It should be stated that such a mechanism is quite probable, keeping in mind PI3K cancer the effect of IL-6 on the generation of CD8+FoxP3+. MSCs can be both a source and a target of the effects of IL-6. It has been established that under the influence of IL-6, MSCs can transform malignant cells and have tumorogenic properties and this effect is mediated through the mechanism of trans-signaling[98]. These facts raise questions about the interactions between MSCs and the tumor microenvironment which is most commonly very rich in IL-6. INTERACTIONS BETWEEN IL-6 AND IL-10 IL-6 stimulates the secretion of IL-10 by different types of cells and this effect has been proved without any

doubt but the reverse interaction has not been demonstrated so far[96]. The effect of IL-6 on monocytes and dendritic cells is of particular importance for the complex process of immunoregulation. Some publications describe a pathway in which MSCs secrete IL-6 which directly or via induction of autocrine secretion of IL-10 influences the monocyte activity inhibiting their differentiation as dendritic cells[37,81]. Both IL-6 and the autocrine reacting IL-10 also suppress the capacity of DCs to present antigens and thus a population of immature tolerogenic dendritic cells is formed which secrete IL-10[37,38,59,64,69,99,100].

Its effect stimulates the generation of T regulatory cells secreting IL-10 by themselves and potentiating further formation of tolerogenic DCs[62,85]. However, it should be noted that IL-6 and IL-10 are not the only cytokines involved in these complex interactions, for example, prostaglandin E2 (PGE2) which is another immunosuppressive factor secreted by MSCs interacting

with IL-6 in suppression of the DCs differentiation[68]. TRANSFORMING GROWTH FACTOR BETA One of the most prominent immunomodulatory cytokines produced and constitutively secreted by MSCs is transforming growth factor beta (TGFβ). As a pleiotropic cytokine, TGFβ regulates multiple fundamental cellular functions, including proliferation, differentiation, migration, adhesion and apoptosis, that affect numerous biological processes such as development, wound healing, carcinogenesis, angiogenesis and immune Cilengitide responses[101]. TGFβ is a member of a superfamily of dimeric polypeptide growth factors that consists of about 40 members in vertebrates, also including bone morphogenetic proteins (BMPs), activins, inhibins, growth differentiation factors (GDFs) and glial cell line-derived neurotrophic factor (GDNF)[102]. In mammals, three homologous TGFβ isoforms have been identified (TGFβ1, TGFβ2 and TGFβ3) that are controlled by specific genes[103]. Each isoform may exert a distinct role which depends on the target cell type, its state of differentiation and growth conditions[103].