RESUMO
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.
Assuntos
Tetracloreto de Carbono/toxicidade , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Heme Oxigenase (Desciclizante)/biossíntese , Interleucina-6/metabolismo , Fígado/efeitos dos fármacos , Animais , Anticorpos Bloqueadores/farmacologia , Relação Dose-Resposta Imunológica , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Heme Oxigenase (Desciclizante)/genética , Injeções Intraperitoneais , Interleucina-6/sangue , Interleucina-6/imunologia , Fígado/enzimologia , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Fator de Transcrição STAT3/biossíntese , Fator de Transcrição STAT3/genética , Regulação para CimaRESUMO
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).
