Hepatocellular carcinoma (HCC) is one of the most frequent tumors worldwide with rising incidence. The inflammatory cytokine, interleukin‐6 (IL‐6), is a critical mediator of HCC development. It can signal through two distinct pathways: the IL‐6 classic and the IL‐6 trans‐signaling pathway. Whereas IL‐6 classic signaling is important for innate and acquired immunity, IL‐6 trans‐signaling has been linked to accelerated liver regeneration and several chronic inflammatory pathologies. However, its implication in liver tumorigenesis has not been addressed yet. Here, we show that IL‐6 trans‐signaling, but not IL‐6 classic signaling, is essential to promote hepatocellular carcinogenesis by two mechanisms: First, it prevents DNA‐damage‐induced hepatocyte apoptosis through suppression of p53 and enhances β‐catenin activation and tumor proliferation. Second, IL‐6 trans‐signaling directly induces endothelial cell proliferation to promote tumor angiogenesis. Consequently, soluble gp130 fused to Fc transgenic mice lacking IL‐6 trans‐signaling are largely protected from tumor formation in a diethylnitrosamine/3,3′,5,5′‐tetrachloro‐1,4‐bis(pyridyloxy)benzene model of HCC. Conclusion: IL‐6 trans‐signaling, and not IL‐6 classic signaling, is mandatory for development of hepatocellular carcinogenesis. Therefore, specific inhibition of IL‐6 trans‐signaling, rather than total inhibition of IL‐6 signaling, is sufficient to blunt tumor initiation and impair tumor progression without compromising IL‐6 classic signaling‐driven protective immune responses. (Hepatology 2017;65:89‐103).

Interleukin-6 (IL-6) is the name-giving cytokine of a family of eleven members, including IL-6, CNTF, LIF, and IL-27. IL-6 was first recognized as a B-cell stimulating factor but we now know that the cytokine plays a pivotal role in the orchestration of inflammatory processes as well as in inflammation associated cancer. Moreover, IL-6 is involved in metabolic regulation and it has been shown to be involved in major neural activities such as neuroprotection, which can help to repair and to reduce brain damage. Receptor complexes of all members formed at the plasma membrane contain one or two molecules of the signaling receptor subunit GP130 and the mechanisms of signal transduction are well understood. IL-6 type cytokines can also signal from endomembranes, in particular the endosome, and situations have been reported in which endocytosis of receptor complexes are a prerequisite of intracellular signaling. Moreover, pathogenic GP130 variants were shown to interfere with spatial activation of downstream signals. We here summarize the molecular mechanisms underlying spatial regulation of IL-6 family cytokine signaling and discuss its relevance for pathogenic processes.

IL-6 signaling via its receptor (IL-6R) and co-receptor (gp130) performs multiple roles in regulating metabolic homeostasis. However, gp130 is also expressed systemically in a soluble form (sgp130), which limits soluble IL-6 receptor (sIL-6R)-mediated signaling – also called trans-signaling. Here we find that transgenic peripheral sgp130-mediated trans-signaling blockade induces mature-onset obesity, while differentially affecting age-dependent behavioral determinants of energy expenditure. In youth, trans-signaling blockade increases feeding associated with reduced leptin sensitivity but increases energy expenditure to maintain metabolic balance. In aging, reduced physical activity predisposes mice to adiposity, adipose tissue macrophage recruitment, hepatosteatosis, hyperglycemia, and insulin resistance. Mechanistically, trans-signaling blockade reduces hepatic Stat3 phosphorylation and suppresses PPARα, associated with miR-21 upregulation, while pharmacological activation of PPARα prevents obesity and hepatosteatosis, and rescues insulin sensitivity. Together these experiments reveal a role for peripheral IL-6 trans-signaling in metabolic homeostasis and provide clinical significance to elevated sgp130 levels found in some obese and diabetic patients.

Proteolysis is an irreversible post-translational modification that regulates protein function and signal transduction. This includes remodelling of the extracellular matrix, release of membrane-bound cytokines and receptor ectodomains, as well as the initiation of intracellular signalling cues. Members of the adamalysin protease subfamily, in particular the ADAM (a disintegrin and metalloprotease) and ADAMTS (the ADAM containing thrombospondin motif) families, are involved in these processes. This review presents an overview of how ADAM and ADAMTS proteins are involved in liver physiology and pathophysiology.

Meprin β is a dimeric type I transmembrane protein and acts as an ectodomain sheddase at the cell surface. It was shown that meprin β cleaves the amyloid precursor protein (APP), thereby releasing neurotoxic amyloid β peptides and implicating a role of meprin β in Alzheimer's disease. In order to identify non-proteolytic regulators of meprin β, we performed a split ubiquitin yeast two-hybrid screen using a small intestinal cDNA library. In this screen we identified tetraspanin 8 (TSPAN8) as interaction partner for meprin β. Since several members of the tetraspanin family were described to interact with metalloproteases thereby affecting their localization and/or activity, we hypothesized similar functions of TSPAN8 in the regulation of meprin β. We employed cell biological methods to confirm direct binding of TSPAN8 to meprin β. Surprisingly, we did not observe an effect of TSPAN8 on the catalytic activity of meprin β nor on the specific cleavage of its substrate APP. However, both proteins were identified being present in tetraspanin-enriched microdomains. Therefore we hypothesize that TSPAN8 might be important for the orchestration of meprin β at the cell surface with impact on certain proteolytic processes that have to be further identified.