Cytokine

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3D medical animation still showing secretion of cytokines Cytokine release.jpg
3D medical animation still showing secretion of cytokines

Cytokines are a broad and loose category of small proteins (~5–25 kDa [1] ) important in cell signaling. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.

Contents

Cytokines include chemokines, interferons, interleukins, lymphokines, and tumour necrosis factors, but generally not hormones or growth factors (despite some overlap in the terminology)[ citation needed ]. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell. [2] [3] They act through cell surface receptors and are especially important in the immune system; cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways. They are different from hormones, which are also important cell signaling molecules. Hormones circulate in higher concentrations, and tend to be made by specific kinds of cells. Cytokines are important in health and disease, specifically in host immune responses to infection, inflammation, trauma, sepsis, cancer, and reproduction.

The word comes from the ancient Greek language: cyto, from Greek κύτος, kytos, 'cavity, cell' + kines, from Greek κίνησις, kinēsis, 'movement'.

Discovery

Interferon-alpha, an interferon type I, was identified in 1957 as a protein that interfered with viral replication. [4] The activity of interferon-gamma (the sole member of the interferon type II class) was described in 1965; this was the first identified lymphocyte-derived mediator. [5] Macrophage migration inhibitory factor (MIF) was identified simultaneously in 1966 by John David and Barry Bloom. [6] [7]

In 1969, Dudley Dumonde proposed the term "lymphokine" to describe proteins secreted from lymphocytes and later, proteins derived from macrophages and monocytes in culture were called "monokines". [8] In 1974, pathologist Stanley Cohen, M.D. (not to be confused with the Nobel laureate named Stanley Cohen, who was a PhD biochemist; nor with the MD geneticist Stanley Norman Cohen) published an article describing the production of MIF in virus-infected allantoic membrane and kidney cells, showing its production is not limited to immune cells. This led to his proposal of the term cytokine. [9] In 1993, Ogawa described the early acting growth factors, intermediate acting growth factors and late acting growth factors. [10]

Difference from hormones

Classic hormones circulate in aqueous solution in nanomolar (10-9 M) concentrations that usually vary by less than one order of magnitude. In contrast, some cytokines (such as IL-6) circulate in picomolar (10-12 M) concentrations that can increase up to 1,000 times during trauma or infection. The widespread distribution of cellular sources for cytokines may be a feature that differentiates them from hormones. Virtually all nucleated cells, but especially endo/epithelial cells and resident macrophages (many near the interface with the external environment) are potent producers of IL-1, IL-6, and TNF-α. [11] In contrast, classic hormones, such as insulin, are secreted from discrete glands such as the pancreas. [12] The current terminology refers to cytokines as immunomodulating agents.

A contributing factor to the difficulty of distinguishing cytokines from hormones is that some immunomodulating effects of cytokines are systemic (i.e., affecting the whole organism) rather than local. For instance, to accurately utilize hormone terminology, cytokines may be autocrine or paracrine in nature, and chemotaxis, chemokinesis and endocrine as a pyrogen. Essentially, cytokines are not limited to their immunomodulatory status as molecules.

Cytokines typically activate second messenger systems, like JAK-STAT pathways, as illustrated on the left side of the diagram. Conversely, hormones typically activate different signaling pathways, like G protein-coupled receptors, seen at the top of the figure. Signal transduction pathways.svg
Cytokines typically activate second messenger systems, like JAK-STAT pathways, as illustrated on the left side of the diagram. Conversely, hormones typically activate different signaling pathways, like G protein-coupled receptors, seen at the top of the figure.

Nomenclature

Cytokines have been classed as lymphokines, interleukins, and chemokines, based on their presumed cell of secretion, function, or target of action. Because cytokines are characterised by considerable redundancy and pleiotropism, such distinctions, allowing for exceptions, are obsolete.

Classification

Structural

Structural homogeneity has been able to partially distinguish between cytokines that do not demonstrate a considerable degree of redundancy so that they can be classified into four types:

  1. the IL-2 subfamily. This is the largest family. It contains several non-immunological cytokines including erythropoietin (EPO) and thrombopoietin (TPO). [13] They can be grouped into long-chain and short-chain cytokines by topology. [14] Some members share the common gamma chain as part of their receptor. [15]
  2. the interferon (IFN) subfamily.
  3. the IL-10 subfamily.

Functional

A classification that proves more useful in clinical and experimental practice outside of structural biology divides immunological cytokines into those that enhance cellular immune responses, type 1 (TNFα, IFN-γ, etc.), and those that enhance antibody responses, type 2 (TGF-β, IL-4, IL-10, IL-13, etc.). A key focus of interest has been that cytokines in one of these two sub-sets tend to inhibit the effects of those in the other. Dysregulation of this tendency is under intensive study for its possible role in the pathogenesis of autoimmune disorders. Several inflammatory cytokines are induced by oxidative stress. [16] [17] The fact that cytokines themselves trigger the release of other cytokines [18] [19] [20] and also lead to increased oxidative stress makes them important in chronic inflammation, as well as other immunoresponses, such as fever and acute phase proteins of the liver (IL-1,6,12, IFN-a). Cytokines also play a role in anti-inflammatory pathways and are a possible therapeutic treatment for pathological pain from inflammation or peripheral nerve injury. [21] There are both pro-inflammatory and anti-inflammatory cytokines that regulate this[ clarification needed ] pathway.

Receptors

In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics and partly because a deficiency of cytokine receptors has now been directly linked to certain debilitating immunodeficiency states. In this regard, and also because the redundancy and pleomorphism of cytokines are, in fact, a consequence of their homologous receptors, many authorities think that a classification of cytokine receptors would be more clinically and experimentally useful.

A classification of cytokine receptors based on their three-dimensional structure has, therefore, been attempted. Such a classification, though seemingly cumbersome, provides several unique perspectives for attractive pharmacotherapeutic targets.

Cellular effects

Each cytokine has a matching cell-surface receptor. Subsequent cascades of intracellular signaling then alter cell functions. This may include the upregulation and/or downregulation of several genes and their transcription factors, resulting in the production of other cytokines, an increase in the number of surface receptors for other molecules, or the suppression of their own effect by feedback inhibition. The effect of a particular cytokine on a given cell depends on the cytokine, its extracellular abundance, the presence and abundance of the complementary receptor on the cell surface, and downstream signals activated by receptor binding; these last two factors can vary by cell type. Cytokines are characterized by considerable redundancy, in that many cytokines appear to share similar functions. It seems to be a paradox that cytokines binding to antibodies have a stronger immune effect than the cytokine alone. This may lead to lower therapeutic doses.

It has been shown that inflammatory cytokines cause an IL-10-dependent inhibition of [23] T-cell expansion and function by up-regulating PD-1 levels on monocytes, which leads to IL-10 production by monocytes after binding of PD-1 by PD-L. [23] Adverse reactions to cytokines are characterized by local inflammation and/or ulceration at the injection sites. Occasionally such reactions are seen with more widespread papular eruptions. [24]

Roles in health and disease

Cytokines are involved in several developmental processes during embryonic development. [25] [nb 1] [26] [nb 2] Cytokines are released from the blastocyst, and are also expressed in the endometrium, and have critical roles in the stages of zona hatching, and implantation. [27] Cytokines are crucial for fighting off infections and in other immune responses. [28] However, they can become dysregulated and pathological in inflammation, trauma, sepsis, [28] and hemorrhagic stroke. [29] Dysregulated cytokine secretion in the aged population can lead to inflammaging, and render these individuals more vulnerable to age-related diseases like neurodegenerative diseases and type 2 diabetes. [30]

A 2019 review was inconclusive as to whether cytokines play any definitive role in ME/CFS. [31]

Adverse effects

Adverse effects of cytokines have been linked to many disease states and conditions ranging from schizophrenia, major depression [32] and Alzheimer's disease [33] to cancer. [34] T regulatory cells (Tregs) and related-cytokines are effectively engaged in the process of tumor immune escape and functionally inhibit immune response against the tumor. Forkhead box protein 3 (Foxp3) as a transcription factor is an essential molecular marker of Treg cells. Foxp3 polymorphism (rs3761548) might be involved in cancer progression like gastric cancer through influencing Tregs function and the secretion of immunomodulatory cytokines such as IL-10, IL-35, and TGF-β. [35] Normal tissue integrity is preserved by feedback interactions between diverse cell types mediated by adhesion molecules and secreted cytokines; disruption of normal feedback mechanisms in cancer threatens tissue integrity. [36]

Over-secretion of cytokines can trigger a dangerous cytokine storm syndrome. Cytokine storms may have been the cause of severe adverse events during a clinical trial of TGN1412. Cytokine storms are also suspected to be the main cause of death in the 1918 "Spanish Flu" pandemic. Deaths were weighted more heavily towards people with healthy immune systems, because of their ability to produce stronger immune responses, with dramatic increases in cytokine levels. Another example of cytokine storm is seen in acute pancreatitis. Cytokines are integral and implicated in all angles of the cascade, resulting in the systemic inflammatory response syndrome and multi-organ failure associated with this intra-abdominal catastrophe. [37] In the COVID-19 pandemic, some deaths from COVID-19 have been attributable to cytokine release storms. [38] [39] [40] Current data suggest cytokine storms may be the source of extensive lung tissue damage and dysfunctional coagulation in COVID-19 infections. [41]

Medical use as drugs

Some cytokines have been developed into protein therapeutics using recombinant DNA technology. [42] Recombinant cytokines being used as drugs as of 2014 include: [43]

See also

Notes

  1. ↑ Saito explains "much evidence has suggested that cytokines and chemokines play a very important role in the reproduction, i.e. embryo implantation, endometrial development, and trophoblast growth and differentiation by modulating the immune and endocrine systems."(15)
  2. ↑ Chen explains the regulatory activity of LIF in human and murine embryos: "In conclusion, human preimplantation embryos express LIF and LIF-R mRNA. The expression of these transcripts indicates that preimplantation embryos may be responsive to LIF originating either from the surrounding environment or from the embryos themselves and exerting its function in a paracrine or autocrine manner." (719)

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<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

<span class="mw-page-title-main">Tumor necrosis factor</span> Protein

Tumor necrosis factor is a cytokine and member of the TNF superfamily, which consists of various transmembrane proteins with a homologous TNF domain. It is the first cytokine to be described as an adipokine as secreted by adipose tissue.

<span class="mw-page-title-main">Cell-mediated immunity</span> Immune response that does not involve antibodies

Cellular immunity, also known as cell-mediated immunity, is an immune response that does not rely on the production of antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in response to an antigen.

Interleukins (ILs) are a group of cytokines that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related proteins.

<span class="mw-page-title-main">Interleukin 10</span> Anti-inflammatory cytokine

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

<span class="mw-page-title-main">Interleukin 12</span> Interleukin

Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, helper T cells and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. IL-12 family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.

<span class="mw-page-title-main">Interleukin 4</span> Mammalian protein found in Mus musculus

The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.

<span class="mw-page-title-main">Interleukin 8</span> Mammalian protein found in humans

Interleukin 8 is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their storage vesicles, the Weibel–Palade bodies. In humans, the interleukin-8 protein is encoded by the CXCL8 gene. IL-8 is initially produced as a precursor peptide of 99 amino acids which then undergoes cleavage to create several active IL-8 isoforms. In culture, a 72 amino acid peptide is the major form secreted by macrophages.

<span class="mw-page-title-main">Interleukin 23 subunit alpha</span>

Interleukin-23 subunit alpha is a protein that in humans is encoded by the IL23A gene. The protein is also known as IL-23p19. It is one of the two subunits of the cytokine Interleukin-23.

<span class="mw-page-title-main">Interleukin 18</span> Protein-coding gene in the species Homo sapiens

Interleukin-18 (IL-18), also known as interferon-gamma inducing factor is a protein which in humans is encoded by the IL18 gene. The protein encoded by this gene is a proinflammatory cytokine. Many cell types, both hematopoietic cells and non-hematopoietic cells, have the potential to produce IL-18. It was first described in 1989 as a factor that induced interferon-γ (IFN-γ) production in mouse spleen cells. Originally, IL-18 production was recognized in Kupffer cells, and liver-resident macrophages. However, IL-18 is constitutively expressed in non-hematopoietic cells, such as intestinal epithelial cells, keratinocytes, and endothelial cells. IL-18 can modulate both innate and adaptive immunity and its dysregulation can cause autoimmune or inflammatory diseases.

<span class="mw-page-title-main">Interleukin 32</span> Protein-coding gene in the species Homo sapiens

Interleukin 32 (IL32) is proinflammatory cytokine that in humans is encoded by the IL32 gene. Interleukin 32 can be found in higher mammals but not in rodents. It is mainly expressed intracellularly and the protein has nine different isoforms, because the pre-mRNA can be alternatively spliced. The most active and studied isoform is IL-32γ. It was first reported in 2005, although the IL-32 gene was first described in 1992. It does not belong to any cytokine family because there is almost no homology with other cytokines.

<span class="mw-page-title-main">Interleukin 29</span> Protein-coding gene in the species Homo sapiens

Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 plays an important role in the immune response against pathogenes and especially against viruses by mechanisms similar to type I interferons, but targeting primarily cells of epithelial origin and hepatocytes.

<span class="mw-page-title-main">Interleukin 19</span> Protein-coding gene in the species Homo sapiens

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

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<span class="mw-page-title-main">Interleukin 20 receptor, alpha subunit</span> Protein-coding gene in the species Homo sapiens

Interleukin 20 receptor, alpha subunit, is a subunit of the interleukin-20 receptor, the interleukin-26 receptor, and the interleukin-24 receptor. The interleukin 20 receptor, alpha subunit is also referred to as IL20R1 or IL20RA. The IL20RA receptor is involved in both pro-inflammatory and anti-inflammatory responses, signaling through the JAK-STAT pathway.

An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include interleukin-1 (IL-1), IL-6, IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), and granulocyte-macrophage colony stimulating factor (GM-CSF) and play an important role in mediating the innate immune response. Inflammatory cytokines are predominantly produced by and involved in the upregulation of inflammatory reactions.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

Immunology is the study of the immune system during health and disease. Below is a list of immunology-related articles.

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<span class="mw-page-title-main">Interleukin 17F</span>

Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.

References

  1. ↑ Janeway's Immunobiology. Garland Science. 2017. p. 107. ISBN   978-0-8153-4551-0.
  2. ↑ Lackie J (2010). "Cytokines". A Dictionary of Biomedicine. Oxford University Press. ISBN   978-0-19-954935-1.
  3. ↑ "Cytokine". Stedman's Medical Dictionary (28th ed.). Wolters Kluwer Health, Lippincott Williams & Wilkins. 2006. ISBN   978-0-7817-6450-6.
  4. ↑ Isaacs A, Lindenmann J (September 1957). "Virus interference. I. The interferon". Proc. R. Soc. Lond. B Biol. Sci. 147 (927): 258–267. Bibcode:1957RSPSB.147..258I. doi:10.1098/rspb.1957.0048. PMID   13465720. S2CID   202574492.
  5. ↑ Wheelock EF (July 1965). "Interferon-Like Virus-Inhibitor Induced in Human Leukocytes by Phytohemagglutinin". Science. 149 (3681): 310–311. Bibcode:1965Sci...149..310W. doi:10.1126/science.149.3681.310. PMID   17838106. S2CID   1366348.
  6. ↑ Bloom BR, Bennett B (July 1966). "Mechanism of a reaction in vitro associated with delayed-type hypersensitivity". Science. 153 (3731): 80–82. Bibcode:1966Sci...153...80B. doi:10.1126/science.153.3731.80. PMID   5938421. S2CID   43168526.
  7. ↑ David JR (July 1966). "Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction". Proc. Natl. Acad. Sci. U.S.A. 56 (1): 72–77. Bibcode:1966PNAS...56...72D. doi: 10.1073/pnas.56.1.72 . PMC   285677 . PMID   5229858.
  8. ↑ Dumonde DC, Wolstencroft RA, Panayi GS, Matthew M, Morley J, Howson WT (October 1969). ""Lymphokines": non-antibody mediators of cellular immunity generated by lymphocyte activation". Nature. 224 (5214): 38–42. Bibcode:1969Natur.224...38D. doi:10.1038/224038a0. PMID   5822903. S2CID   4172811.
  9. ↑ Cohen S, Bigazzi PE, Yoshida T (April 1974). "Commentary. Similarities of T cell function in cell-mediated immunity and antibody production". Cell. Immunol. 12 (1): 150–159. doi:10.1016/0008-8749(74)90066-5. PMID   4156495.
  10. ↑ Ogawa M (1993). "Differentiation and proliferation of hematopoetic stem cells". Blood. 81 (11): 2844–2853. doi: 10.1182/blood.V81.11.2844.2844 . PMID   8499622.
  11. ↑ Boyle JJ (January 2005). "Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture". Current Vascular Pharmacology. 3 (1): 63–68. CiteSeerX   10.1.1.324.9948 . doi:10.2174/1570161052773861. PMID   15638783.
  12. ↑ Cannon JG (December 2000). "Inflammatory Cytokines in Nonpathological States". News in Physiological Sciences. 15 (6): 298–303. doi:10.1152/physiologyonline.2000.15.6.298. PMID   11390930.
  13. ↑ Leonard WJ (December 2001). "Cytokines and immunodeficiency diseases". Nature Reviews. Immunology. 1 (3): 200–208. doi: 10.1038/35105066 . PMID   11905829. S2CID   5466985.
  14. ↑ Rozwarski DA, Gronenborn AM, Clore GM, Bazan JF, Bohm A, Wlodawer A, et al. (March 1994). "Structural comparisons among the short-chain helical cytokines". Structure. 2 (3): 159–173. doi: 10.1016/s0969-2126(00)00018-6 . PMID   8069631.
  15. ↑ Reche PA (April 2019). "The tertiary structure of γc cytokines dictates receptor sharing". Cytokine. 116: 161–168. doi:10.1016/j.cyto.2019.01.007. PMID   30716660. S2CID   73449371.
  16. ↑ Vlahopoulos S, Boldogh I, Casola A, Brasier AR (September 1999). "Nuclear factor-kappaB-dependent induction of interleukin-8 gene expression by tumor necrosis factor alpha: evidence for an antioxidant sensitive activating pathway distinct from nuclear translocation". Blood. 94 (6): 1878–1879. doi:10.1182/blood.V94.6.1878.418k03_1878_1889. PMID   10477716. S2CID   25974629.
  17. ↑ David F, Farley J, Huang H, Lavoie JP, Laverty S (April 2007). "Cytokine and chemokine gene expression of IL-1beta stimulated equine articular chondrocytes". Vet Surg. 36 (3): 221–227. doi:10.1111/j.1532-950X.2007.00253.x. PMID   17461946.
  18. ↑ Chokkalingam V, Tel J, Wimmers F, Liu X, Semenov S, Thiele J, et al. (December 2013). "Probing cellular heterogeneity in cytokine-secreting immune cells using droplet-based microfluidics". Lab Chip. 13 (24): 4740–4744. doi:10.1039/c3lc50945a. PMID   24185478. Archived from the original on 29 November 2020. Retrieved 21 November 2020.
  19. ↑ Carpenter LR, Moy JN, Roebuck KA (March 2002). "Respiratory syncytial virus and TNF alpha induction of chemokine gene expression involves differential activation of Rel A and NF-kappa B1". BMC Infect. Dis. 2: 5. doi: 10.1186/1471-2334-2-5 . PMC   102322 . PMID   11922866.
  20. ↑ Tian B, Nowak DE, Brasier AR (September 2005). "A TNF-induced gene expression program under oscillatory NF-kappaB control". BMC Genomics. 6: 137. doi: 10.1186/1471-2164-6-137 . PMC   1262712 . PMID   16191192.
  21. ↑ Zhang JM, An J (2007). "Cytokines, inflammation, and pain". Int Anesthesiol Clin. 45 (2): 27–37. doi:10.1097/AIA.0b013e318034194e. PMC   2785020 . PMID   17426506.
  22. ↑ Gaffen SL (August 2009). "Structure and signalling in the IL-17 receptor family". Nat. Rev. Immunol. 9 (8): 556–567. doi:10.1038/nri2586. PMC   2821718 . PMID   19575028.
  23. 1 2 Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, et al. (April 2010). "Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection". Nature Medicine. 16 (4): 452–459. doi:10.1038/nm.2106. PMC   4229134 . PMID   20208540.
  24. ↑ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN   0-7216-2921-0.[ page needed ]
  25. ↑ Saito S (2001). "Cytokine cross-talk between mother and the embryo/placenta". J. Reprod. Immunol. 52 (1–2): 15–33. doi:10.1016/S0165-0378(01)00112-7. PMID   11600175.
  26. ↑ Chen HF, Shew JY, Ho HN, Hsu WL, Yang YS (October 1999). "Expression of leukemia inhibitory factor and its receptor in preimplantation embryos". Fertil. Steril. 72 (4): 713–719. doi: 10.1016/S0015-0282(99)00306-4 . PMID   10521116.
  27. ↑ Seshagiri PB, Vani V, Madhulika P (March 2016). "Cytokines and Blastocyst Hatching". American Journal of Reproductive Immunology. 75 (3): 208–217. doi: 10.1111/aji.12464 . PMID   26706391. S2CID   11540123.
  28. 1 2 Dinarello CA (August 2000). "Proinflammatory cytokines". Chest. 118 (2): 503–508. doi:10.1378/chest.118.2.503. PMID   10936147.
  29. ↑ Zhu H, Wang Z, Yu J, et al. (March 2019). "Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage". Prog. Neurobiol. 178: 101610. doi:10.1016/j.pneurobio.2019.03.003. PMID   30923023. S2CID   85495400.
  30. ↑ Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. (June 2000). "Inflamm-aging. An evolutionary perspective on immunosenescence". Annals of the New York Academy of Sciences. 908 (1): 244–254. Bibcode:2000NYASA.908..244F. doi:10.1111/j.1749-6632.2000.tb06651.x. ISSN   0077-8923. PMID   10911963. S2CID   1843716.
  31. ↑ Corbitt M, Eaton-Fitch N, Staines D, Cabanas H, Marshall-Gradisnik S (24 August 2019). "A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID)". BMC Neurology. 19 (1): 207. doi: 10.1186/s12883-019-1433-0 . PMC   6708220 . PMID   31445522.
  32. ↑ Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. (March 2010). "A meta-analysis of cytokines in major depression". Biol. Psychiatry. 67 (5): 446–457. doi:10.1016/j.biopsych.2009.09.033. PMID   20015486. S2CID   230209.
  33. ↑ Swardfager W, Lanctôt K, Rothenburg L, Wong A, Cappell J, Herrmann N (November 2010). "A meta-analysis of cytokines in Alzheimer's disease". Biol. Psychiatry. 68 (10): 930–941. doi:10.1016/j.biopsych.2010.06.012. PMID   20692646. S2CID   6544784.
  34. ↑ Locksley RM, Killeen N, Lenardo MJ (February 2001). "The TNF and TNF receptor superfamilies: integrating mammalian biology". Cell. 104 (4): 487–501. doi: 10.1016/S0092-8674(01)00237-9 . PMID   11239407. S2CID   7657797.
  35. ↑ Ezzeddini R, Somi MH, Taghikhani M, Moaddab SY, Masnadi Shirazi K, Shirmohammadi M, et al. (February 2021). "Association of Foxp3 rs3761548 polymorphism with cytokines concentration in gastric adenocarcinoma patients". Cytokine. 138: 155351. doi:10.1016/j.cyto.2020.155351. ISSN   1043-4666. PMID   33127257. S2CID   226218796.
  36. ↑ Vlahopoulos SA, Cen O, Hengen N, Agan J, Moschovi M, Critselis E, et al. (August 2015). "Dynamic aberrant NF-κB spurs tumorigenesis: a new model encompassing the microenvironment". Cytokine Growth Factor Rev. 26 (4): 389–403. doi:10.1016/j.cytogfr.2015.06.001. PMC   4526340 . PMID   26119834.
  37. ↑ Makhija R, Kingsnorth AN (2002). "Cytokine storm in acute pancreatitis". Journal of Hepato-Biliary-Pancreatic Surgery. 9 (4): 401–410. doi:10.1007/s005340200049. PMID   12483260.
  38. ↑ Cron R, Chatham WW (12 March 2020). "How doctors can potentially significantly reduce the number of deaths from Covid-19". Vox . Retrieved 14 March 2020.
  39. ↑ Ruan Q, Yang K, Wang W, Jiang L, Song J (May 2020). "Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China". Intensive Care Medicine. 46 (5): 846–848. doi:10.1007/s00134-020-05991-x. PMC   7080116 . PMID   32125452.
  40. ↑ Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ (March 2020). "COVID-19: consider cytokine storm syndromes and immunosuppression". Lancet. 395 (10229): 1033–1034. doi:10.1016/S0140-6736(20)30628-0. PMC   7270045 . PMID   32192578.
  41. ↑ Cascella M, Rajnik M, Cuomo A, et al. (4 October 2020). Features, Evaluation, and Treatment of Coronavirus. StatPearls Publishing. PMID   32150360 . Retrieved 4 December 2020.
  42. ↑ De Root AS, Scott DW (November 2007). "Immunogenicity of protein therapeutics". Trends in Immunology. 28 (11): 482–490. doi:10.1016/j.it.2007.07.011. PMID   17964218.
  43. ↑ Dimitrov DS (2012). "Therapeutic Proteins". Methods in Molecular Biology. Vol. 899. pp. 1–26. doi:10.1007/978-1-61779-921-1_1. ISBN   978-1-61779-920-4. PMC   6988726 . PMID   22735943.
  44. ↑ Woodman RC, Erickson RW, Rae J, Jaffe HS, Curnutte JT (March 1992). "Prolonged recombinant interferon-gamma therapy in chronic granulomatous disease: evidence against enhanced neutrophil oxidase activity". Blood. 79 (6): 1558–1562. doi: 10.1182/blood.v79.6.1558.bloodjournal7961558 (inactive 29 July 2024). PMID   1312372.{{cite journal}}: CS1 maint: DOI inactive as of July 2024 (link)
  45. ↑ Key LL, Rodriguiz RM, Willi SM, Wright NM, Hatcher HC, Eyre DR, et al. (June 1995). "Long-term treatment of osteopetrosis with recombinant human interferon gamma". N. Engl. J. Med. 332 (24): 1594–1599. doi: 10.1056/NEJM199506153322402 . PMID   7753137.
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