IMPAIRED STAT3 ACTIVATION FOLLOWING LOCALIZED INFLAMMATORY STIMULUS IN IL-6-DEFICIENT MICE

Interleukin 6 (IL-6) and related gp130-signalling cytokines rapidly ac tivate latent cytoplasmic Stat transcription factors and these are bel ieved to play pivotal roles in the expression of downstream cytokine-r esponsive genes. We have previously shown in IL-6-deficient ((-/-)) mi ce that IL-6 is absolutely required for the transcriptional induction of acute phase response (APR) genes in the liver following localized t issue damage caused by subcutaneous injection of turpentine oil, but i s not required when the inflammatory stimulus is administered systemic ally by intraperitoneal injection of bacterial lipopolysaccharide (LPS ). In this paper we show that Stat3 is the only Stat factor induced in liver tissue upon localized inflammatory stimuli, and that its activa tion is virtually absent in IL-6 deficient mice. During LPS-induced in flammation both Stat1 and Stat3 are activated, and only minor kinetic alterations are detected in IL-6(-/-) mice. These defects are not due to altered intracellular signal transduction, since they could be comp lemented by injection of recombinant cytokines. These results establis h a direct causal relationship in vivo between Stat activation and acu te phase gene expression and define unique functions of IL-6 in Stat3 activation upon localized inflammation. (C) 1997 Academic Press Limite d.