Interleukin-6 belongs to the neuropoietic cytokine family, all of which signal through the transmembrane gp130 receptor and act upon the JAK/STAT pathway. Adult neural stem/progenitor cells do not express the IL-6 receptor; however, IL-6 can first bind to the soluble form of IL-6R and then bind directly to the gp130 receptor expressed on neural stem/progenitor cells, enabling the cytokine to act. Interleukin-6 (IL-6) is a multifunctional cytokine that plays a major role in the inflammatory responses and is the primary inducer of acute-phase proteins. IL-6 was originally identified as a T cell-derived factor, which induced the final maturation of B lymphocytes into antibody-forming plasma cells.
IL-6 decreases the proliferation and survival of neural stem/progenitor cells. However, there are conflicting data on the role of IL-6 in neural stem/progenitor cell differentiation. Vallières et al. found that IL-6 decreases differentiation of neural stem/progenitor cells in the subgranular zone (SGZ) of the hippocampus. However, under some conditions differentiation is increased. IL-6 actually stimulates differentiation in human fetal neural stem/progenitor cell taken from both the striatum and hippocampus. Similarly, highly active IL-6 (H-IL-6) increases differentiation of embryonic stem cells into glutamate responsive neurons and two astroglia cell types via the MAPK/CREB pathway. H-IL-6 also enhances gliogenesis through the STAT-3 pathway. In accordance with these findings, IL-6 promotes neurite elongation of embryonic neural stem/progenitor cells in the SGZ.
Additionally, IL-6 can promote differentiation of neural stem/progenitor cells at low concentrations. A potential explanation of these beneficial effects could be found via the interaction of IL-6 with other cytokines produced in the inflammatory response. IL-6 reduces pro-inflammatory TNF-α and IL-1 production and helps circulate IL-1 receptor antagonist. Further studies are needed to determine when IL-6 is detrimental or beneficial to the differentiation of neural stem/progenitor cells. These conflicting data could also be explained by the finding that IL-6 expression varies as a function of age, indicating that the role IL-6 plays may change over time. Initially, IL-6 may help embryonic neural stem/progenitor cells differentiate, but later, long-term expression is detrimental. Like many cytokines, different concentrations and contexts will lead to distinct physiological effects. Even with a beneficial role in differentiation, if IL-6 is chronically over-expressed, reduced neurogenesis ensues. These results suggest that IL-6 levels should be reduced for effective neural stem cell treatments.
IL-6 promotes the differentiation, proliferation, or both in vitro of cells belonging to several hematopoietic lineages at different stages of their maturation. Among these effects, those on hematopoietic stem and progenitor cells are well documented. IL-6, in combination with IL-3, enhances the formation of multilineage blast cell colonies as well as the proliferation of stem cells in vitro. This synergism has been demonstrated in vivo in several model systems designed to evaluate its effects on the stem cell compartment.
• Breton J, et al. Impact of cytokines on neural stem/progenitor cell fate[J]. J Neurol Neurophysiol, 2011: S4.
• Bernad A, et al. Interleukin-6 is required in vivo for the regulation of stem cells and committed progenitors of the hematopoietic system[J]. Immunity, 1994, 1(9): 725-731.