Cytokine–receptor interactions as drug targets

Abstract

Cytokines are essential proteins that exert potent control over entire cell populations to fight infections and other pathologies, but can by themselves cause disease. Therefore, cytokine related drugs act either by stimulating or blocking their activities. Our knowledge of the structures of cytokine-receptor complexes, the biophysical basis of their binding, and their mode of biological activation has substantially increased in recent years. This knowledge has been translated into new drugs and drug candidates. This review summarizes our current understanding of the receptormediated activity of cytokines, their relation to health and disease, and the agents in use to activate and block their actions.Cytokines, such as interleukins (IL-) and interferons (IFN), are secreted proteins that carry intra-and inter-cellular signals that regulate the immune response to pathogens or other pathological conditions. For their function, cytokines must bind to specific extracellular receptors. Some cytokines, such as the type I interferons, have dedicated receptor chains (IFNAR1 and 2). However, other cytokines bind to both dedicated and shared receptors [1]. Two examples of cytokines that bind shared receptors are IL-4 and IL-13, which bind combinations of IL-4Rα, γ c and IL-13Rα [2*], and the different modes of interaction of GP130/CNTF-Rα/LIF-R with CNTF versus GP130/IL-6Rα with IL-6 [3*]. A combination of structural biology and biophysical methods has provided detailed information on many cytokine-receptor complexes. These studies have revealed that one receptor chain often functions as the "binding" receptor, exhibiting nM affinity, while the other receptor functions as the "signaling" receptor making only weak (μM affinity) interactions within the cytokine receptor complex.The mechanism of cytokine-mediated receptor activation remains controversial. One idea is that cytokine receptors are pre-assembled, or pre-concentrated on the cell surface, and activation occurs by structural changes in the receptors upon ligand binding. A competing model suggests that cytokine receptors are dispersed within a region of the membrane and cytokine binding "oligomerizes" the receptors. A major issue is the role of structural rearrangement versus receptor aggregation upon cytokine binding. FRET and other experiments have shown pre-assembly of the receptor chains for IL-5 [4*], IFNγR1 [5], GP130 [6], IL-10R1 [7] and others. In addition to pre-assembly of receptor chains, it was also suggested that some of the receptors are clustered on the membrane, facilitating rapid complex formation and cellular signaling. A good example for this concept is provided by Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process err...

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