| Chemokines are a group of structurally related 8-12 kDa cytokines which can chemoattract various types of cells, including neutrophils, monocytes and lymphocytes. Chemokines have been shown to mediate inflammation and immune responses. They are also important in other pathophysiological processes and diseases such as, autoimmune diseases, allograft rejection, allergies, angiogenesis, neoplasia and infection. In addition, chemokines can regulate homing, migration and mobilization of hematopoietic stem cells, In recent years, great advances have been achieved in the research of chemokine receptors and their signal transduction, and chemokine regulation of hematopoiesis attracted increased attention. Up to now, most chemokines cell have been demonstrated to negatively regulate hematopoiesis, with only a few chemokines such as SDF-la(CXCL12), MIP-3P(CCL19), SLC(CCL21), able to enhance hematopoiesis. Therefore, the discovery and identification of a novel chemokine which can promote hematopoiesis will give us new insight and constitute a further basis for clinical application to treat diseases.Macrophage inflammatory protein 2γ(MIP-2γ) is a novel CXC chemokine cloned by us from a human peripheral monocyte-derived dendritic cell cDNA library through large-scale automatic sequencing (Cao X et al. The Journal of Immunology, 2000, 165: 2588-2595) .The full-length cDNA of MIP-2γ is 463bp which encodes a 34aa signal peptide and a 77aa secreted mature protein. MIP-2γ shares 16% homology with MIP-2o/P at the protein level. Our previous work showed that recombinant MIP-2γ can promote CFU-GM formation in vitro, suggesting that MIP-2γ might regulate hematopoiesis. Thus, the primary aim of this study is to investigate the regulation of hematopoiesis by MIP-2γ.There are three parts in this study. Part I: MIP-2γ maintains survival of hematopoietic stem cells, and the related underlying mechanisms. Part II: MIP-2γ chemoattracts and mobilizes hematopoietic stem cells both in vitro and in vivo, and the related underlying mechanisms. Part III: In vivo administration of MIP-2γ promotes hematopoietic recovery following lethal dose of irradiation, and the related underlying mechanisms.Part I: MIP-2γ maintains survival of hematopoietic stem cells and the relatedunderlying mechanisms.Hematopoietic stem cell transplantation has been used widely to treat patients with genetic disorders such as sickle cell anaemia and immunodeficiency as well as those with malignancies including leukemia and solid tumors. In 1988, this field was boosted by the discovery that two hematopoietic cytokines, GM-CSF and G-CSF, act to were shown to maintain survival of hematopoietic stem cells and mobilize hematopoietic stem/progenitor cells to the blood stream, In current clinical practice, cancer treatments are often administered in combination with hematopoietic cytokines. The intensity of cytotoxic anticancer drugs or dosages of irradiation can be increased beyond the range that is toxic to bone marrow cells, thus potentially improving the efficacy of these therapies. It is well known that the survival of hematopoietic stem/progenitor cells is dependent on hematopoietic cytokines and growth factors, and that hematopoietic stem/progenitor cells will undergo apoptosis upon withdrawal of hematopoietic cytokines and growth factors in culture systems. In recent years, many kinds of chemokines have been shown to be involved in hematopoieis, but, as stated above, most of them negatively regulate the hematopoiesis or can't maintain the survival of hematopoietic stem/progenitor cells. Up to now, no chemokine has been found that can directly stimulate proliferation of hematopoietic stem/progenitor cells. One of the most extensively studied chemokines, SDF-lct, can maintain the survival but not stimulate the proliferation of hematopoietic stem/progenitor cells. As described previously, recombinant MIP-2γ can promote CFU-GM formation in vitro; so we propose that MIP-2γ may act as a hematopoietic chemokine to promote hematopoiesis. We inve... |
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