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Advanced Science (Weinheim,... Aug 2021Cytokines are critical mediators that oversee and regulate immune and inflammatory responses via complex networks and serve as biomarkers for many diseases.... (Review)
Review
Cytokines are critical mediators that oversee and regulate immune and inflammatory responses via complex networks and serve as biomarkers for many diseases. Quantification of cytokines has significant value in both clinical medicine and biology as the levels provide insights into physiological and pathological processes and can be used to aid diagnosis and treatment. Cytokines and their clinical significance are introduced from the perspective of their pro- and anti-inflammatory effects. Factors affecting cytokines quantification in biological fluids, native levels in different body fluids, sample processing and storage conditions, sensitivity to freeze-thaw, and soluble cytokine receptors are discussed. In addition, recent advances in in vitro and in vivo assays, biosensors based on different signal outputs and intracellular to extracellular protein expression are summarized. Various quantification platforms for high-sensitivity and reliable measurement of cytokines in different scenarios are discussed, and commercially available cytokine assays are compared. A discussion of challenges in the development and advancement of technologies for cytokine quantification that aim to achieve real-time multiplex cytokine analysis for point-of-care situations applicable for both biomedical research and clinical practice are discussed.
Topics: Biomarkers; Cytokines; Humans
PubMed: 34114369
DOI: 10.1002/advs.202004433 -
International Journal of Molecular... Oct 2022The human innate and adaptive immune systems consist of effector cells producing cytokines (interleukins, interferons, chemokines, and numerous other mediators).... (Review)
Review
The human innate and adaptive immune systems consist of effector cells producing cytokines (interleukins, interferons, chemokines, and numerous other mediators). Usually, a fragile equilibrium of pro- and anti-inflammation effects is maintained by complex regulatory mechanisms. Disturbances of this homeostasis can lead to intricate chain reactions resulting in a massive release of cytokines. This may result in a drastic self-reinforcement of various feedback mechanisms, which can ultimately lead to systemic damage, multi-organ failure, or death. Not only pathogens can initiate such disturbances, but also congenital diseases or immunomodulatory therapies. Due to the complex and diverse interactions within the innate and adaptive immune systems, the understanding of this important clinical syndrome is incomplete to date and effective therapeutic approaches remain scarce.
Topics: Chemokines; Cytokine Release Syndrome; Cytokines; Humans; Interferons; Interleukins
PubMed: 36233040
DOI: 10.3390/ijms231911740 -
Nature Immunology Jul 2012The interleukin 12 (IL-12) family is unique in having the only heterodimeric cytokines, including IL-12, IL-23, IL-27 and IL-35. This feature endows these cytokines with... (Review)
Review
The interleukin 12 (IL-12) family is unique in having the only heterodimeric cytokines, including IL-12, IL-23, IL-27 and IL-35. This feature endows these cytokines with a unique set of connections and functional interactions not shared by other cytokine families. Despite sharing many structural features and molecular partners, cytokines of the IL-12 family mediate surprisingly diverse functional effects. Here we discuss the unique and unusual structural and functional characteristics of this cytokine family. We outline how cells might interpret seemingly similar cytokine signals to give rise to the diverse functional outcomes that characterize this cytokine family. We also discuss the therapeutic implications of this complexity.
Topics: Humans; Inflammation; Inflammation Mediators; Interleukin-12; Interleukin-17; Interleukin-23; Interleukins; Protein Multimerization; Signal Transduction; T-Lymphocytes
PubMed: 22814351
DOI: 10.1038/ni.2366 -
The Biochemical Journal Aug 2003The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and... (Review)
Review
The IL (interleukin)-6-type cytokines IL-6, IL-11, LIF (leukaemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokine are an important family of mediators involved in the regulation of the acute-phase response to injury and infection. Besides their functions in inflammation and the immune response, these cytokines play also a crucial role in haematopoiesis, liver and neuronal regeneration, embryonal development and fertility. Dysregulation of IL-6-type cytokine signalling contributes to the onset and maintenance of several diseases, such as rheumatoid arthritis, inflammatory bowel disease, osteoporosis, multiple sclerosis and various types of cancer (e.g. multiple myeloma and prostate cancer). IL-6-type cytokines exert their action via the signal transducers gp (glycoprotein) 130, LIF receptor and OSM receptor leading to the activation of the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and MAPK (mitogen-activated protein kinase) cascades. This review focuses on recent progress in the understanding of the molecular mechanisms of IL-6-type cytokine signal transduction. Emphasis is put on the termination and modulation of the JAK/STAT signalling pathway mediated by tyrosine phosphatases, the SOCS (suppressor of cytokine signalling) feedback inhibitors and PIAS (protein inhibitor of activated STAT) proteins. Also the cross-talk between the JAK/STAT pathway with other signalling cascades is discussed.
Topics: Animals; Cytokines; Humans; Infections; Interleukin-6; Models, Molecular; Phosphorylation; Protein Conformation; Protein Structure, Secondary; Receptors, Interleukin-6; Signal Transduction; Wounds and Injuries
PubMed: 12773095
DOI: 10.1042/BJ20030407 -
The New England Journal of Medicine Dec 2020
Review
Topics: Autoimmune Diseases; Bacterial Infections; Blood Proteins; COVID-19; Chemokines; Cytokine Release Syndrome; Cytokines; Humans; Interleukins; Virus Diseases
PubMed: 33264547
DOI: 10.1056/NEJMra2026131 -
Cold Spring Harbor Perspectives in... Dec 2018Cytokines that control the immune response were shown to have efficacy in preclinical murine cancer models. Interferon (IFN)-α is approved for treatment of hairy cell... (Review)
Review
Cytokines that control the immune response were shown to have efficacy in preclinical murine cancer models. Interferon (IFN)-α is approved for treatment of hairy cell leukemia, and interleukin (IL)-2 for the treatment of advanced melanoma and metastatic renal cancer. In addition, IL-12, IL-15, IL-21, and granulocyte macrophage colony-stimulating factor (GM-CSF) have been evaluated in clinical trials. However, the cytokines as monotherapy have not fulfilled their early promise because cytokines administered parenterally do not achieve sufficient concentrations in the tumor, are often associated with severe toxicities, and induce humoral or cellular checkpoints. To circumvent these impediments, cytokines are being investigated clinically in combination therapy with checkpoint inhibitors, anticancer monoclonal antibodies to increase the antibody-dependent cellular cytotoxicity (ADCC) of these antibodies, antibody cytokine fusion proteins, and anti-CD40 to facilitate tumor-specific immune responses.
Topics: Biological Factors; Cytokines; Humans; Neoplasms
PubMed: 29101107
DOI: 10.1101/cshperspect.a028472 -
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 -
European Journal of Immunology Nov 2007Cytokines affect nearly every biological process; these include embryonic development, disease pathogenesis, non-specific response to infection, specific response to... (Review)
Review
Cytokines affect nearly every biological process; these include embryonic development, disease pathogenesis, non-specific response to infection, specific response to antigen, changes in cognitive functions and progression of the degenerative processes of aging. In addition, cytokines are part of stem cell differentiation, vaccine efficacy and allograft rejection. This short insight focuses on the milestones in cytokine biology and how the various and often contradictory activities of these small, non-structural proteins affected the fields of inflammation and immunology. Multiple biological properties or pleiotropism is the hallmark of a cytokine. Today, the term "cytokine" encompasses interferons, the interleukins, the chemokine family, mesenchymal growth factors, the tumor necrosis factor family and adipokines. As of this writing, 33 cytokines are called interleukins, but many are part of families of related but distinct gene products. There are certainly over 100 separate genes coding for cytokine-like activities, many with overlapping functions and many still unexplored. Also discussed in this overview are the failures and successes of cytokines as therapeutic targets. A recent advance in the field has been that of differential cytokine production, which can be used to classify human disease as being "autoimmune" or "autoinflammatory" thus impacting on therapeutic interventions.
Topics: Allergy and Immunology; Animals; Cytokines; History, 20th Century; Humans
PubMed: 17972343
DOI: 10.1002/eji.200737772 -
International Journal of Oral Science Nov 2019Periodontitis is an inflammatory disease involving the destruction of both soft and hard tissue in the periodontal region. Although dysbiosis of the local microbial... (Review)
Review
Periodontitis is an inflammatory disease involving the destruction of both soft and hard tissue in the periodontal region. Although dysbiosis of the local microbial community initiates local inflammation, over-activation of the host immune response directly activates osteoclastic activity and alveolar bone loss. Many studies have reported on the cytokine network involved in periodontitis and its crucial and pleiotropic effect on the recruitment of specific immunocytes, control of pathobionts and induction or suppression of osteoclastic activity. Nonetheless, particularities in the stimulation of pathogens in the oral cavity that lead to the specific and complex periodontal cytokine network are far from clarified. Thus, in this review, we begin with an up-to-date aetiological hypothesis of periodontal disease and summarize the roles of cytokines in the host immune response. In addition, we also summarize the latest cytokine-related therapeutic measures for periodontal disease.
Topics: Alveolar Bone Loss; Cytokines; Humans; Inflammation; Periodontal Diseases; Periodontitis; Tumor Necrosis Factor-alpha
PubMed: 31685798
DOI: 10.1038/s41368-019-0064-z -
Journal of Interferon & Cytokine... Jan 2019Cytokines are major regulators of innate and adaptive immunity that enable cells of the immune system to communicate over short distances. Cytokine therapy to activate... (Review)
Review
Cytokines are major regulators of innate and adaptive immunity that enable cells of the immune system to communicate over short distances. Cytokine therapy to activate the immune system of cancer patients has been an important treatment modality and continues to be a key contributor to current clinical cancer research. Interferon alpha (IFNα) is approved for adjuvant treatment of completely resected high-risk melanoma patients and several refractory malignancies. High-dose interleukin-2 (HDIL-2) is approved for treatment of metastatic renal cell cancer and melanoma, but both agents are currently less commonly used with the development of newer agents. Granulocyte-macrophage colony-stimulating factor (GM-CSF), IFN gamma (IFNγ), IL-7, IL-12, and IL-21 were evaluated in clinical trials and remain part of certain investigational trials. The initial single-agent clinical trials with the long-awaited IL-15 have been completed and combination trials with antitumor antibodies or checkpoint inhibitors (CPIs) have been initiated. However, cytokines in monotherapy have not fulfilled the promise of efficacy seen in preclinical experiments. They are often associated with severe dose-limiting toxicities that are manageable with appropriate dosing and are now better understood to induce immune-suppressive humoral factors, suppressive cells, and cellular checkpoints, without consistently inducing a tumor-specific response. To circumvent these impediments, cytokines are being investigated clinically with new engineered cytokine mutants (superkines), chimeric antibody-cytokine fusion proteins (immunokines), anticancer vaccines, CPIs, and cancer-directed monoclonal antibodies to increase their antibody-dependent cellular cytotoxicity or sustain cellular responses and anticancer efficacy. In this review, we summarize current knowledge and clinical application of cytokines either as monotherapy or in combination with other biological agents. We emphasize a discussion of future directions for research on these cytokines, to bring them to fruition as major contributors for the treatment of metastatic malignancy.
Topics: Cytokines; Humans; Neoplasms
PubMed: 29889594
DOI: 10.1089/jir.2018.0019