IL-10 is the cytokine most commonly discussed in relation to the immunoregulatory effects of MSCs. Nevertheless, the published data demonstrating the secretion of IL-10 by MSCs are quite contradictory. Almost half of the papers Vicriviroc clinical trial discussed in the present review report positive secretion of IL-10 by MSCs[62,66,81-84], while the other half and our own experimental results reject such a possibility[60,64,69,78,85-88]. It is quite logical to support the concept proposed by some authors claiming that MSCs secrete IL-10 under specific
conditions with the inflammatory environment and presence of cytokines (IFNγ, IL-1b and TNFα) which activate certain Toll-like receptors on MSCs[63,65,67]. Although there is no definite opinion about the conditions under which MSCs secrete IL-10, their role is indisputable as a factor which causes indirect stimulation of IL-10 secretion by other cells. It has been shown that MSCs secrete factors which up-regulate the secretion of IL-10 by peripheral blood mononuclear cells (PBMCs)[59], as well
as by tolerogenic macrophages[89] and tolerogenic DCs[37,69,90]. It is also assumed although not undoubtedly proven that MSCs induce generation of Tregs[59,62,90] and our results show that when cultured in MSC conditioned medium, the fraction of CD4+FoxP3+ lymphocytes is increased and this effect is directly induced by MSCs without any involvement of DCs[69]. IL-6 IL-6 was identified in 1986 as a factor stimulating B lymphocytes[91]. It is now known that it is a pleiotropic cytokine with a key role in a multitude of processes such as regulation of the immune response, hematopoiesis, inflammation, cell survival, apoptosis, cell proliferation and oncogenesis[91,92]. The action of IL-6 is mediated by its binding with a membrane IL-6 receptor (mIL-6R) and gp130 as gp130 interacts with the JAK-STAT system[91]. A small fraction of cells show expression
of mIL-6R but almost all cell types express gp130. Cells expressing only gp130 can bind the complex IL-6/soluble IL-6R (sIL-6R), a process known as trans-signaling, which makes a lot of cell populations susceptible to the effects of IL-6[93,94]. Some authors believe that the effect of IL-6 mediated by trans-signaling (IL-6/sIL-6R) is related to a pro-inflammatory effect, while the “classical” Drug_discovery pathway (IL-6/mIL-6R) of activation is connected to the anti-inflammatory action of the cytokine[94]. Such an assumption sounds quite logical, keeping in mind the dual nature of IL-6 because of its pro-inflammatory and/or anti-inflammatory effects[75,82]. IL-6 is routinely described as a classical pro-inflammatory cytokine based on well proven effects of this cytokine. In concert with IL-1 and TNFα, this cytokine induces secretion of acute phase proteins, causes neutrophil recruitment, expression of cell adhesive molecules and a switch from neutrophil to macrophage induced inflammation[72,75,94].