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65-485: 1Z92 , 2B5I , 2ERJ , 3IU3 , 3NFP 3559 16184 ENSG00000134460 ENSMUSG00000026770 P01589 P01590 NM_000417 NM_001308242 NM_001308243 NM_008367 NP_000408 NP_001295171 NP_001295172 NP_032393 The interleukin-2 receptor alpha chain (also called Tac antigen, P55, and mainly CD25 ) is a protein involved in the assembly of the high-affinity interleukin-2 receptor , consisting of alpha ( IL2RA ), beta ( IL2RB ) and

130-484: A complex that binds IL-2 with high affinity (Kd ~ 10 M) on activated T cells and regulatory T cells . The intermediate and high affinity receptor forms are functional and cause changes in the cell when IL-2 binds to them. The structure of the stable complex formed when IL-2 binds to the high affinity receptor has been determined using X-ray crystallography . The structure supports a model wherein IL-2 initially binds to

195-682: A correlation to HIV viral load and so to disease progression. Similarly in Chagas disease , caused by the protozoan Trypanosoma cruzi , patients have increased levels of sIL-2Rα and autoantibodies . In regard to transplantation , higher levels of sCD25 may be used as a predictor of organ rejection and graft-versus-host disease (GVHD) for hematopoietic transplantations . Concerning CVD (cardiovascular diseases) soluble IL-2Rα has positive correlation with hypertension , type 2 diabetes mellitus , cardiac sarcoidosis , stroke and heart failure . For neurological disorders, high levels of sIL-2Rα are

260-719: A group of pathogens but invariant in their basic structure; and are essential for pathogenicity (ability of an organism to produce an infectious disease in another organism). Proteins involved in microbial pattern recognition include mannose receptor, complement receptors, DC-SIGN, Toll-like receptors(TLRs), the scavenger receptor, CD14 , and Mac-1. PRRs can be divided into three classes: The recognition and clearance of invading microorganisms occurs through both opsonin-dependent and opsonin–independent pathways. The molecular mechanisms facilitating opsonin-dependent phagocytosis are different for specific opsonin/receptor pairs. For example, phagocytosis of IgG-opsonized pathogens occurs through

325-584: A highly developed network of defensive phagocytic cells responsible for the adaptive immune response. During COVID-19 infection, alveolar macrophages play a dual role by acting as the first line of defense against SARS-CoV-2 in the alveolar space, while also contributing to the hyperinflammatory response through excessive cytokine production, which can exacerbate lung damage and acute respiratory distress syndrome (ARDS). The lungs are especially sensitive and prone to damage, thus to avoid collateral damage to type I and type II pneumocytes, alveolar macrophages are kept in

390-454: A marker to identify CD4+FoxP3+ regulatory T cells in mice. However, there are species differences as CD25 is constitutively expressed by a large proportion of resting memory T cells non-regulatory CD4 T cells in humans that are absent in mice. High expression of CD25 is also found on TCR activated conventional T cells (both CD8+ and CD4+ T lymphocytes), where it is considered to be a marker of T cell activation. Additionally, expression of

455-495: A myriad of degradative enzymes and antimicrobial peptides that are released into the phagolysosome, such as proteases, nucleases, phosphatases, esterases, lipases, and highly basic peptides. Moreover, macrophages possess a number of nutrient deprivation mechanisms that are used to starve phagocytosed pathogens of essential micronutrients. Certain microorganisms have evolved countermeasures which enable them to evade being destroyed by phagocytes. Although lysosomal-mediated degradation

520-584: A quiescent state, producing little inflammatory cytokines and displaying little phagocytic activity, as evidenced by downregulated expression of the phagocytic receptor Macrophage 1 antigen (Mac-1). AMs actively suppress the induction of two of the immunity systems of the body: the adaptive immunity and humoral immunity. The adaptive immunity is suppressed through AM's effects on interstitial dendritic cells, B-cells and T-cells, as these cells are less selective of what they destroy, and often cause unnecessary damage to normal cells. To prevent uncontrolled inflammation in

585-406: A short time to signal. IL-2, IL-2Rβ, and γ c are rapidly degraded, but IL-2Rα is recycled to the cell surface. Thus, the concentration of IL-2 and its receptor available determines the tempo, magnitude and extent of T cell immune responses. IL-2 and its receptor have key roles in key functions of the immune system, tolerance and immunity , primarily via their direct effects on T cells . In

650-766: A sign for increased risk of developing schizophrenia . Since Tregs express IL-2Rα subunit constitutively on the surface, some immunotherapeutic approaches try to use this information for selectivity. NARA1 antibody is used in antitumour approaches to preferentially supplement interleukin-2 to conventional CD8+ T cells . NARA1 binds to the cytokine on the IL-2Rα binding site preventing binding to CD25. This complex should therefore interact with conventional T lymphocytes over T regulatory cells and thus increase cytotoxic activity without increasing suppressing activity in tumour environment. Antibodies directly against CD25 have been altered to contain  ‘activating’ Fc regions for

715-472: A strategy to evade host immune systems. There are bacteria which parasitize AMs by invading through their membranes, and thrive by growing and replicating inside of them, exploiting AMs as host cells. Normally, this infection can be eliminated by T-cells, which activate enzymes in alveolar macrophages that destroy the bacteria; but these bacteria have been shown to alter the cytokine signaling network to their advantage. As an inhibitory cytokine, IL-10 facilitates

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780-549: A vesicular phagosome which then undergoes fusion with primary or secondary lysosomes , forming a phagolysosome. There are various mechanisms that lead to intracellular killing; there are oxidative processes, and others independent of the oxidative metabolism. The former involves the activation of membrane enzyme systems that lead to a stimulation of oxygen uptake (known as the respiratory burst), and its reduction to reactive oxygen intermediates (ROIs), molecular species that are highly toxic for microorganisms. The enzyme responsible for

845-453: Is a significant increase in the basal rate of apoptosis upon activation by bacterial products. Apoptosis is particularly regulated by the presence of cytokines: IFNγ increases the rate of apoptosis, whereas IL-10 and TGF-β decrease it. However, IL-10 has counterproductive effects on the immune system, and has been shown to actually promote infection by foreign pathogens. The role of IL-10 in bacterial and parasitic infection has been discovered as

910-657: Is an integral-membrane protein , more precisely type I transmembrane protein . This bitopic polypeptide is constructed by a sequence of 272 amino acids and has a molecular mass of around 30.8 kDa. CD25 consists of three domains: extracellular (N-terminus), transmembrane (alpha-helix) and cytoplasmic (C-terminus). However, while extracellular part is able to function as a binding site for interleukin-2 , short cytoplasmic domain lacks an ability to induce intracellular signalling and therefore needs to oligomerise with other IL-2 receptor subunits. The interleukin-2 (IL2) receptor alpha ( IL2RA ) and beta ( IL2RB ) chains, together with

975-430: Is an efficient means by which to neutralize an infection and prevent colonization, several pathogens parasitize macrophages, exploiting them as a host cell for growth, maintenance and replication. Parasites like Toxoplasma gondii and mycobacteria are able to prevent fusion of phagosomes with lysosomes, thus escaping the harmful action of lysosomal hydrolases. Others avoid lysosomes by leaving the phagocytic vacuole, to reach

1040-414: Is dependent upon several distinct microbicidal mechanisms, like the reduced NADPH oxidase-mediated release of ROI. ROI generation by NADPH oxidase is an important bactericidal mechanism after FcR-mediated phagocytosis. PGE2 activates both Gs-coupled EP2 and EP4 receptors by ligation, stimulating cAMP production and subsequent activation of downstream cAMP effectors, PKA and Epac-1; both which in turn impair

1105-414: Is expressed broadly among leukocytes . The highest surface expression of this protein is on regulatory T cells (Tregs) , where CD25 is expressed constitutively, especially on a subset classified as naturally occurring Tregs. It can also be found on activated B cells , NK (natural killer) cells , thymocytes , and some myeloid lineage cells (e.g. macrophages , dendritic cells ). IL2RA has been used as

1170-657: Is on the short arm of 10th chromosome (10p15.1). Several frequent point mutations , single nucleotide polymorphism (SNP), have been identified in or in close proximity to IL2RA gene in the population. These SNPs have been linked mainly to susceptibility to immune dysregulation disorders, with majority found in research on multiple sclerosis (MS) and type 1 diabetes mellitus . IL2RA gene orthologues with identical protein functionality are relatively abundant and constant among animal species, especially in mammals subgroups. Moreover, conserved homologs of this gene are in mouse, rat, dog, cow, chimpanzee and Rhesus monkey. CD25

1235-462: 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

1300-465: Is processed in the arachidonic acid cascade: the successive oxygenation and isomerization of arachidonic acid by cyclooxygenase and PGE2 synthase enzymes. The regulation of target cells by PGE2 occurs via signaling through four cell membrane-associated G-protein-coupled E-prostanoid (EP) receptors, named EP1, EP2, EP3, and EP4. PGE2 inhibits bacterial killing and ROI production by AM by impairing Fcγ-mediated phagocytosis through its ability to stimulate

1365-686: Is produced during immune activation, it is used as one of biomarkers to track disease progression and to indicate outcome for clinical disorders. Especially, it is a hallmark for hyper-activated immune system and cytokine storm , which may lead to multiple organ system failure. In cancer, increased levels of this soluble protein are diagnostic marker for leukemia and lymphoma . Furthermore, sIL-2Rα levels have some significance also in infectious diseases and transplantation . Higher serum levels were correlated with severity and need for hospitalisation of COVID-19 patients. sIL-2Rα amount in plasma of HIV ( human immunodeficiency virus) positive patients has

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1430-455: Is the third cell type in the alveolus; the others are the type I and type II pneumocytes . Alveolar macrophages are phagocytes that play a critical role in homeostasis , host defense, and tissue remodeling. Their population density is decisive for these many processes. They are highly adaptive and can release many secretions, to interact with other cells and molecules using several surface receptors . Alveolar macrophages are also involved in

1495-454: The Fcγ receptors (FcγR), and involves phagocyte extensions around the microbe, resulting in the production of pro-inflammatory mediators. Conversely, complement receptor-mediated pathogen ingestion occurs without observable membrane extensions (particles just sink into the cell) and does not generally results in an inflammatory mediator response. Following internalization, the microbe is enclosed in

1560-418: The phagocytosis of apoptotic and necrotic cells. They need to be selective of the material that is phagocytized to safeguard the normal cells and structures. To combat infection, the phagocytes facilitate many pattern recognition receptors (PRRs) to help recognize pathogen-associated molecular patterns (PAMPs) on the surface of pathogenic microorganisms. PAMPs all have the common features of being unique to

1625-429: The thymus , where T cells mature, they prevent autoimmune diseases by promoting the differentiation of certain immature T cells into regulatory T cells , which kill off other T cells that are primed to attack normal healthy cells in the body. IL-2/IL2R also promotes the differentiation of T cells into effector T cells and into memory T cells when the initial T cells is also stimulated by an antigen , thus helping

1690-469: The IL-2 receptor alpha subunit can be found in non-lymphoid tissues such as lungs ( alveolar macrophages ), liver ( Kupffer cells ) and skin ( Langerhans cells ). IL2RA protein can be expressed in many types of neoplastic cells , such as in most B-cell neoplasms, T-cell lymphomas , some acute nonlymphocytic leukemias , neuroblastomas , mastocytosis , Waldenstrom macroglobuliaemia and tumor infiltrating lymphocytes . Interleukin-2 receptor alpha chain

1755-1464: The IL-2 receptor and provides enhanced specific binding force. After activation of the receptor by its ligand , heterodimerisation of beta and gamma intracellular domains takes place. This coupling of subunits brings together Janus kinases JAK1 and JAK3 , considering their association with respective cytoplasmic parts of beta and gamma subunits. Downstream phosphorylation leads to initiation of three signalling pathways: JAK-STAT pathway , PI3K/Akt/mTOR pathway and Ras/Raf/MEK/ERK (MAPK) pathway . Regarding JAK-STAT pathway, particular signal transducers and activators of transcription participate in this signalling cascade: STAT5 , STAT1 and STAT3 and after dimerisation , they translocate to nucleus to perform transcription factor functions. All three signalling pathways are important for diverse cellular regulations, in terms of increased survival (anti- apoptotic effect), proliferation and cell growth , transcriptional regulation and cell differentiation . T lymphocytes are influenced by IL-2R signalling in case of CD4+ T helper subtype differentiation: promoting Th1 , Th2 , Th9 , Tfr (T follicular regulatory cells) and suppressing Th17 , Tfh ( T follicular helper cells). Additionally, strength of IL-2R signalling in CD8+ T cytotoxic lymphocytes may be connected to phenotypic fate of these cells for effector and memory T cells formation. Roifman's group

1820-401: The IL-2 receptor, which has three forms, generated by different combinations of three different proteins, often referred to as "chains": α (alpha) (also called IL-2Rα, CD25, or Tac antigen), β (beta) (also called IL-2Rβ, or CD122), and γ (gamma) (also called IL-2Rγ, γ c , common gamma chain , or CD132); these subunits are also parts of receptors for other cytokines. The β and γ chains of

1885-546: The IL-2R are members of the type I cytokine receptor family. The three receptor chains are expressed separately and differently on various cell types and can assemble in different combinations and orders to generate low, intermediate, and high affinity IL-2 receptors. The α chain binds IL-2 with low affinity, the combination of β and γ together form a complex that binds IL-2 with intermediate affinity, primarily on memory T cells and NK cells ; and all three receptor chains form

1950-543: The NADPH oxidase for NADPH in macrophages, as well as an increased rate of gene transcription and message expression for gp91phox protein. TNF-α acts as an autocrine stimulus by increasing the expression of both p47phox and p67phox transcripts. The ROIs produced during the respiration burst response, in turn, enhance production of TNF-α by macrophages. Gas exchange must be restored as quickly as possible to avoid collateral damage, so activated lymphocytes secrete IFNγ to stimulate

2015-447: The ability of human dendritic cells to internalize antigens at sites of inflammation, therefore modulating the beginning steps leading to antigen-specific immune responses. NO production has been implicated as relevant to the pathology of asthma. People with asthma show an increased expression of iNOS in airway epithelial cells and an increased level of nitric oxide in exhaled air. Many other immunomodulating factors have been isolated,

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2080-440: The basal phosphorylation level of SMAD 2/3; subsequently leading to the activation and detachment of alveolar macrophages from the alveolar epithelial cells [15]. Upon activation, macrophages become primed for phagocytosis and begin to secrete proinflammatory cytokines (TNF-α and IL-6). The priming of macrophages involves the enhancement of respiratory burst activity by IFN-γ and TNF-α. IFNγ induces both an increased affinity of

2145-472: The body fight off infections. Through their 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, they also have a key role in enduring cell-mediated immunity . Drugs that inhibit IL-2 receptors, such as basiliximab and daclizumab are used in conjunction with other drugs to prevent immune rejection of transplants . According to an immunology textbook: "IL-2

2210-405: The cell surface, where activation can be tightly coupled to cellular responses to environmental stress in the maintenance of homeostasis; integrins also localize activated TGFβ in the vicinity of the macrophages. Normally mature TGFβ is secreted as a latent complex with its N-terminal fragment, latency-associated peptide (LAP), which inhibits its activity. The latent complex is covalently linked to

2275-404: The common gamma chain ( IL2RG ), constitute the high-affinity IL-2 receptor complex ( K d ~10−11M). Homodimeric alpha chains ( IL2RA ) result in low-affinity receptor ( K d ~10−8M) with no signalling ability, while dimeric beta ( IL2RB ) and gamma chains ( IL2RG ) produce a medium-affinity receptor ( K d ~10−9M). Moreover, CD25 is an exclusive subunit that entirely binds IL-2, while CD132 binds

2340-436: The common gamma chain ( IL2RG ). As the name indicates, this receptor interacts with interleukin-2 , a pleiotropic cytokine which plays an important role in immune homeostasis . The human protein interleukin-2 receptor subunit alpha is encoded by a gene called IL2RA with a length around 51,6 kb. Alternative names for this protein coding gene are IL2R , IDDM10 and TCGFR . Location of IL2RA in human genome

2405-628: The complexes translocates into the nucleus via the nuclear pore with the assistance of importins alpha/beta. Once in the nucleus, these complexes accumulate and eventually act as a transcription factors, regulating the expression of TGF-β target genes. Thus TGF-β signaling involves a direct pathway from the receptors on the surface of a cell to the nucleus. Toll-like receptors (TLRs) are signaling PRRs , capable of recognizing various bacterial proteins. Although bacteria have evolved means of evading host defense mechanisms, they express PAMPs, such as lipoglycans and lipoproteins that are recognized by cells of

2470-553: The cytochrome component, gp91phox/p22phox, on the plasma membrane via cytoskeletal elements. Compared to other phagocytes, the respiratory burst in AM is of a greater magnitude. Oxygen-independent microbicidal mechanisms are based on the production of acid, on the secretion of lysozymes, on iron-binding proteins, and on the synthesis of toxic cationic polypeptides. Macrophages possess a repertoire of antimicrobial molecules packaged within their granules and lysosomes. These organelles contain

2535-496: The cytosolic matrix where their development is unhindered. In these instances, macrophages may be triggered to actively destroy phagocytosed microorganisms by producing a number of highly toxic molecules and inducing deprivational mechanism to starve it. Finally, some microbes have enzymes to detoxify oxygen metabolites formed during the respiratory burst. When insufficient to ward off the threat, alveolar macrophages can release proinflammatory cytokines and chemokines to call forth

2600-712: The development of immune responses. Ig is a class of antibody found only in mammals that plays an important role in allergy response and defense against many kinds of pathogens by protecting the body against them by complement activation, opsonization for phagocytosis, and neutralization of their toxins. IL-4 and IL-10 have both been shown to reduce the production of metalloproteinases (endopeptidases which break down collagen and other extracellular proteins) by human AMs. IL-4 has dual effects upon macrophage biological function, which may be either stimulatory or inhibitory. It enhances MHC class II antigen (extracellular protein complex that interacts exclusively with CD4-T cells as part of

2665-603: The elicitation of the respiratory burst is known as nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is composed of five subunits. One component is a membrane cytochrome made up of two protein subunits, gp91phox and p22phox; the remaining three components are cytosolic-derived proteins: p40phox, p47phox, and p67phox. NADPH oxidase exists in the cytosol of the AM when in a quiescent state; but upon activation, two of its cytosolic components, p47phox and p67phox, have their tyrosine and serine residues phosphorylated, which are then able to mediate translocation of NADPHox to

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2730-468: The exchange proteins directly activated by cAMP (Epac-1 and -2). Epac-1 and PKA are both important factors involved in the inhibition of AM bacterial killing. The effects of PKA results from its ability to phosphorylate serine and threonine residues on many cellular proteins, especially transcription factor cAMP response element binding protein (CREB). cAMP/PKA/CREB axis mediates the inhibition of TNF-alpha release. The killing of phagocytosed bacteria by AMs

2795-411: The exogenous pathway) and Mac-1(surface receptor as part of innate complement system) expression, thus promoting phagocytosis. IL-4 has also been shown to inhibit the production of PGE2 by reducing the expression of the enzyme, prostaglandin H synthase -2 (PGHS-2), which is critical in the production of PGE2. However, IL-4 inhibits production of TNF-alpha, IL-1 and -6, which are all important cytokines in

2860-530: The expression of the αvβ6 integrin. Integrins are dimeric cell-surface receptors composed of alpha and beta subunits, which activates TGF-β.< TGF-β is a multifunctional cytokine that modulates a variety of biological processes such as cell growth, apoptosis, extracellular matrix synthesis, inflammation, and immune responses. TGF-β tightly regulates anti-inflammatory activity by suppressing pro-inflammatory cytokine production, thereby inhibiting T-lymphocyte function. Integrins avβ6 and avβ8 sequester latent TGF-β to

2925-538: The extracellular matrix by binding to latent TGF-β-binding proteins. TGF-β is activated by diverse mechanisms in the lung, ultimately involving either proteolysis or conformational alteration of the LAP. αvβ6 integrin is able to mediate activation of TGF-β by binding to TGF-β1 LAP, which serves as a ligand binding site for the integrin, and is an essential component of the TGF-β activation apparatus. Once activated, TGFβ leads to

2990-598: The gamma chain complexes with another tyrosine kinase called JAK3 . These enzymes are activated by IL-2 binding to the external domains of the IL-2R. As a consequence, three intracellular signaling pathways are initiated, the MAP kinase pathway , the Phosphoinositide 3-kinase (PI3K) pathway, and the JAK-STAT pathway . Once IL-2 binds to the high affinity receptor, the complex is rapidly internalized and has only

3055-442: The growth factors being studied by endocrinologists and biochemists". CD25 deficiency Alveolar macrophage An alveolar macrophage , pulmonary macrophage , (or dust cell ) is a type of macrophage , a professional phagocyte , found in the airways and at the level of the alveoli in the lungs , but separated from their walls. Activity of the alveolar macrophage is relatively high, because they are located at one of

3120-437: The human counterpart of the enhancer element that regulates LPS/IFNγ induced expression of the mouse NOS2 gene. The second is because of the absence of a nuclear factor in human macrophages that is required for optimum expression of gene NOS2 (LPS-inducible nuclear factor-kappa B/Rel complex). It is assumed that the difficulty in verifying NOS2 is due to a much more tightly controlled expression in human AMs as compared to that in

3185-540: The infection of human alveolar macrophages and monocytes by completely reversing the protective effect of IFNγ against intracellular Legionella pneumophila replication. Yersinia enterocolitica has also been shown to releases virulence antigen LcrV, which induces IL-10 through Toll-like receptor-2 and CD14 (an accessory surface protein of TLR4-mediated LPS-signaling), resulting in the suppression of IFNγ and TNF-alpha suppression. In normal conditions, alveolar macrophages adhere closely to alveolar epithelial cells, thus inducing

3250-517: The innate immune system through the TLRs. Upon binding of PAMPs to TLRs, the TLR triggers inflammatory and defensive responses in the host cell, inducing actin polymerization in alveolar macrophages (a crucial component in endocytosis and motility). Actin polymerization in alveolar macrophages causes the suppression of integrin expression, which in turn causes the deactivation of TGF-β and the downregulation of

3315-443: The interleukin-2 (IL-2) receptor, the expression of which is fundamental for T cell proliferation. In humans, however, NOS2 activity has been difficult to verify. There are two explanations for the lack of responsiveness in the promoter of human inducible nitric oxide synthetase (iNOS) to NO activation by lipopolysaccharides (LPS) + interferon gamma (IFNγ). The first is that there are various inactivating nucleotide variations in

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3380-419: The lower respiratory tract, alveolar macrophages secrete nitric oxide, prostaglandins , interleukin-4 and -10(IL-4, IL-10), and transforming growth factor -β (TGF-β). Nitric oxide (NO) is a major source of immunomodulation in rodents, and is produced by enzyme nitric oxide synthetase type 2 (NOS2) in the alveolar macrophage. NO inhibits tyrosine phosphorylation of the kinases involved in production of

3445-455: The major boundaries between the body and the outside world. They are responsible for removing particles such as dust or microorganisms from the respiratory surfaces. Alveolar macrophages are frequently seen to contain granules of exogenous material such as particulate carbon that they have picked up from respiratory surfaces. Such black granules may be especially common in smoker 's lungs or long-term city dwellers. The alveolar macrophage

3510-404: The most important of which are prostaglandins and cytokines. PGE2 was the first immunomodulator to be derived from macrophages and described. PGE2 functions in amplifying peripheral blood lymphocyte IL-10 transcription and protein production; as well as in deactivating macrophages and T-cells. PGE2 is an immunomodulatory eicosanoid derived from the cell membrane component, arachidonic acid , and

3575-535: The other side, treatment strategies for autoimmune and inflammatory diseases need selectivity for Tregs and suppression of immune system. IL-2Rα subunit expression on Tregs secures better sensitivity to IL-2 . Therefore, administration of low doses of the cytokine preferentially stimulates T regulatory cells over others. Low-dose IL-2 therapy is used for graft-versus-host disease , type 1 diabetes mellitus , hepatitis C virus-induced vasculitis and systemic lupus . Interleukin-2 receptor IL-2 binds to

3640-407: The phosphorylation and phagosomal membrane translocation of NADPH oxidase component, p47phox, thereby inhibiting the respiratory burst. IL-4 is a pleiotropic cytokine that plays a key role in the development of T helper type 2(Th2) cells. IL-4 is important for the differentiation of naïve CD4-T cells into mature Th2 type cells; as well as for Immunoglobulin (Ig) class switching to IgE and IgG4 during

3705-422: The production of intracellular cyclic adenosine monophosphate (cAMP) effectors via EP2 and EP4 receptors signaling. EP2 and EP4 receptors signal primarily through stimulatory G protein (Gs), increasing adenylyl cyclase (AC) activity and subsequent cAMP formation. cAMP is a second messenger that influences multiple cellular functions via the activation of two downstream effector molecules, protein kinase A (PKA) and

3770-408: The production of matrix metalloproteinase MMP-9 by macrophages. AMs have been reported to produce MMP-9 partly via PGE2-dependent PKA signaling pathways, which are the pathways involved in the inhibition of phagocytosis. MMP-9 activates latent TGF-β, reinducing expression of αvβ6 integrins on alveolar epithelial cells, thereby returning the alveolar macrophage to a resting state. Activation of TGF-β

3835-435: The proinflammatory response). IL-10 inhibits the secretion of pro-inflammatory cytokines TNF-alpha and INF-gamma, thus suppressing the proliferation of T-cells, NK cells, and AM. IL-10 shares similar immunomodulating mechanisms to TGF-β. It is thought that both cytokines reduce the rate of apoptosis in human alveolar macrophages, thus indirectly enhancing alveolar macrophage-mediated inhibition of T-cell proliferation. There

3900-491: The purpose of antibody-dependent cell-mediated cytotoxicity , in this case Treg depletion. Antibody marks a cell with IL-2Rα subunit on the surface, which is subsequently recognized and cleared by myeloid cell with Fc receptor . Moreover, for treatment of multiple sclerosis , drug called daclizumab binds to IL2RA and so blocks high-affinity IL-2 receptors on recently activated T cells for interaction with IL-2 as well as IL-2 cross-presentation by dendritic cells . From

3965-558: The rodent AMs. NOS2 is part of an autoregulatory feedback loop, wherein an allergen or provoker stimulates inflammatory cytokine production, which in turn stimulates NO production, and NO down-regulates cytokine production. In rats, NO inhibits the granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated maturation of dendritic cells, and in humans it inhibits the TNF-alpha-mediated maturation of human dendritic cells, through cyclic GMP-dependent mechanisms. NO prolongs

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4030-636: The shared γc family cytokines ( IL-4 , IL-7 , IL-9 , IL-15 and IL-21 ), and the CD122 subunit binds also IL-15 . Soluble IL2RA has been isolated and determined to result from extracellular proteolysis during activation of T lymphocytes. Also, alternately-spliced IL2RA mRNAs have been isolated, but the significance of each is currently unknown. Interleukin-2 can interact with intermediate-affinity dimeric IL-2 receptor, which consists of beta ( CD122 ) and gamma ( CD132 ) chains or with high-affinity trimeric complex, where also alpha subunit (CD25) constructs

4095-435: The suppression of macrophage functionality (cytokine production and phagocytosis). Binding of activated TGF-β to its receptors expressed on alveolar macrophages induces a downstream signaling cascade, including phosphorylation of receptor-regulated Small Mothers Against Decapentaplegic (R-SMAD)homologs 2 and 3. Phosphorylated SMAD-2 and -3 then form heteromeric complexes with common-mediator SMAD 4 (co-SMAD-4). Once assembled,

4160-402: The α chain, then the β is recruited, and finally γ. The three IL-2 receptor chains span the cell membrane and extend into the cell, thereby delivering biochemical signals to the cell interior . The alpha chain does not participate in signaling, but the beta chain is complexed with an enzyme called Janus kinase 1 (JAK1), that is capable of adding phosphate groups to molecules. Similarly

4225-465: Was the first to identify immunological consequences of CD25 loss and the patient has suffered from chronic infections and severe autoimmunity resembling Immune dysregulation, Polyendocrinopathy , Enteropathy, X-linked ( IPEX ) syndrome, caused by mutations in FOXP3 gene. Levels of CD25 soluble form, called sIL-2Rα , has been connected to pathogenesis of autoimmune diseases and cancer . Since sCD25

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