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Nature Reviews. Drug Discovery Jan 2023Cytokines are secreted signalling proteins that play essential roles in the initiation, maintenance and resolution of immune responses. Although the unique ability of... (Review)
Review
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.
Topics: Humans; Cytokines; Receptors, Cytokine; Signal Transduction; Protein Engineering; Neoplasms
PubMed: 36131080
DOI: 10.1038/s41573-022-00557-6 -
Annual Review of Immunology 2015Cytokines exert a vast array of immunoregulatory actions critical to human biology and disease. However, the desired immunotherapeutic effects of native cytokines are... (Review)
Review
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.
Topics: Animals; Cytokines; Extracellular Space; Genetic Engineering; Humans; Intracellular Space; Protein Binding; Protein Transport; Receptors, Cytokine; Signal Transduction
PubMed: 25493332
DOI: 10.1146/annurev-immunol-032713-120211 -
Nature Biotechnology Feb 2023Targeted degradation of cell surface and extracellular proteins via lysosomal delivery is an important means to modulate extracellular biology. However, these approaches...
Targeted degradation of cell surface and extracellular proteins via lysosomal delivery is an important means to modulate extracellular biology. However, these approaches have limitations due to lack of modularity, ease of development, restricted tissue targeting and applicability to both cell surface and extracellular proteins. We describe a lysosomal degradation strategy, termed cytokine receptor-targeting chimeras (KineTACs), that addresses these limitations. KineTACs are fully genetically encoded bispecific antibodies consisting of a cytokine arm, which binds its cognate cytokine receptor, and a target-binding arm for the protein of interest. We show that KineTACs containing the cytokine CXCL12 can use the decoy recycling receptor, CXCR7, to target a variety of target proteins to the lysosome for degradation. Additional KineTACs were designed to harness other CXCR7-targeting cytokines, CXCL11 and vMIPII, and the interleukin-2 (IL-2) receptor-targeting cytokine IL-2. Thus, KineTACs represent a general, modular, selective and simple genetically encoded strategy for inducing lysosomal delivery of extracellular and cell surface targets with broad or tissue-specific distribution.
Topics: Cell Membrane; Interleukin-2; Receptors, Cytokine; Signal Transduction; Proteolysis; Proteolysis Targeting Chimera; Chemokine CXCL12
PubMed: 36138170
DOI: 10.1038/s41587-022-01456-2 -
International Journal of Biological... 2012Interleukin-6 (IL-6) is a cytokine with many activities. It has functions in the regulation of the immune system and the nervous system. Furthermore, IL-6 is involved in... (Review)
Review
Interleukin-6 (IL-6) is a cytokine with many activities. It has functions in the regulation of the immune system and the nervous system. Furthermore, IL-6 is involved in liver regeneration and in the metabolic control of the body. On target cells, IL-6 binds to an 80 kDa IL-6 receptor (IL-6R). The complex of IL-6 and IL-6R associates with a second protein, gp130, which thereupon dimerizes and initiates intracellular signaling. Whereas gp130 is expressed on all cells, IL-6R is only present on few cells in the body including hepatocytes and some leukocytes. Cells, which do not express IL-6R cannot respond to the cytokine, since gp130 alone has no measurable affinity for IL-6. Interestingly, a soluble form of IL-6R (sIL-6R) comprising the extracellular portion of the receptor can bind IL-6 with a similar affinity as the membrane bound IL-6R. The complex of IL-6 and sIL-6R can bind to gp130 on cells, which do not express the IL-6R, and which are unresponsive to IL-6. This process has been called trans-signaling. Here I will review published evidence that IL-6 trans-signaling is pro-inflammatory whereas classic IL-6 signaling via the membrane bound IL-6R is needed for regenerative or anti-inflammatory activities of the cytokine. Furthermore, the detailed knowledge of IL-6 biology has important consequences for therapeutic strategies aimed at the blockade of the cytokine IL-6.
Topics: Animals; Cytokine Receptor gp130; Humans; Interleukin-6; Mice; Mice, Transgenic; Models, Biological; Receptors, Interleukin-6; Signal Transduction; Solubility
PubMed: 23136552
DOI: 10.7150/ijbs.4989 -
Cancer Discovery Nov 2017Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant...
Successful adoptive T-cell immunotherapy of solid tumors will require improved expansion and cytotoxicity of tumor-directed T cells within tumors. Providing recombinant or transgenic cytokines may produce the desired benefits but is associated with significant toxicities, constraining clinical use. To circumvent this limitation, we constructed a constitutively signaling cytokine receptor, C7R, which potently triggers the IL7 signaling axis but is unresponsive to extracellular cytokine. This strategy augments modified T-cell function following antigen exposure, but avoids stimulating bystander lymphocytes. Coexpressing the C7R with a tumor-directed chimeric antigen receptor (CAR) increased T-cell proliferation, survival, and antitumor activity during repeated exposure to tumor cells, without T-cell dysfunction or autonomous T-cell growth. Furthermore, C7R-coexpressing CAR T cells were active against metastatic neuroblastoma and orthotopic glioblastoma xenograft models even at cell doses that had been ineffective without C7R support. C7R may thus be able to enhance antigen-specific T-cell therapies against cancer. The constitutively signaling C7R system developed here delivers potent IL7 stimulation to CAR T cells, increasing their persistence and antitumor activity against multiple preclinical tumor models, supporting its clinical development. .
Topics: Animals; Antigens, Neoplasm; Cell Line, Tumor; Cell Proliferation; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Immunotherapy, Adoptive; Interleukin-7; Mice; Neuroblastoma; Receptors, Antigen, T-Cell; Receptors, Cytokine; Signal Transduction; T-Lymphocytes; Xenograft Model Antitumor Assays
PubMed: 28830878
DOI: 10.1158/2159-8290.CD-17-0538 -
International Journal of Molecular... Jan 2022Cytokines and their receptors have a vital function in regulating various processes such as immune function, inflammation, haematopoiesis, cell growth and... (Review)
Review
Cytokines and their receptors have a vital function in regulating various processes such as immune function, inflammation, haematopoiesis, cell growth and differentiation. The interaction between a cytokine and its specific receptor triggers intracellular signalling cascades that lead to altered gene expression in the target cell and consequent changes in its proliferation, differentiation, or activation. In this review, we highlight the role of the soluble type I cytokine receptor CRLF1 (cytokine receptor-like factor-1) and the Interleukin (IL)-6 cytokine CLCF1 (cardiotrophin-like cytokine factor 1) during development in physiological and pathological conditions with particular emphasis on Crisponi/cold-induced sweating syndrome (CS/CISS) and discuss new insights, challenges and possibilities arising from recent studies.
Topics: Animals; Cytokines; Death, Sudden; Disease Models, Animal; Facies; Hand Deformities, Congenital; Human Development; Humans; Hyperhidrosis; Receptors, Cytokine; Signal Transduction; Trismus
PubMed: 35055176
DOI: 10.3390/ijms23020992 -
European Journal of Biochemistry Jul 1998Structure of growth-hormone receptor and the class I type of cytokine receptors: common structural features; cytokine-receptor isoforms; oligomerization of receptor... (Review)
Review
Structure of growth-hormone receptor and the class I type of cytokine receptors: common structural features; cytokine-receptor isoforms; oligomerization of receptor components initiates cytokine signalling. Role of the Jak kinases in mediating specific functions of growth-hormone receptor and cytokine receptors. Role of signal transducer and activator of transcription (Stat) proteins in growth hormone and cytokine functions. Other pathways activated by cytokine receptors: the mitogen-activated protein kinase pathway; insulin-receptor substrates 1 and 2 and phosphatidylinositol-3-kinase pathways; the Src pathways and other tyrosine kinase pathways; the phospholipase C/protein kinase C/Ca2+ pathways. Regulation of growth-hormone receptor and cytokine receptor signaling: binding sites, internalization and ubiquitination; phosphatases and Janus kinase/Stat inhibitors. Conclusions and future prospects.
Topics: DNA-Binding Proteins; Gene Expression Regulation; Models, Biological; Protein-Tyrosine Kinases; Receptors, Cytokine; Receptors, Somatotropin; Signal Transduction; Trans-Activators
PubMed: 9692895
DOI: 10.1046/j.1432-1327.1998.2550001.x -
International Journal of Molecular... Jun 2023This Special Issue represents a collective celebration of the cytokine receptor superfamily and the myriad of functions mediated by these important molecules in...
This Special Issue represents a collective celebration of the cytokine receptor superfamily and the myriad of functions mediated by these important molecules in development and homeostasis, as well as their disruption in disease [...].
Topics: Receptors, Cytokine; Signal Transduction; Homeostasis
PubMed: 37373498
DOI: 10.3390/ijms241210352 -
Frontiers in Immunology 2019Allogeneic hematopoietic cell transplantation (allo-HCT) is performed with curative intent for high- risk blood cancers and bone marrow failure syndromes; yet the... (Review)
Review
Allogeneic hematopoietic cell transplantation (allo-HCT) is performed with curative intent for high- risk blood cancers and bone marrow failure syndromes; yet the development of acute and chronic graft-vs.-host disease (GVHD) remain preeminent causes of death and morbidity. The IL-12 family of cytokines is comprised of IL-12, IL-23, IL-27, IL-35, and IL-39. This family of cytokines is biologically distinct in that they are composed of functional heterodimers, which bind to cognate heterodimeric receptor chains expressed on T cells. Of these, IL-12 and IL-23 share a common β cytokine subunit, p40, as well as a receptor chain: IL-12Rβ1. IL-12 and IL-23 have been documented as proinflammatory mediators of GVHD, responsible for T helper 1 (Th1) differentiation and T helper 17 (Th17) stabilization, respectively. The role of IL-27 is less defined, seemingly immune suppressive via IL-10 secretion by Type 1 regulatory (Tr1) cells yet promoting inflammation through impairing CD4 T regulatory (Treg) development and/or enhancing Th1 differentiation. More recently, IL-35 was described as a potent anti-inflammatory agent produced by regulatory B and T cells. The role of the newest member, IL-39, has been implicated in proinflammatory B cell responses but has not been explored in the context of allo-HCT. This review is directed at discussing the current literature relevant to each IL-12-family cytokine and cognate receptor engagement, as well as the consequential downstream signaling implications, during GVHD pathogenesis. Additionally, we will provide an overview of translational strategies targeting the IL-12 family cytokines, their receptors, and subsequent signal transduction to control GVHD.
Topics: Allografts; Animals; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Interleukin-12; Receptors, Cytokine; T-Lymphocytes, Helper-Inducer
PubMed: 31139181
DOI: 10.3389/fimmu.2019.00988 -
Frontiers in Immunology 2022
Topics: Cytokines; Immunotherapy; Receptors, Cytokine
PubMed: 35958607
DOI: 10.3389/fimmu.2022.985326