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46-532: IL-12 or IL 12 may refer to: Interleukin 12 , a protein encoded in humans Ilyushin Il-12 , a Soviet twin-engine airliner and military transport aircraft Illinois's 12th congressional district Illinois Route 12 , a highway in Illinois, United States [REDACTED] Topics referred to by the same term This disambiguation page lists articles associated with

92-435: A T Cell Receptor (a TCR) and an HLA-peptide complex. As a result of that conjunction a signalling pathway (signalling a cell's protein making machinery to express or 'make' IL-2), a PhosphoLipase-C (PLC) dependent pathway, is set up. PLC activates 3 major transcription factors and their pathways: NFAT , NFkB and AP-1 . In addition and after costimulation from CD28 the optimal activation of expression of IL-2 and these pathways

138-414: 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

184-407: A broad range of doses, without serious side effects. Tumour blood vessels are more vulnerable than normal blood vessels to the actions of IL-2. When injected inside a tumor, i.e. local application, a process mechanistically similar to the vascular leakage syndrome, occurs in tumor tissue only. Disruption of the blood flow inside of the tumor effectively destroys tumor tissue. In local application,

230-549: A free cytokine, mammalian IL-2 that is secreted by activated T cells is important for a negative feedback loop by the stimulation of regulatory T cells, the latter being the cells with the highest constitutive IL-2Rα (aka CD25) expression. Besides this negative feedback loop, mammalian IL-2 also participates in a positive feedback loop because activated T cells enhance their own IL-2Rα expression. As in mammals, fish IL-2 also stimulates T cell proliferation and appears to preferentially stimulate regulatory T cells. Fish IL-2 induces

276-456: A manner reminiscent of how mammalian IL-15 binds to IL-15Rα. Despite fish IL-2 and IL-15 sharing the same IL-15Rα chain, the stability of fish IL-2 is independent of it whereas IL-15 and especially IL-15L depend on binding to (co-presentation with) IL-15Rα for their stability and function. This suggests that, like in mammals, fish IL-2, in contrast to fish IL-15 and IL-15L, is not relying on "in trans" presentation by its receptor alpha chain. As

322-406: A point of disagreement. The commercial interest in local IL-2 therapy has been very low. Because only a very low dose IL-2 is used, treatment of a patient would cost about $ 500 commercial value of the patented IL-2. The commercial return on investment is too low to stimulate additional clinical studies for the registration of intratumoral IL-2 therapy. Usually, in the U.S., the higher dosage option

368-490: 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

414-400: A promising immunotherapeutic agent due to significant drawbacks which are listed above. Some of the issues can be overcome using IL-2 ic. They are composed of IL-2 and some of its monoclonal antibody (mAb) and can potentiate biologic activity of IL-2 in vivo . The main mechanism of this phenomenon in vivo is due to the prolongation of the cytokine half-life in circulation. Depending on

460-577: 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

506-416: A similar genomic location. In fish, IL-2 shares a single receptor alpha chain with its related cytokines IL-15 and IL-15-like (IL-15L). This "IL-15Rα" receptor chain is similar to mammalian IL-15Rα, and in tetrapod evolution a duplication of its coding gene plus further diversification created mammalian IL-2Rα. Sequences, and structural analysis of grass carp IL-2, suggest that fish IL-2 binds IL-15Rα in

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552-532: 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)

598-407: 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

644-464: Is a recombinant IL-2 with a serine at residue 125, sold by Shenzhen Neptunus. Neoleukin 2/15 is a computationally designed mimic of IL-2 that was designed to avoid common side effects. However, clinical trials into this candidate were discontinued. Various dosages of IL-2 across the United States and across the world are used. The efficacy and side effects of different dosages is often

690-494: 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. IL12

736-477: Is commenced by IL-2 binding to its receptor, following which cytoplasmatic domains of CD122 and CD132 heterodimerize . This leads to the activation of Janus kinases JAK1 and JAK3 which subsequently phosphorylate T338 on CD122. This phosphorylation recruits STAT transcription factors , predominantly STAT5 , which dimerize and migrate to the cell nucleus where they bind to DNA . with an "express other proteins" signal. The proteins expressed by means of

782-521: 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

828-543: Is dephosphorylated and therefore translocated to the nucleus. AP-1 is a dimer and is composed of c-Jun and c-Fos proteins. It cooperates with other transcription factors including NFkB and Oct. NFkB is translocated to the nucleus after costimulation through CD28. NFkB is a heterodimer and there are two binding sites on the IL-2 promoter. IL-2 has essential roles in key functions of the immune system, tolerance and immunity , primarily via its direct effects on T cells . In

874-577: Is expressed by memory CD8 T cells and NK cells , whereas regulatory T cells and activated T cells express high levels of trimeric IL-2R. Instructions to express proteins in response to an IL-2 signal (called IL-2 transduction) can take place via 3 different signaling pathways ; they are: (1) the JAK-STAT pathway, (2) the PI3K/Akt/mTOR pathway and (3) the MAPK/ERK pathway. The signalling

920-419: Is generally well tolerated. This is also the case for intralesional IL-2 in other forms of cancer, like nasopharyngeal carcinoma. Eisai markets a drug called denileukin diftitox (trade name Ontak), which is a recombinant fusion protein of the human IL-2 ligand and the diphtheria toxin . This drug binds to IL-2 receptors and introduces the diphtheria toxin into cells that express those receptors, killing

966-615: Is induced. In summary therefore before a cell will make IL-2 in accordance with this pathway there have to be two reactions: TCR+HLA and protein complex on the one hand and CD28 costimulation on the other indeed mere IL-2 ligation to its receptor is too low affinity to enable pathway. At the same time Oct-1 is expressed. It helps the activation. Oct1 is expressed in T-lymphocytes and Oct2 is induced after cell activation. NFAT has multiple family members, all of them are located in cytoplasm and signaling goes through calcineurin, NFAT

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1012-556: Is involved in itchy psoriasis . Aldesleukin is a form of recombinant interleukin-2. It is manufactured using recombinant DNA technology and is marketed as a protein therapeutic and branded as Proleukin. It has been approved by the Food and Drug Administration (FDA) with a black box warning and in several European countries for the treatment of cancers ( malignant melanoma , renal cell cancer ) in large intermittent doses and has been extensively used in continuous doses. Interking

1058-465: 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

1104-461: Is particularly important historically, as it is the first type I cytokine that was cloned, the first type I cytokine for which a receptor component was cloned, and was the first short-chain type I cytokine whose receptor structure was solved. Many general principles have been derived from studies of this cytokine including its being the first cytokine demonstrated to act in a growth factor–like fashion through specific high-affinity receptors, analogous to

1150-523: 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

1196-647: Is shared by all family members. The IL-2 receptor (IL-2R) α subunit binds IL-2 with low affinity (K d ~ 10 M). Interaction of IL-2 and CD25 alone does not lead to signal transduction due to its short intracellular chain but has the ability (when bound to the β and γ subunit) to increase the IL-2R affinity 100-fold. Heterodimerization of the β and γ subunits of IL-2R is essential for signalling in T cells . IL-2 can signalize either via intermediate-affinity dimeric CD122/CD132 IL-2R (K d ~ 10 M) or high-affinity trimeric CD25/CD122/CD132 IL-2R (K d ~ 10 M). Dimeric IL-2R

1242-449: Is tightly regulated and functions as part of both transient positive and negative feedback loops in mounting and dampening immune responses. Through its role in the development of T cell immunologic memory, which depends upon the expansion of the number and function of antigen-selected T cell clones, it plays a key role in enduring cell-mediated immunity . IL-2 has been discovered in all classes of jawed vertebrates, including sharks, at

1288-421: Is used, affected by cancer type, response to treatment and general patient health. Patients are typically treated for five consecutive days, three times a day, for fifteen minutes. The following approximately 10 days help the patient to recover between treatments. IL-2 is delivered intravenously on an inpatient basis to enable proper monitoring of side effects. A lower dose regimen involves injection of IL-2 under

1334-584: Is vascular leak syndrome (VLS; also termed capillary leak syndrome ). It is caused by lung endothelial cells expressing high-affinity IL-2R. These cells, as a result of IL-2 binding, causes increased vascular permeability. Thus, intravascular fluid extravasate into organs, predominantly lungs, which leads to life-threatening pulmonary or brain oedema. Other drawbacks of IL-2 cancer immunotherapy are its short half-life in circulation and its ability to predominantly expand regulatory T cells at high doses. Intralesional IL-2 used to treat in-transit melanoma metastases

1380-489: 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. Interleukin 2 3558 16183 ENSG00000109471 ENSMUSG00000027720 P60568 P04351 NM_000586 NM_008366 NP_000577 NP_032392 Interleukin-2 ( IL-2 ) is an interleukin , a type of cytokine signaling molecule in

1426-515: The immune system . It is a 15.5–16  kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes ) that are responsible for immunity. IL-2 is part of the body's natural response to microbial infection , and in discriminating between foreign ("non-self") and "self". IL-2 mediates its effects by binding to IL-2 receptors , which are expressed by lymphocytes. The major sources of IL-2 are activated CD4 T cells and activated CD8 T cells . Put shortly

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1472-418: The thymus , where T cells mature, it prevents autoimmune diseases by promoting the differentiation of certain immature T cells into regulatory T cells , which suppress other T cells that are otherwise primed to attack normal healthy cells in the body. IL-2 enhances activation-induced cell death (AICD) . IL-2 also promotes the differentiation of T cells into effector T cells and into memory T cells when

1518-404: 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

1564-607: 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

1610-558: 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

1656-810: The cells. In some leukemias and lymphomas, malignant cells express the IL-2 receptor, so denileukin diftitox can kill them. In 1999 Ontak was approved by the U.S. Food and Drug Administration (FDA) for treatment of cutaneous T cell lymphoma (CTCL). IL-2 does not follow the classical dose-response curve of chemotherapeutics. The immunological activity of high and low dose IL-2 show sharp contrast. This might be related to different distribution of IL-2 receptors (CD25, CD122, CD132) on different cell populations, resulting in different cells that are activated by high and low dose IL-2. In general high doses are immune suppressive, while low doses can stimulate type 1 immunity. Low-dose IL-2 has been reported to reduce hepatitis C and B infection. IL-2 has been used in clinical trials for

1702-530: The clone of IL-2 mAb, IL-2 ic can selectively stimulate either CD25 (IL-2/JES6-1 complexes), or CD122 cells (IL-2/S4B6). IL-2/S4B6 immune complexes have high stimulatory activity for NK cells and memory CD8 T cells and they could thus replace the conventional IL-2 in cancer immunotherapy . On the other hand, IL-2/JES6-1 highly selectively stimulate regulatory T cells and they could be potentially useful for transplantations and in treatment of autoimmune diseases . According to an immunology textbook: "IL-2

1748-517: The expression of cytokines of both type 1 (Th1) and type 2 (Th2) immunity. As has been found in some studies on mammalian IL-2, data suggest that fish IL-2 can form homodimers and that this is an ancient property of the IL-2/15/15L-family cytokines. Homologues of IL-2 have not been reported for jawless fish (hagfish and lamprey) or invertebrates. While the causes of itchiness are poorly understood, some evidence indicates that IL-2

1794-464: The function of IL-2 is to stimulate the growth of helper, cytotoxic and regulatory T cells. IL-2 is a member of a cytokine family, each member of which has a four alpha helix bundle ; the family also includes IL-4 , IL-7 , IL-9 , IL-15 and IL-21 . IL-2 signals through the IL-2 receptor , a complex consisting of three chains, termed alpha ( CD25 ), beta ( CD122 ) and gamma ( CD132 ). The gamma chain

1840-448: The initial T cell is also stimulated by an antigen , thus helping the body fight off infections. Together with other polarizing cytokines, IL-2 stimulates naive CD4 T cell differentiation into T h 1 and T h 2 lymphocytes while it impedes differentiation into T h 17 and folicular T h lymphocytes. IL-2 increases the cell killing activity of both natural killer cells and cytotoxic T cells . Its expression and secretion

1886-487: The level of dosing usually determines the severity of the side effects. In the case of local IL-2 application, the therapeutic window spans several orders of magnitude. Some common side effects: More serious and dangerous side effects sometimes are seen, such as breathing problems, serious infections , seizures , allergic reactions , heart problems, kidney failure or a variety of other possible complications. The most common adverse effect of high-dose IL-2 therapy

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1932-531: The same title formed as a letter–number combination. If an internal link led you here, you may wish to change the link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=IL-12&oldid=544120580 " Category : Letter–number combination disambiguation pages Hidden categories: Short description is different from Wikidata All article disambiguation pages All disambiguation pages Interleukin 12 Interleukin 12 ( IL-12 )

1978-477: The skin typically on an outpatient basis. It may alternatively be given on an inpatient basis over 1–3 days, similar to and often including the delivery of chemotherapy . Intralesional IL-2 is commonly used to treat in-transit melanoma metastases and has a high complete response rate. In preclinical and early clinical studies, local application of IL-2 in the tumor has been shown to be clinically more effective in anticancer therapy than systemic IL-2 therapy, over

2024-433: The systemic dose of IL-2 is too low to cause side effects, since the total dose is about 100 to 1000 fold lower. Clinical studies showed painful injections at the site of radiation as the most important side effect, reported by patients. In the case of irradiation of nasopharyngeal carcinoma the five-year disease-free survival increased from 8% to 63% by local IL-2 therapy Systemic IL-2 has a narrow therapeutic window , and

2070-401: The three pathways include bcl-6 (the PI3K/Akt/mTOR pathway), CD25 & prdm-1 (the JAK-STAT pathway) and certain cyclins (the MAPK/ERK pathway). Gene expression regulation for IL-2 can be on multiple levels or by different ways. One of the checkpoints (in other words one of the things which needs to be done before IL-2 is expressed) is that there must be signaling through a conjunction of

2116-629: The treatment of chronic viral infections and as a booster (adjuvant) for vaccines. The use of large doses of IL-2 given every 6–8 weeks in HIV therapy, similar to its use in cancer therapy, was found to be ineffective in preventing progression to an AIDS diagnosis in two large clinical trials published in 2009. More recently low dose IL-2 has shown early success in modulating the immune system in disease like type 1 diabetes and vasculitis. There are also promising studies looking to use low dose IL-2 in ischaemic heart disease. IL-2 cannot accomplish its role as

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