Biological networks and signal transduction pathways corresp......
Biological networks and signal transduction pathways corresponding to the identified gene set suggested putative dysregulated functions for several hormone-type factors previously implicated in depression (insulin, interleukin-1, thyroid hormone, estradiol and glucocorticoids; p<0.01 for association with depression-related networks).More...
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 IL1A and other components at different levels (count: 0)
Positive relationship network of IL1A in MK4MDD
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Note:
1. The different color of the nodes denotes the level of the nodes.
Genetic/Epigenetic Locus
Protein and Other Molecule
Cell and Molecular Pathway
Neural System
Cognition and Behavior
Symptoms and Signs
Environment
MDD
2. Besides the component related relationships from literature, gene mapped protein and protein mapped gene are also shown in the network.
If the mapped gene or protein is not from literature, square node would be used instead of Circle node.
Accordingly, the relationship is marked with dot line.
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3. The network is generated using Cytoscape Web
Negative relationships between IL1A and MDD (count: 0)
Negative relationships between IL1A 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...
Graft-versus-host disease (GVHD) pathophysiology can be summ......
Graft-versus-host disease (GVHD) pathophysiology can be summerized in a three-step process. During step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to damage, activation of host tissues and induction of inflammatory cytokines secretion. Increased expression of major histocompatibility complex (MHC) antigens and adhesion molecules leads to enhancement of the recognition of host MHC and/or minor histocompatibility antigens by mature donor T cells. Donor T-cell activation in step II is characterized by the predominance of Th1 cells and the secretion of IL-2 and IFN-gamma. These cytokines induce further T-cell expansion, induce cytotoxic T lymphocytes (CTL) and natural killer (NK) cells responses and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. Also, nitric oxide (NO) is produced by activated macrophages, and it may contribute to the tissue damage seen during step 3. Lipopolysaccharide (LPS), which leaks through the intestinal mucosa that was damaged during step 1, together with IFN-gamma, from step 2, further stimulate macrophages to secrete cytokines and NO. During step 3, the effector phase, activated CTL and NK cells mediate cytotoxicity against target host cells through Fas-Fas ligand interactions and perforin-granzyme B.More...
Prion diseases, also termed transmissible spongiform encepha......
Prion diseases, also termed transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative diseases that affect humans and a number of other animal species. The etiology of these diseases is thought to be associated with the conversion of a normal protein, PrPC, into an infectious, pathogenic form, PrPSc. The conversion is induced by prion infections (for example, variant Creutzfeldt-Jakob disease (vCJD), iatrogenic CJD, Kuru), mutations (familial CJD, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia (FFI)) or unknown factors (sporadic CJD (sCJD)), and is thought to occur after PrPC has reached the plasma membrane or is re-internalized for degradation. The PrPSc form shows greater protease resistance than PrPC and accumulates in affected individuals, often in the form of extracellular plaques. Pathways that may lead to neuronal death comprise oxidative stress, regulated activation of complement, ubiquitin-proteasome and endosomal-lysosomal systems, synaptic alterations and dendritic atrophy, corticosteroid response, and endoplasmic reticulum stress. In addition, the conformational transition could lead to the lost of a beneficial activity of the natively folded protein, PrPC.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...
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...
Blood-cell development progresses from a hematopoietic stem ......
Blood-cell development progresses from a hematopoietic stem cell (HSC), which can undergo either self-renewal or differentiation into a multilineage committed progenitor cell: a common lymphoid progenitor (CLP) or a common myeloid progenitor (CMP). A CLP gives rise to the lymphoid lineage of white blood cells or leukocytes-the natural killer (NK) cells and the T and B lymphocytes. A CMP gives rise to the myeloid lineage, which comprises the rest of the leukocytes, the erythrocytes (red blood cells), and the megakaryocytes that produce platelets important in blood clotting. Cells undergoing these differentiation process express a stage- and lineage-specific set of surface markers. Therefore cellular stages are identified by the specific expression patterns of these genes.More...
Apoptosis is a genetically controlled mechanisms of cell dea......
Apoptosis is a genetically controlled mechanisms of cell death involved in the regulation of tissue homeostasis. The 2 major pathways of apoptosis are the extrinsic (Fas and other TNFR superfamily members and ligands) and the intrinsic (mitochondria-associated) pathways, both of which are found in the cytoplasm. The extrinsic pathway is triggered by death receptor engagement, which initiates a signaling cascade mediated by caspase-8 activation. Caspase-8 both feeds directly into caspase-3 activation and stimulates the release of cytochrome c by the mitochondria. Caspase-3 activation leads to the degradation of cellular proteins necessary to maintain cell survival and integrity. The intrinsic pathway occurs when various apoptotic stimuli trigger the release of cytochrome c from the mitochondria (independently of caspase-8 activation). Cytochrome c interacts with Apaf-1 and caspase-9 to promote the activation of caspase-3. Recent studies point to the ER as a third subcellular compartment implicated in apoptotic execution. Alterations in Ca2+ homeostasis and accumulation of misfolded proteins in the ER cause ER stress. Prolonged ER stress can result in the activation of BAD and/or caspase-12, and execute apoptosis.More...
The mitogen-activated protein kinase (MAPK) cascade is a hig......
The mitogen-activated protein kinase (MAPK) cascade is a highly conserved module that is involved in various cellular functions, including cell proliferation, differentiation and migration. Mammals express at least four distinctly regulated groups of MAPKs, extracellular signal-related kinases (ERK)-1/2, Jun amino-terminal kinases (JNK1/2/3), p38 proteins (p38alpha/beta/gamma/delta) and ERK5, that are activated by specific MAPKKs: MEK1/2 for ERK1/2, MKK3/6 for the p38, MKK4/7 (JNKK1/2) for the JNKs, and MEK5 for ERK5. Each MAPKK, however, can be activated by more than one MAPKKK, increasing the complexity and diversity of MAPK signalling. Presumably each MAPKKK confers responsiveness to distinct stimuli. For example, activation of ERK1/2 by growth factors depends on the MAPKKK c-Raf, but other MAPKKKs may activate ERK1/2 in response to pro-inflammatory stimuli.More...
Stem cells in the bone marrow produce a variety of hematopoi......
Stem cells in the bone marrow produce a variety of hematopoietic cell types from common progenitor cells under the influence of cytokines and growth factors. CFU-GEMM cells are a key intermediate in the differentiation of granulocytes, erythrocytes, monocytes and megakaryocytes. Erythropoietin (EPO) is a cytokine produced in the kidneys that, along with other cytokines, induces red blood cell (erythrocyte) differentiation in the bone marrow from CFU-GEMM cells. As the erythrocyte lineage progresses, cells lose their nuclei, and move out of the bone marrow into circulation. The ability of EPO to selectively induce red blood cell differentiation has allowed extensive therapeutic use of the recombinant form of this cytokine to treat anemias.More...
Interleukin-1 (IL-1) is a pro-inflammatory cytokine that sig......
Interleukin-1 (IL-1) is a pro-inflammatory cytokine that signals primarily through the type 1 IL-1 receptor (IL-1R1). The activities of IL-1 include induction of fever, expression of vascular adhesion molecules, and roles in arthritis and septic shock. The inflammatory activities of IL-1 are partially derived by transcriptionally inducing expression of cytokines such as TNF-alpha and interferons, as well as inducing the expression of other inflammation-related genes. There are two forms of IL-1 encoded by distinct genes, IL-1 alpha and IL-1 beta. IL-1 beta is produced as a 269 amino acid precursor that is cleaved by IL-1beta converting enzyme (ICE) to the active IL-1 beta form that is secreted. IL-1 signaling is opposed by the naturally occurring peptide IL-1 receptor antagonist which is a therapeutic agent for the treatment of arthritis. The type 1 IL-1 receptor protein binds IL-1 beta but requires the IL-1 receptor accessory protein (IL-1RAcP) to transduce a signal. IL-1 binding causes activation of two kinases, IRAK-1 and IRAK-2, associated with the IL-1 receptor complex. IRAK-1 (IL-1 Receptor Associated Kinase) activates and recruits TRAF6 to the IL-1 receptor complex. TRAF6 activates two pathways, one leading to NF-kB activation and another leading to c-jun activation. The TRAF associated protein ECSIT leads to c-Jun activation through the Map kinase/JNK signaling system. TRAF6 also signals through the TAB1/TAK1 kinases to trigger the degradation of I-kB, and activation of NF-kB. The IL-1 signaling cascade represents a highly conserved response to pathogens through evolution, with homologs in insects and even in plants. The signal transduction cascade utilized by IL-1 receptor is similar to that of TNF, resulting in NF-kB activation, and is most similar to that of the Toll-like receptors that also participate in inflammatory signaling responses to pathogen components like endotoxin.More...
Nuclear factor kB (NF-kB) is a nuclear transcription factor ......
Nuclear factor kB (NF-kB) is a nuclear transcription factor that regulates expression of a large number of genes that are critical for the regulation of apoptosis, viral replication, tumorigenesis, inflammation, and various autoimmune diseases. The activation of NF-kB is thought to be part of a stress response as it is activated by a variety of stimuli that include growth factors, cytokines, lymphokines, UV, pharmacological agents, and stress. In its inactive form, NF-kB is sequestered in the cytoplasm, bound by members of the IkB family of inhibitor proteins, which include IkBa, IkBb, IkBg, and IkBe. The various stimuli that activate NF-kB cause phosphorylation of IkB, which is followed by its ubiquitination and subsequent degradation. This results in the exposure of the nuclear localization signals (NLS) on NF-kB subunits and the subsequent translocation of the molecule to the nucleus. In the nucleus, NF-kB binds with a consensus sequence (5'GGGACTTTCC-3') of various genes and thus activates their transcription. IkB proteins are phosphorylated by IkB kinase complex consisting of at least three proteins; IKK1/IKKa, IKK2/IKKb, and IKK3/IKKg. These enzymes phosphorylate IkB leading to its ubiquitination and degradation. Tumor necrosis factor (TNF) which is the best-studied activator binds to its receptor and recruits a protein called TNF receptor death domain (TRADD). TRADD binds to the TNF receptor-associated factor 2 (TRAF-2) that recruits NF-kB-inducible kinase (NIK). Both IKK1 and IKK2 have canonical sequences that can be phosphorylated by the MAP kinase NIK/MEKK1 and both kinases can independently phosphorylate IkBa or IkBb. TRAF-2 also interacts with A20, a zinc finger protein whose expression is induced by agents that activate NF-kB. A20 functions to block TRAF2-mediated NF-kB activation. A20 also inhibits TNF and IL-1 induced activation of NF-kB suggesting that it may act as a general inhibitor of NF-kB activation.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...
Cell adhesion is a fundamental feature of multicellular orga......
Cell adhesion is a fundamental feature of multicellular organisms including their defense mechanisms. In the later case in mammals, leukocytes play central role. They bind bacteria, parasites, viruses, tumor cells etc. Furthermore, their interactions with the endothelium are of special importance. During an inflammation or immune reaction, specialized leukocytes (eosinophilic granulocytes) adhere to and pass through the endothelium of the blood vessels and the underlying matrix. The reaction passes through the following steps: 1. Rolling (the flow of cells is slowed down by first making contacts to the endothelium via P-, E-, and L-selectins and their receptors); 2. Adhesion (After activation of leukocyte integrins, firm contacts are established between them and endothelium molecules of the Ig superfamily - LFA-1, Mac-1, VLA-4 etc.); 3. Flattening of the cells and diapedesis (Adhering leukocytes crawl to an intercellular junction of the endothelium and then transmigrate to or even through the intercellular matrix. This is mediated by a homophilic interactions of PECAM and CD31.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...
Cell adhesion is a fundamental feature of multicellular orga......
Cell adhesion is a fundamental feature of multicellular organisms including their defense mechanisms. In the later case in mammals, leukocytes play central role. They bind bacteria, parasites, viruses, tumor cells etc. Furthermore, their interactions with the endothelium are of special importance. Generally, lymphocyte adhesion and passage from the bloodstream to the lymphatic system occurs in the high endothelial venules of the lymphnodes. This way the lymphocytes can communicate with each other in the lymphatic system and search for foreign compounds after their recirculation to the bloodstream, this fulfilling their role in the immune system. The reaction passes through the following steps: 1. Rolling (the flow of cells is slowed down by first making contacts to the endothelium via P-, E-, and L-selectins and their receptors); 2. Adhesion (After activation of leukocyte integrins, firm contacts are established between them and endothelium molecules of the Ig superfamily - LFA-1, Mac-1, VLA-4 etc.); 3. Flatteningof the cells and diapedesis (Adhering leukocytes crawl to an intercellular junction of the endothelium and then transmigrate to or even through the intercellular matrix. This is mediated by a homophilic interactions of PECAM and CD31.More...
Cells and Molecules involved in local acute inflammatory response
Inflammation has several distinct components, including the ......
Inflammation has several distinct components, including the localized response at the site of tissue injury or infection. Tissue injury stimulates the release of inflammatory signaling molecules such as bradykinin. Bacterial infection stimulates an immune response in several ways. Bacteria that are phagocytosed can activate macrophages, causing the release of inflammatory cytokines such as IL-1, TNF, and IL-6. Bacteria can also activate the complement cascade through either the antibody-mediated pathway (classical pathway) or the alternative complement pathway. In extravascular tissues, cells that respond to infection or injury include macrophages and mast cells. Macrophages and other immune cells secrete chemokines that recruit leukocytes from the circulation to the site of inflammation. Mast cells release histamine, prostaglandins, and leukotrienes that act as chemokines, increase vascular permeability, and act on the vascular endothelium to increase tissue recruitment of leukocytes. Chemokines can recruit leukocytes or lymphocytes out of the blood stream into tissues and make blood vessels more permeable. Leukocytes are activated by inflammatory signals to express adhesion molecules that cause them to interact with the vascular endothelium, penetrate the endothelial wall and migrate into the extracellular space of tissues. The combined response of immune cells and signaling molecules at the site of inflammation induces swelling, activation of immune cells, and clearance of potential infectious agents. Chronic inflammation can however also lead to tissue damage in conditions such as arthritis, in which anti-inflammatory drugs act on various steps in inflammation to prevent disease.More...
Mammalian cells can respond to a variety of stresses such as......
Mammalian cells can respond to a variety of stresses such as heat, cold, oxidative stress, metabolic disturbance, and environmental toxins through necrotic or apoptotic cell death, while increased expression and phosphorylation of heat shock proteins such as Hsp27 can protect cells against cellular stress. Heat shock proteins commonly exhibit molecular chaperone activity and also interact with a wide variety of proteins to exert specific effects. The small heat shock protein Hsp27 exists as monomers, dimers, and oligomers in the cell, and each form has distinct activities. Oligomers are the main form of Hsp27 with molecular chaperone activity and are disrupted by phosphorylation of Hsp27 to form dimers and monomers. S-thiolation of Hsp27 on cysteine also dissociates oligomers and may provide another route of regulating the action of Hsp27 in stress. Map kinase cascades mediate Hsp27 phosphorylation. Heat stress activates the p38 kinase cascade and induces phosphorylation of Hsp27 by the downstream Map kinases Mapkapk2 and Mapkap3. Cytokines such as TNF and IL-1 can also induce Hsp27 phoshorylation through this Map kinase cascade, protecting cells in some settings against cytotoxic responses. In stressful conditions, dissociation of oligomeric Hsp27 by phosphorylation may allow lower molecular weight forms to perform other non-chaperone functions. One action of Hsp27 induced by stress is to protect cells against apoptosis and a common component of apoptotic pathways is the mitochondrial release of cytochrome c. One way that Hsp27 reduces apoptosis is by preventing the release of cytochrome c and by binding to cytochrome c in the cytosol. Downstream, Hsp27 also blocks caspase 9 activation and the subsequent activation of caspase 3, inhibiting the rest of the proteolytic caspase cascade. Yet a further role of Hsp27 in blocking apoptosis is through blocking Fas-induced apoptosis. Fas is a receptor in the TNF receptor gene family that induces apoptosis when stimulated by its cell-bound ligand, Fas-ligand. Fas induces apoptosis through two pathways, one mediated by the protein Daxx. Phosphorylated Hsp27 dimers block apoptosis by binding with Daxx and preventing downstream activation of the kinase Ask1. The interaction of Hsp27 with actin filaments may also prevent apoptosis triggered by some agents like staurosporine that damage actin. Unphosphorylated Hsp27 monomers regulate actin filament growth by binding to the end of fibers and capping them. Finally, Hsp27 appears to prevent damage to cells by reactive oxygen species (ROS), by altering the oxidative environment of the cell through induction of glutathione expression, as well as blocking apoptosis induced by ROS. Modulation of Hsp27 expression and phosphorylation may provide a useful means to alter cellular sensitivity to stress.More...
IL-10 is a cytokine with potent anti-inflammatory properties......
IL-10 is a cytokine with potent anti-inflammatory properties, repressing the expression of inflammatory cytokines such as TNF-alpha, IL-6 and IL-1 by activated macrophages. The IL-10 receptor is in the JAK/STAT class of receptors but activation of the JAK/STAT pathways by IL-10 does not appear on its own to be responsible for the anti-inflammatory properties of this cytokine. The anti-inflammatory actions of IL-10 appear to require induction of the enzyme heme oxygenase-1 (HO-1) through a map kinase pathway involving the p38 kinases. HO-1 is involved in the biosynthesis of heme, and catalyzes a reaction producing carbon monoxide, free iron, and the heme precursor biliverdin. HO-1 is induced by IL-10 and is also induced by oxidative stress. Blocking HO-1 with inhibitors or antisense blocks the anti-inflammatory actions of IL-10. The anti-inflammatory actions of HO-1 appear to be the result of signaling by carbon monoxide it produces since removal of CO blocks the anti-inflammatory action of IL-10 and HO-1. The anti-inflammatory actions of IL-10 may be therapeutically useful either directly or through modulation of HO-1 activity.More...
IL1A related Reactome pathways (count: 0)
IL1A related interactors from protein-protein interaction data in HPRD (count: 10)
Basic Information
Positive relationships between IL1A and other components at different levels (count: 0)
