INTERLEUKIN-6 AND RELATED CYTOKINES - EFFECT ON THE ACUTE-PHASE REACTION

The acute phase response is the answer of the organism to disturbances of its physiological homeostasis. It consists of a local and a system ic reaction. The latter is characterized by dramatic changes in the co ncentration of some plasma proteins called acute phase proteins. Inter leukin-6 (IL-6) has been identified in vitro and in vivo as the major hepatocyte stimulating factor. Subsequently, additional hepatocyte sti mulating factors, such as leukemia inhibitory factor, oncostatin-M, in terleukin-11 and ciliary neurotrophic factor have been discovered. IL- 6 and related cytokines belong to the so-called alpha-helical cytokine family characterized by four antiparallel helices. IL-6 and IL-6-type cytokines exert their action via plasma membrane receptor complexes c onsisting of specific cytokine binding subunits and a common signal tr ansducing protein gp130. In this presentation we focus on structure/fu nction studies of IL-6, its receptor subunits gp80 and gp130, the inte rnalization of the ligand/receptor complex and a recently elucidated s ignal transduction pathway. We have shown that protein tyrosine kinase s of the JAK family are associated with the cytoplasmic domain of gp13 0 and are activated in response to IL-6. Subsequently, the transcripti on factors - named STATs (signal transducers and activators of transcr iption) - STAT1 alpha and STAT3 are transiently recruited to the cytop lasmic domain of gp130, where they become tyrosine phosphorylated by J AK kinases. In addition to the tyrosine phosphorylation we have observ ed that IL-6 also induces a serine phosphorylation of STAT3. This modi fication occurs with a delayed time-course as compared to the tyrosine phosphorylation and is inhibited by the protein kinase inhibitor H7. We propose that the STAT3 serine phosphorylation is required for trans activation of IL-6 target genes which is also inhibited by H7.