Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a glycoprotein that regulates proliferation and differentiation of myeloid progenitor cells, and functional activation in host defense circuits of mature monocytes and granulocytes. It is produced by immune-competent cells, and by mesenchymal cells present in bone marrow, including endothelium and fibroblasts (see ref. 58). GM-CSF heterodimeric receptor is composed by two transmembrane glycoprotidic subunits, termed a and p. The 60-90 kDa a-chain specifically binds the ligand with low affinity and dimerizes with the 120-140 kDa P-chain, which is also shared by IL-3 and IL-5 receptors (see ref. 59).
Several studies have suggested that GM-CSF responsiveness may not be limited to hematopoietic lineages (59), and endothelial cells is another target for this cytokine (60-64). GM-CSFR-mediated endothelium activation includes functions related to angiogenesis and inflammation (i.e., proliferation, migration, expression of adhesion molecules). Although GM-CSF is less potent that other more classic angiogenic molecules (i.e., fibroblast growth factor) in promoting endothelial proliferation, it activates a fully migratory phenotype (65). In addition, it has also been shown that GM-CSF interaction with specific binding sites on endothelial cell surface induces the expression of c-fos mRNA (60), rapid activation of Na+/H+ exchanger, and JAK-2 tyrosine kinase (66,67). It is emerging that other cytokines, which act primarily on hematopoietic cells (IL-3, granulocyte-CSF), affect endothelial cell function related to angiogenesis and inflammation (27,60,61,65,68,69), and many angiogenic molecules have positive or negative effect on hematopoiesis (reviewed in ref. 70). Therefore, the ability of GM-CSF and other CSF-like molecules to induce migration and proliferation of endothelial cells, including that of bone marrow (64), could be essential for the survival and renewal of bone marrow microenvironment in physiologic and pathologic conditions.
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