Cytokine Deprivation and Cell Death

Abstract

It has long been known that many cell types are dependent on specific cytokines that signal proliferation, regulate differentiation and suppress apoptosis. A detailed picture of the structure of several cytokine receptors has added to our understanding of the molecular mechanism of receptor activation. An explosion of knowledge of apoptosis pathways and the ways in which the Bcl-2 family of proteins function has deepened the understanding of the effector arm of the programmed cell death pathway. The challenge is to uncover the molecular links between these two pathways. In this article, we will try to examine what is known of the intersections between cytokine signalling pathways and apoptosis pathways, with particular reference to receptor signalling by the haematopoietic cytokines Interleukin-3 (IL-3) and Granulocyte-Macrophage-Colony Stimulating Factor (GM-CSF). IL-3 AND GM-CSF IL-3 and GM-CSF are haematopoietic cytokines involved in normal haematopoiesis, including the maintenance and proliferation of myeloid progenitor cells and regulation mye- loid differentiation (1). GM-CSF and IL-3 have important physiological roles and deregulated signalling contributes to a number of human diseases. In normal physiology, GM- CSF and IL-3 signalling are not required for the develop- ment of a functioning haematopoietic system, but are impor- tant in the expansion or repopulation of certain haematopoie- tic lineages in response to infection or cytopenias, for example after treatment with chemotherapeutic agents (2, 3). This property underpins the most striking clinical application of GM-CSF (and now more commonly G-CSF) to enhance granulopoiesis after chemotherapy (reviewed in (4)). In Acute Myeloid Leukaemia (AML), overexpression of the IL- 3 receptor alpha chain ( chain or CD123) is observed in a subset of leukaemias and is associated with a worse prognosis (5). Whilst the biological mechanisms by which overexpression of this receptor subunit contributes to the progression of AML remain to be determined, the potential of the  chain as a therapeutic target, particularly to attack leukaemic stem cells, is being actively explored (6). The proinflammatory functions of GM-CSF, IL-3 as well as other cytokines may contribute to a number of chronic inflammatory diseases, including arthritis (7). At least in animal models, depletion or blocking GM-CSF signalling can substantially lessen disease severity, although this has not yet translated into an established therapeutic option in humans.