Gene set analysis suggested up-regulation of a variety of pr......
Gene set analysis suggested up-regulation of a variety of pro- and anti-inflammatory cytokines, including interleukin 1alpha (IL-1alpha), IL-2, IL-3, IL-5, IL-8, IL-9, IL-10, IL-12A, IL-13, IL-15, IL-18, interferon gamma (IFNgamma), and lymphotoxin alpha (TNF superfamily member 1).More...
Positive relationships between IL12A and other components at different levels (count: 0)
Positive relationship network of IL12A in MK4MDD
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Cell and Molecular Pathway
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Cognition and Behavior
Symptoms and Signs
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MDD
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Negative relationships between IL12A and MDD (count: 0)
Negative relationships between IL12A and other components at different levels (count: 0)
Type I diabetes mellitus is a disease that results from auto......
Type I diabetes mellitus is a disease that results from autoimmune destruction of the insulin-producing beta-cells. Certain beta-cell proteins act as autoantigens after being processed by antigen-presenting cell (APC), such as macrophages and dendritic cells, and presented in a complex with MHC-II molecules on the surface of the APC. Then immunogenic signals from APC activate CD4+ T cells, predominantly of the Th1 subset. Antigen-activated Th1 cells produce IL-2 and IFNgamma. They activate macrophages and cytotoxic CD8+ T cells, and these effector cells may kill islet beta-cells by one or both of two types of mechanisms: (1) direct interactions of antigen-specific cytotoxic T cells with a beta-cell autoantigen-MHC-I complex on the beta-cell, and (2) non-specific inflammatory mediators, such as free radicals/oxidants and cytokines (IL-1, TNFalpha, TNFbeta, IFNgamma). Type I diabetes is a polygenic disease. One of the principle determining genetic factors in diabetes incidence is the inheritance of mutant MHC-II alleles. Another plausible candidate gene is the insulin gene.More...
Specific families of pattern recognition receptors are respo......
Specific families of pattern recognition receptors are responsible for detecting microbial pathogens and generating innate immune responses. Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. Mammalian TLRs are expressed on innate immune cells, such as macrophages and dendritic cells, and respond to the membrane components of Gram-positive or Gram-negative bacteria. Pathogen recognition by TLRs provokes rapid activation of innate immunity by inducing production of proinflammatory cytokines and upregulation of costimulatory molecules. TLR signaling pathways are separated into two groups: a MyD88-dependent pathway that leads to the production of proinflammatory cytokines with quick activation of NF-{kappa}B and MAPK, and a MyD88-independent pathway associated with the induction of IFN-beta and IFN-inducible genes, and maturation of dendritic cells with slow activation of NF-{kappa}B and MAPK.More...
Cytokines are soluble extracellular proteins or glycoprotein......
Cytokines are soluble extracellular proteins or glycoproteins that are crucial intercellular regulators and mobilizers of cells engaged in innate as well as adaptive inflammatory host defenses, cell growth, differentiation, cell death, angiogenesis, and development and repair processes aimed at the restoration of homeostasis. Cytokines are released by various cells in the body, usually in response to an activating stimulus, and they induce responses through binding to specific receptors on the cell surface of target cells. Cytokines can be grouped by structure into different families and their receptors can likewise be grouped.More...
Specific families of pattern recognition receptors are respo......
Specific families of pattern recognition receptors are responsible for detecting viral pathogens and generating innate immune responses. Non-self RNA appearing in a cell as a result of intracellular viral replication is recognized by a family of cytosolic RNA helicases termed RIG-I-like receptors (RLRs). The RLR proteins include RIG-I, MDA5, and LGP2 and are expressed in both immune and nonimmune cells. Upon recognition of viral nucleic acids, RLRs recruit specific intracellular adaptor proteins to initiate signaling pathways that lead to the synthesis of type I interferon and other inflammatory cytokines, which are important for eliminating viruses.More...
After transplantation of organ allografts, there are two pat......
After transplantation of organ allografts, there are two pathways of antigen presentation. In the direct pathway, recipient T cells react to intact allogeneic MHC molecules expressed on the surface of donor cells. This pathway would activate host CD4 or CD8 T cells. In contrast, donor MHC molecules (and all other proteins) shed from the graft can be taken up by host APCs and presented to recipient T cells in the context of self-MHC molecules - the indirect pathway. Such presentation activates predominantly CD4 T cells. A direct cytotoxic T-cell attack on graft cells can be made only by T cells that recognize the graft MHC molecules directly. Nontheless, T cells with indirect allospecificity can contribute to graft rejection by activating macrophages, which cause tissue injury and fibrosis, and are also likely to be important in the development of an alloantibody response to graft.More...
The Janus kinase/signal transducers and activators of transc......
The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in animals, from humans to flies. In mammals, the JAK/STAT pathway is the principal signaling mechanism for a wide array of cytokines and growth factors. Following the binding of cytokines to their cognate receptor, STATs are activated by members of the JAK family of tyrosine kinases. Once activated, they dimerize and translocate to the nucleus and modulate the expression of target genes. In addition to the activation of STATs, JAKs mediate the recruitment of other molecules such as the MAP kinases, PI3 kinase etc. These molecules process downstream signals via the Ras-Raf-MAP kinase and PI3 kinase pathways which results in the activation of additional transcription factors.More...
Leishmania is an intracellular protozoan parasite of macroph......
Leishmania is an intracellular protozoan parasite of macrophages that causes visceral, mucosal, and cutaneous diseases. The parasite is transmitted to humans by sandflies, where they survive and proliferate intracellularly by deactivating the macrophage. Successful infection of Leishmania is achieved by alteration of signaling events in the host cell, leading to enhanced production of the autoinhibitory molecules like TGF-beta and decreased induction of cytokines such as IL12 for protective immunity. Nitric oxide production is also inhibited. In addition, defective expression of major histocompatibility complex (MHC) genes silences subsequent T cell activation mediated by macrophages, resulting in abnormal immune responses.More...
Dendritic cells in regulating TH1 and TH2 Development
While T cells and B cells carry out the actions of antigen-s......
While T cells and B cells carry out the actions of antigen-specific immune responses, antigen-presenting cells called dendritic cells are required for this to happen. The name of dendritic cells is based on their shape, with activated dendritic cells displaying long processes on their surface. When immature dendritic cells found throughout the body internalize and present antigen, they express markers that stimulate the activation of lymphocytes, and migrate to lymphocyte rich tissues like the spleen and lymph nodes to initiate immune responses. In addition to stimulating responses against antigens, dendritic cells also produce tolerance to self antigens. Dendritic cells can be derived from either myeloid or lymphoid lineages. Monocyte derived lineages (pDC1) stimulate Th1 cell differentiation while plasmacytoid (lymphoid) dendritic cells (pDC2) induce Th2 cell differentiation. Factors that stimulate the maturation of monocytes derived dendritic cells include GM-CSF, and IL-4. IL-3 stimulates the differentiation of pDC2 cells into DC2 cells. A variety of factors are involved in antigen-recognition and processing by immature dendritic cells and in the maturation of these cells. The transition to mature dendritic cells down-regulates the factors involved in antigen internalization, and increases the expression of MHC, costimulatory molecules involved in lymphocyte activation, adhesion molecules, and specific cytokines and chemokines. Toll-like receptors on the surface of immature dendritic cells recognize microbial components to induce dendritic cell maturation. In addition to stimulating B cell responses, dendritic cells are potent activators of T cells. IL-12 secretion by dendritic cells stimulates T cell responses, particularly differentiation of Th1 cells that produce interferon-gamma and other pro-inflammatory cytokines. While IL-4 generally stimulates Th2 differentiation, the stimulation of Th2 cell formation by DC2 cells does not appear to involve IL-4. The stimulation of Th1 and Th2 cell formation by dendritic cells appears to be balanced by counter-regulation of each pathway by the other. Interferon-gamma produced by Th1 cells blocks the further stimulation of Th1 differentiation by DC1 cells. The IL-4 produced by Th2 cells kills dendritic cell precursors that contribute to Th2 cell creation. Direct interactions between T cells and dendritic cells are enhanced through the expression of adhesion molecules and costimulatory receptors CD80 and CD86 expressed by mature dendritic cells activate T cells in concert with the recognition of antigen/MHC by the T cell receptor. The central role of dendritic cells as modulators of immune responses makes them an important focus of studies about autoimmune disease, transplant rejection, allergies, responses to infections, and other alterations of the immune response.More...
Selective expression of chemokine receptors during T-cell polarization
Chemokine receptors expressed by T helper cells help recruit......
Chemokine receptors expressed by T helper cells help recruit cells to specific locations based on their chemoattractant ligands. The polarization of T cells into Th1 and Th2 cells is associated with their expression of different subsets of chemokine receptors. Naive CD4 positive cells that have not been exposed to antigen express CXCR4 and CCR7. The most abundant chemokine receptors on Th1 cells involved in the cellular immune response to microbial agents include CXCR3, CCR1, CCR2 and CCR5, while Th2 cells express CCR2, CCR3 and CCR5. An additional class of T cells termed semi-nave cells may be induced by TGF-beta to express yet another class of chemokine receptors, CCR4 and CCR7. Although the expression of chemokine receptors in different cells is preferred in these cases, it is not absolute or exclusive, and there is overlap in expression between Th1 and Th2 cells. Although CCR7 positive cells have been reported to lack effector action, not be polarized, and to home only to lymphoid tissues, other studies have found CCR7 positive Th1 and Th2 cells and have identified CCR7 positive cells in non-lymphoid tissues. CCR4 appears associated with homing of lymphocytes to the skin, and CCR9 is associated with homing to the small intestine, while other chemokines like CXCR3 and CCR5 are associated with homing toward inflamed tissues more broadly. The expression of different chemokine receptors by subsets of T helper cells plays an important role in the migration and homing of these cells in tissues, and targeting of the immune response to specific cells.More...
IL12 and Stat4 Dependent Signaling Pathway in Th1 Development
Interleukin-12 (IL-12) promotes cell-mediated immunity by in......
Interleukin-12 (IL-12) promotes cell-mediated immunity by inducing Th1 cell differentiation and activation of both T cells and NK cells. Dendritic cells and macrophages in peripheral tissues act as antigen presenting cells and secrete IL-12 as one component of the antigen response, Th1 differentiation. The role of IL-12 in cellular immunity is largely mediated by the STAT-4 transcription factor. STAT-4 is essential for IL-12 activity and the phenotype of mice lacking STAT-4 is very similar to the phenotype of mice lacking the IL-12 receptor or IL-12. The role of IL-12 in Th1 differentiation may not be to induce the Th1 cell fate, but to stimulate growth of cells determined for the Th1 cell fate by the T-bet transcription factor. Several signaling pathways contribute to IL-12 activation of STAT-4 to regulate cell-mediated immune responses. The JAK kinases such as JAK2 and TYK2 interact with the activated IL-12 receptor and tyrosine phosphorylate the IL-12 receptor and STAT-4. IL-12 also activates a map kinase pathway activating the map kinase kinase MKK6 and p38. Phosphorylation of STAT-4 on serine 721 by p38 contributes to the full transcriptional activation of genes by STAT-4. Some of the events downstream of IL-12 appear to include genes activated indirectly by STAT-4, such as genes activated by the transcription factor ERM. ERM is in the Ets family of transcription factors, is activated by IL-12 and activates IL-12 inducible genes such as Interferon-gamma that are not activated by STAT-4 itself. Interferon-gamma transcription in T cells is also activated by other signals such as from the T cell receptor. Other proteins activated transcriptionally downstream of IL-12 and STAT-4 include the chemokine receptor CCR5 and IL-18 and its receptor. Some viruses, including HIV, repress cell-mediated immunity by blocking IL-12 signaling.More...
Helper T cells are found in two distinct cell types, Th1 and......
Helper T cells are found in two distinct cell types, Th1 and Th2, distinguished by the cytokines they produce and respond to and the immune responses they are involved in. Th1 cells produce pro-inflammatory cytokines like IFN-g, TNF-b and IL-2, while Th2 cells produce the cytokines IL-4, IL-5, IL-6 and IL-13. The cytokines produced by Th1 cells stimulate the phagocytosis and destruction of microbial pathogens while Th2 cytokines like IL-4 generally stimulate the production of antibodies directed toward large extracellular parasites. IL-5 stimulates eosinophil responses, also part of the immune response toward large extracellular parasites Th1 and Th2 are produced by differentiation from a non-antigen exposed precursor cell type, Thp. Exposure of Thp cells to antigen by antigen-presenting cells may result in their differentiation to Th0 cells, not yet committed to become either Th1 or Th2 cells, although the existence of Th0 cells is controversial. Cells committed as either Th1 and Th2 cells are called polarized, whether they are effector cells actively secreting cytokines or are memory cells. The stimulation of Thp cells by exposure to antigen-presenting cells induces the proliferation of undifferentiated cells, and their expression of IL-2 and IL-2 receptor. The differentiation of Th1 cells and Th2 cells depends on the cytokines they are exposed to. IL-12 causes Th1 differentiation and blocks Th2 cell production , while IL-4 causes Th2 differentiation and antagonizes Th1 development. IL-18 also induces Th1 differentiation. Polarized Th1 and Th2 cells also express distinct sets of chemokine receptors that further modify their homing and other cellular responses. Improved understanding of Th1 and Th2 differentiation will improve our overall understanding of the immune system, its response to infection and aberrant responses that lead to disease.More...
Inflammation is a protective response to infection by the im......
Inflammation is a protective response to infection by the immune system that requires communication between different classes of immune cells to coordinate their actions. Acute inflammation is an important part of the immune response, but chronic inappropriate inflammation can lead to destruction of tissues in autoimmune disorders and perhaps neurodegenerative or cardiovascular disease. Secreted cytokine proteins provide signals between immune cells to coordinate the inflammatory response. Some cytokines such as IL-1, IL-6 and TNF act to broadly provoke the inflammatory response while others act on specific types of immune cells. Macrophages and other phagocytotic cells provide a front-line defense against bacterial infection. Macrophages stimulate the inflammatory responses of neutrophils, fibroblasts, and endothelial cells in response infection by secreting IL-1 and TNF. IL-1 and TNF cause fever through alteration of the body temperature set-point in the hypothalamus. Fibroblasts and endothelial cells respond to IL-1 and TNF by recruiting more immune cells to the site of inflammation. Secreted IL-8 is a chemokine that attracts neutrophils to sites of infection. Macrophages also present antigen to T helper cells that play a central role in coordinating immune responses. T helper cells induce clonal expansion of T cells that respond to antigen, with IL-2 as a key mediator of T cell proliferation and activation. TGF-beta is a negative regulator of proliferation in many cells, have anti-inflammatory actions in some settings. The cytotoxic activity of Natural Killer cells (NK cells) and lymphokine activated killer cells (LAK cells) toward viral infected or tumor cells is stimulated by IL-2 and other cytokines. T helpers secrete IL-3 and IL-5 to stimulate eosinophil proliferation and activation. Eosinophils are involved in the immune response to parasitic infection. T helper cells are required to stimulate B cell responses as well, with the cytokines IL-10, IL-4 and other cytokines regulating the clonal selection and differentiation of antigen-specific B cells to form antibody-secreting plasma B cells and memory cells. In addition to inducing activation and proliferation of specific differentiated immune cells, cytokines act on hematopoeitic stem cells, causing their proliferation and differentiation into the full range of immune cells.More...
Several different cell types coordinate their efforts as par......
Several different cell types coordinate their efforts as part of the immune system, including B cells, T cells, macrophages, neutrophils, basophils and eosinophils. Each of these cell types has a distinct role in the immune system, and communicates with other immune cells using secreted factors called cytokines, including interleukins, TNF, and the interferons. Macrophages phagocytose foreign bodies and are antigen-presenting cells, using cytokines to stimulate specific antigen dependent responses by B and T cells and non-specific responses by other cell types. T cells secrete a variety of factors to coordinate and stimulate immune responses to specific antigen, such as the role of helper T cells in B cell activation in response to antigen. The proliferation and activation of eosinophils, neutrophils and basophils respond to cytokines as well. Cytokine communication is often local, within a tissue or between cells in close proximity. Each of the cytokines is secreted by one set of cells and provokes a response in another target set of cells, often including the cell that secretes the cytokine. Some cytokines, like IL-1, interferons and TNF, stimulate a broad inflammatory response in response to infection or injury. Other cytokines have more specific functions such the following examples. IL-2 stimulates the proliferation and activation of B and T cells. IL-4 plays a role in the differentiation of Th2 cells, in allergic responses, and in the switching of antibody types. IL-5 stimulates the production and maturation of eosinophils during inflammation. IL-8 is a chemokine, a chemotactic factor that attracts neutrophils, basophils and T cells to sites of inflammation. IL-12 and IL-18 are involved in helper T cell differentiation. IL-10 apparently acts to repress secretion of proinflammatory cytokines. The complex interplay of these different cytokine functions with immune cells is essential for correct immune function.More...
Macrophages and NK cells help provide innate immunity agains......
Macrophages and NK cells help provide innate immunity against infection by intracellular parasites and communicate with each other to regulate this process. When stimulated, macrophages secrete the cytokine IL-12 that is essential for activation of the cytotoxic activity of natural killer (NK) cells. IL-12 stimulates this NK cell response through activation of a JAK/STAT signaling pathway. Binding of IL-12 to its receptor on NK cells causes tyrosine phosphorylation and activation of JAK2 and another JAK kinase, Tyk2. Tyk2 in turn phosphorylates the transcription factor STAT4, which can then translocate to the nucleus to activate genes, including the expression of interferon-gamma. IFN-gamma and IL-12 induce the differentiation of TH1 helper T cells that activate macrophages through interferon-gamma. A key modulator of NK cell activation by IL-12 is nitric oxide, NO, produced from arginine by the inducible nitric oxide synthase NOS2. Inactivation of the NOS2 gene in mice impairs the initial innate response to infection, including the activation of NK cells. This phenotype is similar to that of mice lacking interferon-gamma or IL-12 and a similar effect can be produced by inhibiting NOS2 with L-N6-iminoethyl-lysine (L-NIL) during infection, blocking the activation of NK cells by IL-12. NO production does not affect the activation of JAK2 by IL-12, but is required for Tyk2 activity, the downstream activation of STAT-4 and the production of interferon-gamma by NK cells. The role of NO in Tyk2 activation is not yet known, but does not seem to involve change the phosphorylation status of Tyk2. Curiously, activation of T cells by IL-12 does not appear to involved NO production, indicating a distinct mechanism is involved in NK cells. NO also plays a role as a feedback inhibitor of IL-12 production by macrophages, helping to prevent over-activation of the Th1 cells by IL-12. NO appears to make an important contribution to the early innate response to infections before specific immunity is active.More...
IL12A related Reactome pathways (count: 0)
IL12A related interactors from protein-protein interaction data in HPRD (count: 6)
Basic Information
Positive relationships between IL12A and other components at different levels (count: 0)
