It is quite reasonable to assume that the types and the combinations kinase inhibitor of chemokines expressed by MSCs could vary depending on the specific microenvironment

and contacts with surrounding cells, especially as the latter are immune cells. The target cells attracted by the cited group of chemokines are neutrophils, monocytes, eosinophils, basophils, T and B lymphocytes, DCs, NK cells, hematopoietic and endothelial progenitors[142]. These data might suggest that the MSC secreted chemokines just have a chemoattractive effect which does not seem to be related to immunoregulation. Nevertheless, chemokines could be considered a crucial element in exerting the immunomodulatory activity of MSCs in vivo because it is assumed that the chemokines mediate the interactions between MSCs and other types of immunocompetent cells. By attracting immune cells in close proximity with MSCs, the secreted chemokines provide direct cell-to-cell contact as well as a possible paracrine immunoregulatory

effect of other effector molecules also secreted by the MSCs. Thus, Ren et al[143] established that the chemokines CXCL9, CXCL10 and CXCL11 stimulate the migration of T cells in the proximity of MSCs and that these cells are targets of the local suppressive effect of nitrogen oxide secreted by the stem cells. Nevertheless, MSC secreted chemokines predominantly exert chemotactic activity and many data point to their direct role in the process of immunomodulation. Monocyte chemoattractant protein-1 (CCL2/MCP-1) CCL2 is a key chemokine regulating the recruitment and migration of cells of the monocyte-macrophage system. It is secreted from monocytes and other types of cells, including endothelial cells,

microglial cells, NK cells etc[144]. CCL2 is related to multiple disorders associated with accumulation of activated monocytes, including atherosclerosis, bronchial asthma, inflammatory processes of the intestines etc[144]. CCL2 plays a role of direct mediator for angiogenesis and its effect is manifested by formation of new blood vessels, as proven in animal models[145]. Much data shows that CCL2 modulates the T cell immune response, causing a switch from Th0 to Th2 with predominant secretion of IL-4[146,147]. The role of CCL2 in immune regulation has been proven by the fact that it induces secretion of MCPIP1 (MCP-1 induced protein-1) which acts Dacomitinib as RNAse and stimulates mRNA degradation for some cytokines such as IL-6 and IL-1[148]. MCPIP1 acts as a negative regulator of CCL2 and inhibits macrophage activation[149]. It has also been established that CCL2, CCL5 and some other chemokines induce proliferation and activation of specific CD56+ cytolytic cells designated as CHAK (CC chemokine-activated killer) which act similarly to the IL-2 activated cells (LAK)[150]. Some recent studies report that CCL2 is one of the factors associated with the immune modulation caused by MSCs. Secretion of this chemokine by the MSCs causes enhanced FasL dependent apoptosis of T lymphocytes.