NK enter into the circulation after creation and

NK cells activity, as one of the cytotoxic innate immune system lymphocytes, are generally involved in the early defenses against both autologous malignant and allogeneic cells withstand types of stress, such as infection (1). The large papulation of the NK cells in a health body are found in the spleen, liver, gut, and uterus. Also, 10–15% of all circulating lymphoid cells are consists of this cells and they have approximately 7–10 days half-life in circulation (2-6). NK cells enter into the circulation after creation and maturation are accrue in bone marrow, lymph nodes, spleen, tonsils, and thymus (7). Under stimulation by stromal cell-derived factor (SDF) and interleukin-7 (IL-7), Nk cells development are switched from CD34+ hematopoietic stem cells (HSCs) differentiation into the bone marrow (8). Through the NK cells differentiation pathway, early after generation of common lymphoid progenitor cells (CLPCs) from HSCs, NK/T progenitors (NK/TPCs) and also B cells create by CLPCs differentiation. In this proses, NK cells and also T cells directly generate from the NK/TPCs (9). In the above pathway, both in vivo and in vitro conditions, IL-2 and IL-15 play a key role in the mature NK cells formation from the NK/TPCs (6) (Figure 1). The mature NK cells characterized by expression of surface markers such as CD16 (Fc?RIII) and CD56 in humans and also NK1.1 or NK1.2 in mice. It should been know that the surface immunoglobulins (Ig) B cell receptors, T-cell antigen receptors (TCR), and CD3 never express in this cells (10, 11). On the other view, NK cells are classified by expression of CD56 surface antigen. About 90% of NK cells called as CD56dim NK cells which express low levels of CD56, while 5-10% of NKs express high levels of CD56 and calls called CD56bright NK cells (12). It should be know that the CD56dim NK cells are more cytotoxic than CD56bright NKs, but the CD56bright NK cells are the primary papulation of NK cell-derived immune regulatory cytokines (13).

NK cells activating and migration proses from peripheral blood to the targeted tissue are largely mediated by expression of tissue specific cytokines and chemokines (14). It has been proved that some of the cytokine members including interleukin-2 (IL-2), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), and interferon-gamma (IFN-?) have a vital role in NKs activation and trafficking toward the SDs (15, 16). On the other hand, some studies have shown that the activated NK cells express variations of CXCR1, CXCR4, CX3CR1, CXCR2, CXCR3, CCR2, CCR4, CCR5,  and CCR8 chemokine receptors (18-20). Also, chemotactic migration of the resting human NK cells in response to tissue expression of CCL2-5, CCL7-8, CX3CL1 and CXCL9-12 have shown (21, 22). Through migration, expression and release of some matrix metalloproteinases (MMPs) members for tumor extracellular matrix (ECM) degradation and are need to the NK cells extravasate and induction their cytotoxicity effect. The ability of human activated NK cells for expression of MMPs family has carefully understood. In this base, MMP-1, MMP-2, MMP-9, MMP-13, MT1-MMP, MT2-MMP, MT3-MMP, and MT6-MMP expression ledes to human NKs actively migration (23-25). Meanwhile, the role of the cytokines and the chemokine in the NK cells MMPs expression not be ignored. Interleukin-1 alpha and betta (IL-1? and ?) (26). IL-2, interleukin-6 (IL-6), and interleukin-18 (IL-18) as the main cytokines and also CCL2, CCL3, CCL8, CXCL10, and CXCL12 as the main chemokines stimulates NK cells to expression of the MMPs (24, 26).

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By stimulation of the NK cells cytotoxicity receptors (NCRs) superfamily including NKp30 (CD337), NKp44 (CD336), and NKp46 (CD335), and NKG2D (CD94), NK cells anti-tumor activity switched in SDs microenvironment (6, 16, 27, 28). The mentioned proses are activity induced via expression of MHC class I polypeptide-related sequence A (MICA), MHC Class I Polypeptide-Related Sequence B (MICB), and UL16 binding protein 1-3 (ULBP1-3) in the malignant tumor cells (30, 31). The stimulated NK cells through chains of paracrine and autocrine pathways case to inhibition of tumor cells survival and death. Briefly, in a stimulated NK cell, MAPK/ERK signaling pathway (also known as the Ras-Raf-MEK-ERK pathway) activate immediately after NCRs stimulation. Activation of MAPK/ERK signaling pathway directly ledes to expression of some of the main cytokine genes such as INF-?, tumor necrotic factor-alpha (TNF-?), and also granulocyte-macrophage colony-stimulating factor (GM-CSF) (32-34). Via a autocrine pathway, secretion of the INF-? through stimulation of interferons receptor (INFsR) and fallowing them activation of JAK-STAT signaling pathway case to expression of TNF-related apoptosis-inducing ligand (TRAIL) (35). Also, stimulation of INFsR via secreted INF-? in tumor cells, leads to expression of first apoptosis signal receptor (FAS) (36). On the other hand, activation of extracellular signal–regulated kinases 1/ 2 (ERK1/ 2), as one of the MAPK/ERK signaling pathway mediators, case to formation and exocytosis of the cytotoxic granolas from the NK cells cytoplasm to the membrane, localization and accumulation of Fas ligand (FASL or CD95L) on the surface of NK cells, and finally release of granzymes (kinds of serine proteases) (32-34).  In this cascade, tumor cells apoptosis has induced by stimulation of TRAILR and FAS via NK cells TRAIL and FASL ligands (37) and also activation of caspase-3 related cascade which induced by granzymes secretion (37) (Figure 1).