Insights into Cytokine–Receptor Interactions from Cytokine Engineering
Open accessAbstract
Cytokines exert a vast array of immunoregulatory actions critical to human biology and disease. However, the desired immunotherapeutic effects of native cytokines are often mitigated by toxicity or lack of efficacy, either of which results from cytokine receptor pleiotropy and/or undesired activation of off-target cells. As our understanding of the structural principles of cytokine–receptor interactions has advanced, mechanism-based manipulation of cytokine signaling through protein engineering has become an increasingly feasible and powerful approach. Modified cytokines, both agonists and antagonists, have been engineered with narrowed target cell specificities, and they have also yielded important mechanistic insights into cytokine biology and signaling. Here we review the theory and practice of cytokine engineering and rationalize the mechanisms of several engineered cytokines in the context of structure. We discuss specific examples of how structure-based cytokine engineering has opened new opportunities for cytokines as drugs, with a focus on the immunotherapeutic cytokines interferon, interleukin-2, and interleukin-4.
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Depending on their dose-dependent selectivity for one or several JAKs, JAK inhibitors exert a broad immunopharmacological impact by blocking signal transduction pathways of multiple type I and type II cytokine receptors.
“Depending on their dose-dependent selectivity for one or several JAKs, the JAK inhibitors (JAKi) exert a broad immunopharmacological impact because they block the signal transduction pathways of multiple type I (haematopoietic family) and type II (interferon) cytokine receptors17,214.”
From Atopic dermatitis: an expanding therapeutic pipeline for a complex disease (2022) · cites this paper as [214]
The Introduction (page unavailable) says cytokine–receptor complexes activate associated JAKs, and the type I interferon section identifies JAK1 and TYK2 in interferon-receptor signaling. The paper does not establish the claimed dose-dependent selectivity of JAK inhibitors or their broad blocking effects across type I and type II cytokine receptors. (LLM, conf=0.84)
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Intratumorally anchored cytokine therapy
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- Authors
- Spangler, J. B., Moraga, I., Mendoza, J. L., & Garcia, K. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- Howard Hughes Medical Institute, Department of Molecular and Cellular Physiology, Department of Structural Biology, Stanford University School of Medicine, Stanford, California 94305;, , ,
- Venue
- Annual Review of Immunology
- Publisher
- Annual Reviews
- Published
- 2015-03-21
- Volume
- 33
- Issue
- 1
- Pages
- 139-167
- ISSN
- 0732-0582 (ISSN-L)
- 1545-3278
- PMC
- PMC4445396
- OpenAlex
- W2098212097
- Cited by
- 304
- References
- 202
- Citations by year
- 2026: 19 · 2025: 30 · 2024: 38 · 2023: 32 · 2022: 48 · 2021: 48 · 2020: 24 · 2019: 16 · 2018: 18 · 2017: 18 · 2016: 6 · 2015: 7
- FWCI
- 1.17
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annual Review of Immunology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Cancer Institute (K01CA175127)
- National Institute of Allergy and Infectious Diseases (R01 AI51321, R37AI051321, R01AI051321)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- cytokine engineering, cytokine-cytokine receptor interaction, cytokine signaling, structure-based protein engineering, cytokine antagonists, target cell specificity, cytokine toxicity, immunotherapy, interferon, interleukin-2, IL-4
- MeSH terms
- Animals, Extracellular Space, Genetic Engineering, Humans, Protein Binding, Signal Transduction, Cytokines, Receptors, Cytokine, Protein Transport, Intracellular Space
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