Cytokines are secreted signalling proteins that play essential roles in the initiation, maintenance and resolution of immune responses. Although the unique ability of cytokines to control immune function has garnered clinical interest in the context of cancer, autoimmunity and infectious disease, the use of cytokine-based therapeutics has been limited. This is due, in part, to the ability of cytokines to act on many cell types and impact diverse biological functions, resulting in dose-limiting toxicity or lack of efficacy. Recent studies combining structural biology, protein engineering and receptor pharmacology have unlocked new insights into the mechanisms of cytokine receptor activation, demonstrating that many aspects of cytokine function are highly tunable. Here, we discuss the pharmacological principles underlying these efforts to overcome cytokine pleiotropy and enhance the therapeutic potential of this important class of signalling molecules.
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K.C.G. is an investigator of the Howard Hughes Medical Institute (HHMI). This work was supported by National Institutes of Health (NIH) grant R01-AI51321 (K.C.G.) as well as funding from the Helen Hay Whitney Foundation (R.A.S.).
K.C.G. is the founder of Synthekine Therapeutics. R.A.S., C.R.G. and K.C.G. are inventors on patents relating to molecules discussed in this Review that are being commercialized.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Receptor tyrosine kinases
(RTKs). Cell surface receptors with intrinsic tyrosine kinase activity.
- Janus kinases
(JAKs). A family of cytosolic tyrosine kinases that associate with cytokine receptor intracellular domains.
The ligand concentration that induces half-maximal response.
- E max
The maximal response elicited by saturating ligand concentrations.
- Regulatory T cells
(Treg cells). A subpopulation of immunosuppressive T cells important for maintaining self-tolerance and homeostasis.
- Cellular pleiotropy
Pleiotropy arising from the ability of one molecule to stimulate multiple distinct cell types or tissues.
- Functional pleiotropy
Pleiotropy arising from the ability of one molecule to activate multiple signalling pathways and, thereby, induce multiple functional responses on a target cell type.
- G proteins
Guanine nucleotide binding proteins that mediate signal transduction in a GTP-dependent manner.
- Diamond–Blackfan anaemia
A genetic disorder resulting in reduced production of red blood cells.
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Saxton, R.A., Glassman, C.R. & Garcia, K.C. Emerging principles of cytokine pharmacology and therapeutics. Nat Rev Drug Discov (2022). https://doi.org/10.1038/s41573-022-00557-6