Role Of Cytokines In Mobilization Of Peripheral Blood Stem Cells And In The Biological Behavior Of Multiple Myeloma Cells

Recently, autologus peripheral blood stem cell transplantation has become a major way to treat the hematological malignancies .Up to day, the mechanisms and specific molecules involved in the experimental mobilization of hematopoietic stem/progenitor cells(HS/PC) from the BM into peripheral blood(PB) or in the homing of HPC and in their trafficking through the BM are still unclear,but they might be similar to those utilized by HPC to recirculate and migrate during their maturation.In previous studies, the results from vivo and in vitro experiments indicated that the mobilization of HS/PC was a multistep process, which requires the sequential engagement of adhesion molecules and the activation through chemokine receptor.Endogenous cytokine-mediated regulation of hematopoiesis is involved in circulating progenitor cells.Interleukin-8 (IL-8) is a member of the CXC family of chemokines. Bioactivities of IL-8 include neutrophil chemotaxis and activation and upregulation of intergrin family adhesion molecules.In the process ofstem cell mobilization with granulocyte colong-stimulating factor(G-CSF) ,Serum IL-8 levels correlated with CD34+cell numbers and colony-forming unit-granulocyte-macrophage(CFU-GM) numbers. These suggested that the endogenous production of IL-8 may be critical to G-CSF-induced stem cell mobilization, although the underlying mechanism has not been clarified. Further studies showed that metalloproteinase gelatinase B (MMP-B) mediated IL-8-induced stem cell mobilization.Stromal cell-derived factor-1(SDF-1 a )is a member of the chemokine CXC subfamily initially cloned from the murine bone marrow stromal cell line ST-2 and PA6,then purified from supernatant from the murine MS-5 cell line. SDF-1 a is a highly effective lympho-monocyte chemoattractant and supports B-cell progenitor proliferation.The constitutive expression of SDF-1 a in various tissues and its highly conserved nucleotide and amino aid sequences suggested that this molecule may play an important biological role in the immune response and regulation.Gene knockout experiments have confirmed the essential role of SDF-1 in hematopoietic development. SDF-1-deficient mice have fewer myeloid progenitors than normal mice in bone marrow,but fetal liver hematopoiesis is unaffected in these mice,suggesting that SDF-1 is involved in the migration of hematopoietic stem cells between embryonic hematopoietic sites.Other studies have implicated the role of SDF-1 in cell trafficking, in which hematopoietic progentor migration and mobilization are caused by a gradient of SDF-1 concentration in the bone marrow microenvironment.Several authors have reported the expression of CXCR4 on CD34+hematopoietic progenitor cells,including more primitive,pluripotent subsets and leukemic cells, and the transendothelialmigration induced by SDF-l.It is therefore conceivable that the SDF-1/CXCR4 mediated migration is involved in the homing of hematopoietic progenitor stem cells to the bone marrow.CXCR4 expressed in leukemic cells is functionally active and may be involved in the metastasic trafficking of malignant hematopoietic cells.A report demonstrated that integrins of VLA-4(CD49d) and LFA-1(CD11) expressed on CD34+cells and involved in mobilization of hematopoietic progenitor.Interlutin-6 enhances hematopoietic stem cell proliferation and differentiation.Some reports showed that gplSO expressed on immature hematopoietic progenitor cells while IL-6 receptor a chain did not,IL-6/sIL-6R complex activates the gp!30 signals and plays an important role in the process of proliferation of HS/PC.IL-11 secreted by bone marrow stromal cells is a kind of cytokines with multi-biological effects and belongs to the family of gp!30 cytokines. IL-11 trigger the gp!30 signaling which promotes cell proliferation and activation. IL-11 functions as a key promotion factor for hematopoietic proliferation and remarkablely promotes trilineage hematopoietic reconsitution after total body irradiation, myeloablative chemotherapy and bone marrow transplantation.