the central nervous system (CNS) is complex; interleukin-6 exerts neurotrophic and neuroprotective effects and yet can also function as a mediator of inflammation, demyelination, and astrogliosis depending on the cellular context. However, the roles of interleukin-6 in astrocytes are poorly understood. In the present study, we investigated the effect of the pro-inflammatory cytokine interleukin-6 on the production of the inflammatory mediator prostaglandin E(2) in mouse astrocytes. Interleukin-6 stimulated prostaglandin E(2) production in a time-dependent fashion via a rapid and transient induction of cyclooxygenase-2 messenger RNA, followed by cyclooxygenase-2 protein synthesis. Interleukin-6 may act on the nervous system by interacting with its specific soluble interleukin-6 receptor and the signal transducer 130-kDa glycoprotein. Simultaneous treatment of astrocytes with interleukin-6 and soluble interleukin-6 receptor caused marked induction of prostaglandin E(2) synthesis, and this effect was suppressed by adding a neutralizing antibody against soluble interleukin-6 receptor. Furthermore, the mouse 130-kDa glycoprotein antibody suppressed prostaglandin E(2) formation induced by interleukin-6, as well as interleukin-6/soluble interleukin-6 receptor complexes, in a dose-dependent manner. These results indicate that interleukin-6/soluble interleukin-6 receptor complexes and the signal transducer 130-kDa glycoprotein play an important role in the regulation of cyclooxygenase-2 expression and subsequent prostaglandin E(2) formation in mouse astrocytes and that interleukin-6 is an important regulator of immune and inflammatory processes in the CNS.

We previously reported that interleukin-6 (IL-6) was locally produced in the early period after intraperitoneal (i.p.) or subcutaneous carbon tetrachloride (CCl4) administration, but not after oral (p.o.) administration. In the present study, we focused on the up-regulation of stress-inducible proteins induced by IL-6 after i.p. CCl4 administration. The expression of heme oxygenase-1 (HO-1) (EC 1.14.99.3) mRNA and protein were induced more in rats administered CCl4 via the i.p. route, compared with the p.o. route; however, expression of heat shock protein (HSP) 72 and HSP90 mRNA were increased to similar extents in both experimental groups. The induction of HO-1 mRNA and protein after i.p. CCl4 administration were significantly reduced after pretreatment with anti-rat IL-6 antibody. Activation of the signal transducer and activator of transcription factor 3 (STAT3), which promotes HO-1 expression, peaked together with plasma levels of IL-6 after i.p. CCl4 administration, suggesting that hepatic HO-1 expression was increased by IL-6 via the Janus kinase/STAT3 pathway. The present data indicate that hepatic HO-1 is up-regulated by endogenously produced IL-6, in addition to its up-regulation by heme derived from cytochrome P450 which has already been reported in rats administered i.p. CCl4. The up-regulation of hepatic HO-1 expression may reduce the tissue injury to livers caused by CCl4.

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-1alpha, IL-1beta and tumor necrosis factor-alpha (TNF-alpha) 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-1alpha>IL-1beta>TNF-alpha>>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-1alpha, IL-1beta, TNF-alpha and PGE(2). These inflammatory factors may be released from tissues or cells either stimulated or injured directly by CCl(4).

IL-6 induction depending on the mode of carbon tetrachloride (CCl4) administration was investigated in rats. After the intraperitoneal (i.p.) administration of CCl4 in 50% corn oil at 1.0 ml/kg body weight, IL-6 level markedly increased in plasma and peaked at 4h. TNF-alpha and IL-1beta levels gradually increased, reaching the maximum at 24h. IL-10 level transiently peaked at 4h and then decreased, but later further increased, reaching the second peak at 24h. Plasma alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities peaked at 24h. As the vehicle-to-CCl4 ratio increased, the level of IL-6 decreased and the activities of ALT and SDH increased. After oral CCl4 administration, IL-6 was not significantly detected. IL-6 level in peritoneal exudate fluid (PEF) increased simultaneously with plasma IL-6 level after i.p. CCl4 administration, but the total amount of PEF IL-6 was 37-fold as much as that of plasma IL-6, in contrast to the result that the total amount of plasma IL-6 was 19-fold as much as that of PEF IL-6 after i.p. lipopolysaccharide administration. These results suggest that i.p. administration of CCl4 dissolved in a small amount of vehicle selectively induces a high production of IL-6 in the peritoneal cavity early after the administration. Since IL-6 is a protective cytokine against hepatotoxicity, its induction should be taken into consideration during analysis of data obtained using the CCl4-induced liver injury model.

The physiological function of interleukin-6 within the central nervous system (CNS) is complex; interleukin-6 exerts neurotrophic and neuroprotective effects and yet can also function as a mediator of inflammation, demyelination, and astrogliosis depending on the cellular context. However, the roles of interleukin-6 in astrocytes are poorly understood. In the present study, we investigated the effect of the pro-inflammatory cytokine interleukin-6 on the production of the inflammatory mediator prostaglandin E2 in mouse astrocytes. Interleukin-6 stimulated prostaglandin E2 production in a time-dependent fashion via a rapid and transient induction of cyclooxygenase-2 messneger RNA, followed by cyclooxygenase-2 protein synthesis. Interleukin-6 may act on the nervous system by interacting with its specific soluble interleukin-6 receptor and the signal transducer 130-kDa glycoprotein. Simultaneous treatment of astrocytes with interleukin-6 and soluble interleukin-6 receptor caused marked induction of prostaglandin E2 synthesis, and this effect was suppressed by adding a neutralizing antibody against soluble interleukin-6 receptor. Furthermore, the mouse 130-kDa glycoprotein antibody suppressed prostaglandin E2 formation induced by interleukin-6, as well as interleukin-6/soluble interleukin-6 receptor complexes, in a dose-dependent manner. These results indicate that interleukin-6/soluble interleukin-6 receptor complexes and the signal transducer 130-kDa glycoprotein play an important role in the regulation of cyclooxygenase-2 expression and subsequent prostaglandin E2 formation in mouse astrocytes and that interleukin-6 is an important regulator of immune and inflammatory processes in the CNS. [ABSTRACT FROM AUTHOR]