INTERLEUKIN-6 AND CAAT ENHANCER BINDING-PROTEIN BETA-DEFICIENT MICE ACT AS TOOLS TO DISSECT THE IL-6 SIGNALING PATHWAY AND IL-6 REGULATION/

Interleukin-6 (IL-6) is a pleiotropic cytokine playing important roles in immunity, hemopoiesis and inflammation. IL-6 signalling is known t o involve the activation of two independent transcription factors: Sta t3 (through phosphorylation by Jak kinases) and C/EBP beta (through ac tivation of the ras pathway). In addition, C/EBP beta is believed to a ct as a transcriptional activator of the IL-6 gene itself. Making use of IL-6-deficient mice, we have recently demonstrated that IL-6 is ess ential for the induction of acute phase mRNAs in the liver upon locali zed tissue damage, but not upon systemically induced inflammation. Her e we show that the defective mRNA lnduction is paralleled by a defecti ve activation of Stat3, thus establishing a direct relationship betwee n IL-6 function, Stat3 activation and acute phase genes induction. On the other hand, making use of C/EBP beta-deficient mice, we show that the induction of IL-6 by a variety of stimuli does nor require C/EBP b eta activity. In contrast to tile predicted activating role of C/EBP b eta, IL-6 levels are increased in the C/EBP beta-deficient mice, sugge sting that C/EBP beta may act as a down-modulator of the IL-6 gene. Th rough the generation of C/EBP beta, IL-6 double mutant mice we show th at IL-6 hyperproduction is responsible for the development of the Cast leman's like lymphoproliferative disease described in the C/EBP beta-d eficient mice, since the disorder is completely blocked by inactivatin g the IL-6 gene.