Interleukin-6 (IL-6) is a cytokine originally identified almost 30 years ago as a B-cell differentiation factor, capable of inducing the maturation of B cells into antibody-producing cells. As with many other cytokines, it was soon realized that IL-6 was not a factor only involved in the immune response, but with many critical roles in major physiological systems including the nervous system. IL-6 is now known to participate in neurogenesis (influencing both neurons and glial cells), and in the response of mature neurons and glial cells in normal conditions and following a wide arrange of injury models. In many respects, IL-6 behaves in a neurotrophin-like fashion, and seemingly makes understandable why the cytokine family that it belongs to is known as neuropoietins. Its expression is affected in several of the main brain diseases, and animal models strongly suggest that IL-6 could have a role in the observed neuropathology and that therefore it is a clear target of strategic therapies.

Summary Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of viral hepatitis, insulin resistance, hepatosteatosis and non-alcoholic steatohepatitis (NASH), disorders that increase risk of hepatocellular carcinoma (HCC). To determine whether and how ER stress contributes to obesity-driven hepatic tumorigenesis we fed wild type (WT) and MUP-uPA mice, in which hepatocyte ER stress is induced by plasminogen activator expression, with high fat diet. Although both strains were equally insulin resistant, the MUP-uPA mice exhibited more liver damage, immune infiltration and increased lipogenesis, and as a result displayed classical NASH signs and developed typical steatohepatitic HCC. Both NASH and HCC development were dependent on TNF produced by inflammatory macrophages that accumulate in the MUP-uPA liver in response to hepatocyte ER stress.

Antigen presentation, but not antibody secretion, by B cells drives CNS autoimmunity induced by immunization with human MOG.

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The cellular sources of interleukin-6 (IL-6) that are relevant for the differentiation of TH17 cells remain unclear. Here, we used a novel strategy of IL-6 conditional deletion of distinct IL-6-producing cell types to show that Sirpα+ dendritic cells (DC) were essential for the generation of pathogenic TH17 cells. During the process of cognate interaction, Sirpα+ DCs trans-presented IL-6 to T cells using their own IL-6Rα. While ambient IL-6 was sufficient to suppress the induction of the transcription factor Foxp3 in T cells, IL-6 trans-presentation by DC-bound IL-6Rα (here defined as IL-6 cluster signaling) was required to prevent premature induction of IFN-γ in T cells and to generate pathogenic TH17 cells in vivo. These findings will guide therapeutic approaches for TH17-mediated autoimmune diseases.