Early hepatocyte DNA synthetic response posthepatectomy is modulated by IL-6 trans-signaling and PI3K/AKT activation.

BACKGROUND & AIMS: Interleukin-6 (IL-6) is a crucial factor in liver regeneration following partial hepatectomy (PH); however, the role of IL-6 and IL-6 trans-signaling in particular, in hepatocyte mitosis remains controversial. IL-6 trans-signaling relies upon the release of the soluble IL-6R (sIL-6R), which binds IL-6 to form an agonistic IL-6/sIL-6R complex. Herein we have examined the hypothesis that IL-6 trans-signaling plays a crucial and distinct role in liver regeneration following PH. METHODS: The specific IL-6/sIL-6R antagonist, sgp130Fc, was expressed in mice and analyzed for its effect on hepatocyte mitosis following PH. Alternatively, we examined the effect of the IL-6/sIL-6R super-agonist, Hyper-IL-6, or IL-6 expressed either alone or in combination with hepatocyte growth factor (HGF) on hepatocyte mitosis in the absence of PH. RESULTS: Following PH, the dramatic rise of circulating IL-6 levels is accompanied by a concurrent ∼2-fold increase in circulating sIL-6R levels. Ectopic expression of sgp130Fc reduced hepatocyte mitosis by about 40% at early times following PH, while substantially reducing AKT, but not STAT3, activation. But, ectopic Hyper-IL-6 expression in mice without PH was not mitogenic to hepatocytes in vivo. Rather, Hyper-IL-6, but not IL-6, markedly increased HGF-induced hepatocyte mitosis. This cooperative effect correlated with greater resistance of HIL-6 than IL-6 to HGF-mediated reduction of AKT activation, rather than changes in STAT3 or MAPK signaling, and was completely blocked by PI3K inhibition. CONCLUSIONS: Following PH, IL-6/sIL-6R cooperates with growth factors, through a PI3K/AKT-dependent mechanism to promote entry of hepatocytes into the cell cycle.

State of the art therapy in multiple myeloma and future perspectives.

Treatment for multiple myeloma (MM) has changed beyond recognition in the past decades. While until the early 1980s, MM caused a slow progressive decline in quality of life until death after about two years, today's patients can expect a 50% chance of achieving a complete remission, a median survival time of five years and a 20% chance of surviving longer than ten years. State of the art therapy comprises: evidence-based supportive care; highly effective and well tolerated chemotherapeutic regimens; and for patients qualifying for intensive high-dose conditioning, autologous haematopoietic stem cell transplantation (HSCT) is an option. Maintenance therapy has become increasingly important since a majority of patients is able to achieve a good remission after front-line therapy which is aimed to be preserved as long as possible. In addition, improved understanding of the disease biology has led to the development of novel biological treatment agents, such as thalidomide, bortezomib and others, targeted at cellular mechanisms and interactions, e.g. with the bone marrow microenvironment. These strategies are incrementally integrated into modern MM care. This review considers recent clinical advancements in anti-myeloma strategies and provides an overview of the state of the art management of MM patients.