Granulocyte colony-stimulating factor

Neutrophilic granulocytes (neutrophils) serve as the critical circulating cell for nonspecific host defense against microbial infection. The short-lived circulating population of neutrophils is continuously renewing, being replenished via newly developed cells originating from the bone marrow hematopoietic stem cell population. The chapter focuses on Granulocyte colony-stimulating factor (G-CSF), which is a 20000 M_r glycoprotein that plays a critical role in this process, acting to stimulate the basal and stress-induced production of neutrophils, and enhancing their anti-microbial processes. G-CSF is produced by a variety of cell types, including bone marrow stromal cells, fibroblasts, endothelial cells, and activated macrophages. Production of G-CSF in large quantities as a recombinant protein in Escherichia coli has allowed its clinical use as a drug to treat neutropenia because of a variety of causes. The G-CSFR is a type 1 membrane protein of the hematopoietic growth factor receptor family. Its expression is demonstrated on myeloid progenitors, and circulating neutrophils, as well as non-hematopoietic cell types such as placental cytotrophoblasts. Signal transduction classically occurs following the binding of one G-CSF molecule to one G-CSFR molecule with subsequent receptor dimerization producing activation of signal transduction molecules. While the G-CSFR does not contain any intrinsic protein kinase activity, tyrosine phosphorylation of signaling molecules and the receptor itself occurs because of the activation of members of the Janus kinase (JAK) family. The chapter closes with molecular and biochemical properties of the G-CSF, and its receptor, their role in normal and pathologic physiology, a detailed description of G-CSFR signal transduction, and ongoing research.