Interleukin-3, Interleukin-5 and GM-CSF signaling

IL-3 is a 20-26 kDa product of CD4+ T cells that acts on the most immature marrow progenitors. IL-3 is capable of inducing the growth and differentiation of multi-potential hematopoietic stem cells, neutrophils, eosinophils, megakaryocytes, macrophages, lymphoid and erythroid cells. IL-3 has been used to support the proliferation of murine cell lines with properties of multi-potential progenitors, immature myeloid as well as T and pre-B lymphoid cells. IL-5 is a hematopoietic growth factor responsible for the maturation and differentiation of eosinophils. It was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells. It also promotes the generation of cytotoxic T-cells from thymocytes. IL-5 induces the expression of IL-2 receptors. GM-CSF is produced by cells (T-lymphocytes, tissue macrophages, endothelial cells, mast cells) found at sites of inflammatory responses. It stimulates the growth and development of progenitors of granulocytes and macrophages, and the production and maturation of dendritic cells. It stimulates myeloblast and monoblast differentiation, synergises with Epo in the proliferation of erythroid and megakaryocytic progenitor cells, acts as an autocrine mediator of growth for some types of acute myeloid leukemia, is a strong chemoattractant for neutrophils and eosinophils. It enhances the activity of neutrophils and macrophages. Under steady-state conditions GM-CSF is not essential for the production of myeloid cells, but it is required for the proper development of alveolar macrophages, otherwise, pulmonary alvelolar proteinosis (PAP) develops. A growing body of evidence suggests that GM-CSF plays a key role in emergency hematopoiesis (predominantly myelopoiesis) in response to infection, including the production of granulocytes and macrophages in the bone marrow and their maintenance, survival, and functional activation at sites of injury or insult.

All three receptors have alpha chains that bind their specific ligands with low affinity (de Groot et al. 1998). Bc then associates with the alpha chain forming a high affinity receptor, though the in vivo receptor is likely be a higher order multimer as recently demonstrated for the GM-CSF receptor.

The receptor chains lack intrinsic kinase activity, instead they interact with and activate signaling kinases, notably Janus Kinase 2 (JAK2). These phosphorylate the common beta subunit, allowing recruitment of signaling molecules such as Shc, the phosphatidylinositol 3-kinases (PI3Ks), and the Signal Transducers and Activators of Transcription (STATs). The cytoplasmic domain of Bc has two distinct functional domains: the membrane proximal region mediates the induction of proliferation-associated genes such as c-myc, pim-1 and oncostatin M. This region binds multiple signal-transducing proteins including JAK2, STATs, c-Src and PI3 kinase. The membrane distal domain is required for cytokine-induced growth inhibition and is necessary for the viability of hematopoietic cells. This region interacts with signal-transducing proteins such as Shc and SHP and mediates the transcriptional activation of c-fos, c-jun, c-Raf and p70S6K.

Figure reproduced by permission from Macmillan Publishers Ltd: Leukemia, WL Blalock et al. 13:1109-1166, copyright 1999. Note that residue numbering in this diagram refers to the mature Common beta chain with signal peptide removed.