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50-574: SASP is heterogenous, with the exact composition dependent upon the senescent-cell inducer and the cell type. Interleukin 12 (IL-12) and Interleukin 10 (IL-10) are increased more than 200-fold in replicative senescence in contrast to stress-induced senescence or proteosome-inhibited senescence where the increases are about 30-fold or less. Tumor necrosis factor (TNF) is increased 32-fold in stress-induced senescence, 8-fold in replicative senescence, and only slightly in proteosome-inhibited senescence. Interleukin 6 (IL-6) and interleukin 8 (IL-8) are

100-411: A p53 -dependent process. Autophagy is upregulated to promote survival. SASP factors can maintain senescent cells in their senescent state of growth arrest, thereby preventing cancerous transformation. Additionally, SASP secreted by cells that have become senescent because of stresses can induce senescence in adjoining cells subject to the same stresses. thereby reducing cancer risk. SASP can play

150-414: A T cell-stimulating factor, which can stimulate the growth and function of T cells. It stimulates the production of interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) from T cells and natural killer (NK) cells, and reduces IL-4 mediated suppression of IFN-γ. T cells that produce IL-12 have a coreceptor , CD30 , which is associated with IL-12 activity. IL-12 plays an important role in

200-408: A beneficial role by promoting wound healing. SASP may play a role in tissue regeneration by signaling for senescent cell clearance by immune cells, allowing progenitor cells to repopulate tissue. In development, SASP also may be used to signal for senescent cell clearance to aid tissue remodeling. The ability of SASP to clear senescent cells and regenerate damaged tissue declines with age. In contrast to

250-528: A cluster on chromosome 9. IFN-α is also made synthetically as medication in hairy cell leukemia. The International Nonproprietary Name (INN) for the product is interferon alfa . The recombinant type is interferon alfacon-1 . The pegylated types are pegylated interferon alfa-2a and pegylated interferon alfa-2b . Recombinant feline interferon omega is a form of cat IFN-α (not ω) for veterinary use. The IFN-β proteins are produced in large quantities by fibroblasts . They have antiviral activity that

300-1087: A more extensive characterization of avian genomes. Functional lizard type I IFNs can be found in lizard genome databases. Turtle type I IFNs have been purified (references from 1970s needed). They resemble mammalian homologs. The existence of amphibian type I IFNs have been inferred by the discovery of the genes encoding their receptor chains. They have not yet been purified, or their genes cloned. Piscine (bony fish) type I IFN has been cloned first in zebrafish. and then in many other teleost species including salmon and mandarin fish. With few exceptions, and in stark contrast to avian and especially mammalian IFNs, they are present as single genes (multiple genes are however seen in polyploid fish genomes, possibly arising from whole-genome duplication). Unlike amniote IFN genes, piscine type I IFN genes contain introns, in similar positions as do their orthologs, certain interleukins. Despite this important difference, based on their 3-D structure these piscine IFNs have been assigned as Type I IFNs. While in mammalian species all Type I IFNs bind to

350-490: A possible anti- cancer drug. However, it has not been shown to have substantial activity in the tumors tested to this date. There is a link that may be useful in treatment between IL-12 and the diseases psoriasis & inflammatory bowel disease. There has also been research indicating that interleukin 12 is linked with interleukin 23 and antibodies against these factors have a possible role in creating an anti-inflammatory effect in inflammatory bowel disease. IL-12 binds to

400-577: A result, IFNγ production by the child's lymphocytes was markedly impaired. This suggested that IL-12 is essential for protective immunity to intracellular bacteria such as mycobacteria and Salmonella . Support is lent to this idea by the observation that a receptor for IL-12 is important for IFNγ production by lymphocytes. T and NK cells from seven unrelated patients who had severe idiopathic mycobacterial and Salmonella infections failed to produce IFNγ when stimulated with IL-12. The patients were otherwise healthy. They were found to have mutations in

450-719: A specific cell surface receptor complex known as the IFN-α receptor ( IFNAR ) that consists of IFNAR1 and IFNAR2 chains. Type I IFNs are found in all mammals, and homologous (similar) molecules have been found in birds, reptiles, amphibians and fish species. IFN-α and IFN-β are secreted by many cell types including lymphocytes ( NK cells , B-cells and T-cells ), macrophages, fibroblasts, endothelial cells, osteoblasts and others. They stimulate both macrophages and NK cells to elicit an anti-viral response, involving IRF3/IRF7 antiviral pathways, and are also active against tumors . Plasmacytoid dendritic cells have been identified as being

500-532: A treatment of mice with IL-12 specific antibodies ameliorated the disease. Results published in the Journal of Allergy and Clinical Immunology from a study where mice that were bred to be allergic to peanuts, interleukin-12 has been shown to not be present, suggesting that the molecule normally stops allergies to food from developing. Further investigation is underway, to determine whether the results found in mice are as profound in humans. Interleukin 12 (IL-12)

550-407: Is a heterodimeric cytokine encoded by two separate genes, IL-12A (p35) and IL-12B (p40). The active heterodimer (referred to as ' p70 '), and a homodimer of p40 are formed following protein synthesis. IL12A is composed of a bundle of four alpha helices . IL12B has three beta sheet domains. IL-12 is involved in the differentiation of naive T cells into Th1 cells . It is known as

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600-563: Is also a key initiator of SASP. Interleukin 1 alpha (IL1A) is found on the surface of senescent cells, where it contributes to the production of SASP factors due to a positive feedback loop with NF-κB. Translation of mRNA for IL1A is highly dependent upon mTOR activity. mTOR activity increases levels of IL1A, mediated by MAPKAPK2 . mTOR inhibition of ZFP36L1 prevents this protein from degrading transcripts of numerous components of SASP factors. Inhibition of mTOR supports autophagy , which can generate SASP components. Ribosomal DNA (rDNA)

650-505: Is associated with many aging-associated diseases , including not only cancer, but atherosclerosis and osteoarthritis . For this reason, senolytic therapy has been proposed as a generalized treatment for these and many other diseases. The flavonoid apigenin has been shown to strongly inhibit SASP production. SASP can aid in signaling to immune cells for senescent cell clearance , with specific SASP factors secreted by senescent cells attracting and activating different components of both

700-490: Is both a promoter of DNA damage response and a consequence of DNA damage response, in an autocrine and paracrine manner. Aberrant oncogenes , DNA damage, and oxidative stress induce mitogen-activated protein kinases , which are the upstream regulators of NF-κB. Demethylation of DNA packaging protein Histone H3 ( H3K27me 3) can lead to up-regulation of genes controlling SASP. mTOR (mammalian target of rapamycin)

750-521: Is demonstrated by IFN-γ production and killing of target cells. IL-12 also has anti- angiogenic activity, which means it can block the formation of new blood vessels. It does this by increasing production of interferon gamma , which in turn increases the production of a chemokine called inducible protein-10 (IP-10 or CXCL10 ). IP-10 then mediates this anti-angiogenic effect. Because of its ability to induce immune responses and its anti-angiogenic activity, there has been an interest in testing IL-12 as

800-402: Is effectively treated with the selective serotonin reuptake inhibitor class of antidepressants. Interferonopathies are a class of hereditary auto-inflammatory and autoimmune diseases characterised by upregulated type 1 interferon and downstream interferon stimulated genes. The symptoms of these diseases fall in a wide clinical spectrum, and often resemble those of viral infections acquired while

850-491: Is essential for induction of cellular senescence by DNA damage. SASP secretion can also be initiated by the microRNAs miR-146 a/b. Senescent cells release mt-dsRNA into the cytosol driving the SASP via RIGI/MDA5/MAVS/MFN1. Moreover, senescent cells are hypersensitive to mt-dsRNA-driven inflammation due to reduced levels of PNPT1 and ADAR1. Senescent cells are highly metabolically active, producing large amounts of SASP, which

900-847: Is involved mainly in innate immune response. Two types of IFN-β have been described, IFN-β1 ( IFNB1 ) and IFN-β3 ( IFNB3 ) (a gene designated IFN-β2 is actually IL-6 ). IFN-ε, -κ, -τ, and -ζ appear, at this time, to come in a single isoform in humans, IFNK . Only ruminants encode IFN-τ, a variant of IFN-ω. So far, IFN-ζ is only found in mice, while a structural homolog, IFN-δ is found in a diverse array of non-primate and non-rodent placental mammals. Most but not all placental mammals encode functional IFN-ε and IFN-κ genes. . IFN-ω, although having only one functional form described to date ( IFNW1 ), has several pseudogenes : IFNWP2 , IFNWP4 , IFNWP5 , IFNWP9 , IFNWP15 , IFNWP18 , and IFNWP19 in humans. Many non-primate placental mammals express multiple IFN-ω subtypes. This subtype of type I IFN

950-520: Is known as the JAK-STAT pathway . An extensive review and visualization of IL-12 signaling can be found at the peer-reviewed pathway database Reactome: Interleukin-12 family IL-12 is linked with autoimmunity . Administration of IL-12 to people suffering from autoimmune diseases was shown to worsen the autoimmune phenomena. This is believed to be due to its key role in induction of Th1 immune responses. In contrast, IL-12 gene knock-out in mice or

1000-825: Is known to be important. Few endogenous regulators have been found to elicit this important regulatory function, such as SOCS1 and Aryl Hydrocarbon Receptor Interacting Protein (AIP). The mammalian types are designated IFN-α (alpha), IFN-β (beta), IFN-κ (kappa), IFN-δ (delta), IFN-ε (epsilon), IFN-τ (tau), IFN-ω (omega), and IFN-ζ (zeta, also known as limitin). Of these types, IFN-α, IFN -ω, and IFN-τ can work across species. The IFN-α proteins are produced mainly by plasmacytoid dendritic cells (pDCs). They are mainly involved in innate immunity against viral infection. The genes responsible for their synthesis come in 13 subtypes that are called IFNA1 , IFNA2 , IFNA4 , IFNA5 , IFNA6 , IFNA7 , IFNA8 , IFNA10 , IFNA13 , IFNA14 , IFNA16 , IFNA17 , IFNA21 . These genes are found together in

1050-446: Is more vulnerable to DNA damage than DNA elsewhere in the genome such than rDNA instability can lead to cellular senescence, and thus to SASP The high-mobility group proteins ( HMGA ) can induce senescence and SASP in a p53 -dependent manner. Activation of the retrotransposon LINE1 can result in cytosolic DNA that activates the cGAS–STING cytosolic DNA sensing pathway upregulating SASP by induction of interferon type I . cGAS

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1100-469: 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. IL12

1150-646: Is not completely understood, the use of IFN-β1 has been found to reduce brain lesions, increase the expression of anti-inflammatory cytokines and reduce T cell infiltration into the brain. One of the major limiting factors in the efficacy of type I interferon therapy are the high rates of side effects. Between 15% - 40% of people undergoing type 1 IFN treatment develop major depressive disorders. Less commonly, interferon treatment has also been associated with anxiety, lethargy, psychosis and parkinsonism. Mood disorders associated with IFN therapy can be reversed by discontinuation of treatment, and IFN therapy related depression

1200-523: Is produced by activated antigen-presenting cells ( dendritic cells , macrophages ). It promotes the development of Th1 responses and is a powerful inducer of IFNγ production by T and NK cells . A child with Bacillus Calmette–Guérin and Salmonella enteritidis infection was found to have a large homozygous deletion within the IL-12 p40 subunit gene, precluding expression of functional IL-12 p70 cytokine by activated dendritic cells and phagocytes. As

1250-460: Is used by IFN-α to reduce pain; IFN-α interacts with the μ-opioid receptor to act as an analgesic . In mice, IFN-β inhibits immune cell production of growth factors, thereby slowing tumor growth, and inhibits other cells from producing vessel-producing growth factors, thereby blocking tumor angiogenesis and hindering the tumour from connecting into the blood vessel system. In both mice and human, negative regulation of type I interferon signaling

1300-582: Is why senescent cells consisting of only 2% or 3% of tissue cells can be a major cause of aging-associated diseases . SASP factors cause non-senescent cells to become senescent. SASP factors induce insulin resistance . SASP disrupts normal tissue function by producing chronic inflammation , induction of fibrosis and inhibition of stem cells . Transforming growth factor beta family members secreted by senescent cells impede differentiation of adipocytes , leading to insulin resistance . SASP factors IL-6 and TNF α enhance T-cell apoptosis , thereby impairing

1350-480: The STAT1 gene, which were associated with lower production of interferon-γ, IL-17, and IL-22 in response to IL-12 or IL-23 receptor associated Jak2 and Tyk2 activity. Interferon type I 1itf :24-186 1au1 B:22-187 2hif :24-182 The type-I interferons (IFN) are cytokines which play essential roles in inflammation , immunoregulation , tumor cells recognition, and T-cell responses. In

1400-860: The US Food and Drug Administration (FDA) for cancer. To date, pharmaceutical companies produce several types of recombinant and pegylated IFNα for clinical use; e.g., IFNα2a ( Roferon-A , Roche), IFNα2b ( Intron-A , Schering-Plough) and pegylated IFNα2b (Sylatron, Schering Corporation) for treatment of hairy cell leukemia , melanoma , renal cell carcinoma , Kaposi's sarcoma , multiple myeloma , follicular and non-Hodgkin lymphoma, and chronic myelogenous leukemia . Human IFNβ ( Feron , Toray ltd.) has also been approved in Japan to treat glioblastoma , medulloblastoma , astrocytoma , and melanoma . By combining PD-1/PD-L1 inhibitors with type I interferons, researchers aim to tackle multiple resistance mechanisms and enhance

1450-410: The innate and adaptive immune system . The SASP cytokine CCL2 (MCP1) recruits macrophages to remove cancer cells. Although transient expression of SASP can recruit immune system cells to eliminate cancer cells as well as senescent cells, chronic SASP promotes cancer. Senescent hematopoietic stem cells produces a SASP that induces an M1 polarization of macrophages which kills the senescent cells in

1500-454: The IFN gene cluster is prevalent among 24 cancer types. Notably deletion of this cluster is significantly associated with increased mortality in many cancer types particularly uterus , kidney , and brain cancers. The Cancer Genome Atlas PanCancer analysis also showed that copy number alteration of the IFN gene cluster is significantly associated with decreased overall survival . For instance,

1550-404: The IL-12 receptor β1 chain, resulting in premature stop codons in the extracellular domain, resulting in unresponsiveness to this cytokine, again demonstrating IL-12's crucial role in host defense. Defective Th1 and Th17 immune responses leading to chronic mucocutaneous candidiasis result from a mutation further downstream in the IL-12 signalling pathway . The trait was mapped to mutations in

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1600-607: The IL-12 receptor, which is a heterodimeric receptor formed by IL-12Rβ1 and IL-12Rβ2 . IL-12Rβ2 is considered to play a key role in IL-12 function, since it is found on activated T cells and is stimulated by cytokines that promote Th1 cells development and inhibited by those that promote Th2 cells development. Upon binding, IL-12R-β2 becomes tyrosine phosphorylated and provides binding sites for kinases, Tyk2 and Jak2 . These are important in activating critical transcription factor proteins such as STAT4 that are implicated in IL-12 signaling in T cells and NK cells. This pathway

1650-439: The SASP by stabilizing Oct-4 and sirtuin 1 mRNAs. A SASP index composed of 22 SASP factors has been used to evaluate treatment outcomes of late life depression . Higher SASP index scores corresponded to increased incidence of treatment failure, whereas no individual SASP factors were associated with treatment failure. Chronic inflammation associated with aging has been termed inflammaging , although SASP may be only one of

1700-422: The SASP composition, notably including p53 status. Despite the fact that cellular senescence likely evolved as a means of protecting against cancer early in life, SASP promotes the development of late-life cancers. Cancer invasiveness is promoted primarily though the actions of the SASP factors metalloproteinase , chemokine , interleukin 6 (IL-6), and interleukin 8 (IL-8). In fact, SASP from senescent cells

1750-558: The activities of natural killer cells and T lymphocytes. IL-12 mediates enhancement of the cytotoxic activity of NK cells and CD8 + cytotoxic T lymphocytes . There also seems to be a link between IL-2 and the signal transduction of IL-12 in NK cells. IL-2 stimulates the expression of two IL-12 receptors, IL-12R-β1 and IL-12R-β2, maintaining the expression of a critical protein involved in IL-12 signaling in NK cells . Enhanced functional response

1800-465: The capacity of the adaptive immune system . SASP factors from senescent cells reduce nicotinamide adenine dinucleotide (NAD+) in non-senescent cells, thereby reducing the capacity for DNA repair and sirtuin activity in non-senescent cells. SASP induction of the NAD+ degrading enzyme CD38 on non-senescent cells ( macrophages ) may be responsible for most of this effect. By contrast, NAD+ contributes to

1850-491: The child is in utero, although lacking any infectious origin. The aetiology is largely still unknown, but the most common genetic mutations are associated with nucleic acid regulation, leading most researchers to suggest these arise from the failure of antiviral systems to differentiate between host and viral DNA and RNA. Avian type I IFNs have been characterized and preliminarily assigned to subtypes (IFN I, IFN II, and IFN III), but their classification into subtypes should await

1900-419: The human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cytoband over approximately 400 kb including coding genes for IFNα ( IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17 and IFNA21 ), IFNω ( IFNW1 ), IFNɛ ( IFNE ), IFNк ( IFNK ) and IFNβ ( IFNB1 ), plus 11 IFN pseudogenes. Interferons bind to interferon receptors . All type I IFNs bind to

1950-432: The most conserved and robust features of SASP. But some SASP components are anti-inflammatory. Senescence and SASP can also occur in post-mitotic cells, notably neurons. The SASP in senescent neurons can vary according to cell type, the initiator of senescence, and the stage of senescence. An online SASP Atlas serves as a guide to the various types of SASP. SASP is one of the three main features of senescent cells,

2000-465: The most potent producers of type I IFNs in response to antigen, and have thus been coined natural IFN producing cells. IFN-ω is released by leukocytes at the site of viral infection or tumors. IFN-α acts as a pyrogenic factor by altering the activity of thermosensitive neurons in the hypothalamus thus causing fever. It does this by binding to opioid receptors and eliciting the release of prostaglandin-E 2 (PGE 2 ). A similar mechanism

2050-529: The other two features being arrested cell growth , and resistance to apoptosis . SASP factors can include the anti-apoptotic protein Bcl-xL , but growth arrest and SASP production are independently regulated. Although SASP from senescent cells can kill neighboring normal cells, the apoptosis-resistance of senescent cells protects those cells from SASP. The concept and abbreviation of SASP was first established by Judith Campisi and her group, who first published on

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2100-455: The overall anti-tumor immune response. The approach is supported by preclinical and clinical studies that show promising synergistic effects, particularly in melanoma and renal carcinoma . These studies reveal increased infiltration and activation of T cells within the tumor microenvironment , the development of memory T cells , and prolonged patient survival. Due to their strong antiviral properties, recombinant type 1 IFNs can be used for

2150-422: The overall survival of patients with brain glioma reduced from 93 months (diploidy) to 24 months. In conclusion, the copy number alteration of the IFN gene cluster is associated with increased mortality and decreased overall survival in cancer. From the 1980s onward, members of type-I IFN family have been the standard care as immunotherapeutic agents in cancer therapy. In particular, IFNα has been approved by

2200-709: The persistent character of SASP in the chronic inflammation of multiple age-related diseases, beneficial SASP in wound healing is transitory. Temporary SASP in the liver or kidney can reduce fibrosis , but chronic SASP could lead to organ dysfunction. Senescent cells have permanently active mTORC1 irrespective of nutrients or growth factors, resulting in the continuous secretion of SASP. By inhibiting mTORC1, rapamycin reduces SASP production by senescent cells. SASP has been reduced through inhibition of p38 mitogen-activated protein kinases and janus kinase . The protein hnRNP A1 (heterogeneous nuclear ribonucleoprotein A1) antagonizes cellular senescence and induction of

2250-418: The possible causes of this condition. Chronic systemic inflammation is associated with aging-associated diseases . Senolytic agents have been recommended to counteract some of these effects. Chronic inflammation due to SASP can suppress immune system function, which is one reason elderly persons are more vulnerable to COVID-19 . Interleukin 12 Interleukin 12 ( IL-12 ) is an interleukin that

2300-430: The secondary (pro-inflammatory) manifestation of SASP. SASP induces an unfolded protein response in the endoplasmic reticulum because of an accumulation of unfolded proteins, resulting in proteotoxic  impairment of cell function. SASP cytokines can result in an inflamed stem cell niche, leading to stem cell exhaustion and impaired stem cell function. SASP can either promote or inhibit cancer , depending on

2350-457: The subject in 2008. SASP expression is induced by a number of transcription factors , including MLL1 (KMT2A), C/EBPβ , and NF-κB . NF-κB and the enzyme CD38 are mutually activating. NF-κB is expressed as a result of inhibition of autophagy -mediated degradation of the transcription factor GATA4 . GATA4 is activated by the DNA damage response factors, which induce cellular senescence. SASP

2400-410: The treatment for persistent viral infection. Pegylated IFN-α is the current standard of care when it comes to chronic Hepatitis B and C infection. Currently, there are four FDA approved variants of IFN-β1 used as a treatment for relapsing multiple sclerosis . IFN-β1 is not an appropriate treatment for patients with progressive, non-relapsing forms of multiple sclerosis. Whilst the mechanism of action

2450-453: Was recently described as a pseudogene in human, but potentially functional in the domestic cat genome. In all other genomes of non-feline placental mammals, IFN-ν is a pseudogene; in some species, the pseudogene is well preserved, while in others, it is badly mutilated or is undetectable. Moreover, in the cat genome, the IFN-ν promoter is deleteriously mutated. It is likely that the IFN-ν gene family

2500-1111: Was rendered useless prior to mammalian diversification. Its presence on the edge of the type I IFN locus in mammals may have shielded it from obliteration, allowing its detection. From the 1980s onward, members of type-I IFN family have been the standard care as immunotherapeutic agents in cancer therapy. In particular, IFNα has been approved by the US Food and Drug Administration (FDA) for cancer. To date, pharmaceutical companies produce several types of recombinant and pegylated IFNα for clinical use; e.g., IFNα2a ( Roferon-A , Roche), IFNα2b ( Intron-A , Schering-Plough) and pegylated IFNα2b (Sylatron, Schering Corporation) for treatment of hairy cell leukemia , melanoma , renal cell carcinoma , Kaposi's sarcoma , multiple myeloma , follicular and non-Hodgkin lymphoma, and chronic myelogenous leukemia . Human IFNβ ( Feron , Toray ltd.) has also been approved in Japan to treat glioblastoma , medulloblastoma , astrocytoma , and melanoma . [1] A large individual patient data meta-analysis using 9937 patients obtained from cBioportal indicates that copy number alteration of

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