Annexin A1, also known as lipocortin I, is a protein that is encoded by the ANXA1 gene in humans. [5]
Annexin A1, also known as lipocortin I, is a protein that is encoded by the ANXA1 gene in humans. [5]
Annexin A1 belongs to the annexin family of Ca2+-dependent phospholipid-binding proteins that have a molecular weight of approximately 35,000 to 40,000 Dalton and are preferentially located on the cytosolic face of the plasma membrane. Annexin A1 protein has an apparent relative molecular mass of 40 kDa with phospholipase A2 inhibitory activity. [6]
Glucocorticoids (such as budesonide, cortisol, and beclomethasone) are a class of endogenous or synthetic anti-inflammatory steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. They are used in medicine to treat diseases caused by an overactive immune system, including allergies, asthma, autoimmune diseases, and sepsis. [7] Because they suppress inflammatory pathways, long-term use of glucocorticoid drugs can lead to side-effects such as immunodeficiency and adrenal insufficiency.
The main mechanism of glucocorticoids' anti-inflammatory effects is to increase the synthesis and function of annexin A1. [8] Annexin A1 both suppresses phospholipase A2, thereby blocking eicosanoid production, and inhibits various leukocyte inflammatory events (epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst, etc.). In other words, glucocorticoids not only suppress immune response, but also inhibit the two main products of inflammation, prostaglandins and leukotrienes. They inhibit prostaglandin synthesis at the level of phospholipase A2 as well as at the level of cyclooxygenase/PGE isomerase (COX-1 and COX-2), [9] the latter effect being much like that of NSAIDs, potentiating the anti-inflammatory effect.
In resting conditions, human and mouse immune cells such as neutrophils, monocytes, and macrophages contain high levels of annexin A1 in their cytoplasm. Following cell activation (for example, by neutrophil adhesion to endothelial-cell monolayers), annexin A1 is promptly mobilized to the cell surface and secreted. Annexin A1 promotes neutrophil detachment and apoptosis, and phagocytosis of apoptotic neutrophils by macrophages. On the other hand, it reduces the tendency of neutrophils to penetrate the endothelium of blood vessels. In vitro and in vivo analyses show that exogenous and endogenous annexin A1 counter-regulate the activities of innate immune cells, particularly extravasation and the generation of proinflammatory mediators, which ensures that a sufficient level of activation is reached but not exceeded. [8]
Annexin A1 has important opposing properties during innate and adaptive immune responses: it inhibits innate immune cells and promotes T-cell activation. The activation of T cells results in the release of annexin A1 and the expression of its receptor. This pathway seems to fine-tune the strength of TCR signalling. Higher expression of annexin A1 during pathological conditions could increase the strength of TCR signalling through the mitogen-activated protein kinase signalling pathway, thereby causing a state of hyperactivation of T cells. [8]
Since phospholipase A2 is required for the biosynthesis of the potent mediators of inflammation, prostaglandins, and leukotrienes, annexin A1 may have potential anti-inflammatory activity. [6]
Glucocorticoids stimulate production of lipocortin. [10] In this way, synthesis of eicosanoids are inhibited.
Annexin A1 has been of interest for use as a potential anticancer drug. Upon induction by modified NSAIDS and other potent anti-inflammatory drugs, annexin A1 inhibits the NF-κB signal transduction pathway, which is exploited by cancerous cells to proliferate and avoid apoptosis. ANXA1 inhibits the activation of NF-κB by binding to the p65 subunit. [11]
The gene for annexin A1 (ANXA1) is upregulated in hairy cell leukemia. ANXA1 protein expression is specific to hairy cell leukemia. Detection of ANXA1 (by immunocytochemical means) reportedly provides a simple, highly sensitive, and specific assay for the diagnosis of hairy cell leukemia. [12]
Altered annexin A1 expression levels through modulation of the immune system effects the initiation and spread of breast cancer, but the association is complex and conclusions of published studies often conflict. [13]
Exposure of MCF-7 breast cancer cells to high physiological levels (up to 100 nM) of estrogen lead to an up-regulation of annexin A1 expression partially through the activation of CREB, and dependent on activation of the estrogen receptor alpha. Treatment of MCF-7 cells with physiological levels of estrogen (1 nM) induced proliferation while high pregnancy levels of estrogen (100 nM) induced a growth arrest of MCF-7 cells. Silencing of ANXA1 with specific siRNA reverses the estrogen-dependent proliferation as well as growth arrest. ANXA1 is lost in clinical breast cancer, indicating that the anti-proliferative protective function of ANXA1 against high levels of estrogen may be lost in breast cancer. This data suggests that ANXA1 may act as a tumor suppressor gene and modulate the proliferative functions of estrogens. [14]
Annexin A1 protects against DNA damage induced by heat in breast cancer cells, adding to the evidence that it has tumor suppressive and protective activities. When ANXA1 is silenced or lost in cancer, cells are more prone to DNA damage, indicating its unidentified diverse role in genome maintenance or integrity. [15] Annexin A1 has also been shown to be associated with treatment resistance. ARID1A loss activates annexin A1 expression, which is required for drug resistance (mTOR inhibitor or trastuzumab) through its activation of AKT. [16]
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.
Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. The name "glucocorticoid" is a portmanteau and is composed from its role in regulation of glucose metabolism, synthesis in the adrenal cortex, and its steroidal structure.
The enzyme phospholipase A2 (EC 3.1.1.4, PLA2, systematic name phosphatidylcholine 2-acylhydrolase) catalyse the cleavage of fatty acids in position 2 of phospholipids, hydrolyzing the bond between the second fatty acid “tail” and the glycerol molecule:
Annexin is a common name for a group of cellular proteins. They are mostly found in eukaryotic organisms.
The chemokine ligand 1 (CXCL1) is a small peptide belonging to the CXC chemokine family that acts as a chemoattractant for several immune cells, especially neutrophils or other non-hematopoietic cells to the site of injury or infection and plays an important role in regulation of immune and inflammatory responses. It was previously called GRO1 oncogene, GROα, neutrophil-activating protein 3 (NAP-3) and melanoma growth stimulating activity, alpha (MGSA-α). CXCL1 was first cloned from a cDNA library of genes induced by platelet-derived growth factor (PDGF) stimulation of BALB/c-3T3 murine embryonic fibroblasts and named "KC" for its location in the nitrocellulose colony hybridization assay. This designation is sometimes erroneously believed to be an acronym and defined as "keratinocytes-derived chemokine". Rat CXCL1 was first reported when NRK-52E cells were stimulated with interleukin-1β (IL-1β) and lipopolysaccharide (LPS) to generate a cytokine that was chemotactic for rat neutrophils, cytokine-induced neutrophil chemoattractant (CINC). In humans, this protein is encoded by the gene Cxcl1 and is located on human chromosome 4 among genes for other CXC chemokines.
Annexin A2 also known as annexin II is a protein that in humans is encoded by the ANXA2 gene.
Annexin A5 is a cellular protein in the annexin group. In flow cytometry, annexin V is commonly used to detect apoptotic cells by its ability to bind to phosphatidylserine, a marker of apoptosis when it is on the outer leaflet of the plasma membrane. The function of the protein is unknown; however, annexin A5 has been proposed to play a role in the inhibition of blood coagulation by competing for phosphatidylserine binding sites with prothrombin and also to inhibit the activity of phospholipase A1. These properties have been found by in vitro experiments.
Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. TLR9 has also been designated as CD289. It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expressed in immune system cells including dendritic cells, macrophages, natural killer cells, and other antigen presenting cells. TLR9 is expressed on endosomes internalized from the plasma membrane, binds DNA, and triggers signaling cascades that lead to a pro-inflammatory cytokine response. Cancer, infection, and tissue damage can all modulate TLR9 expression and activation. TLR9 is also an important factor in autoimmune diseases, and there is active research into synthetic TLR9 agonists and antagonists that help regulate autoimmune inflammation.
Insulin receptor substrate 1(IRS-1) is a signaling adapter protein that in humans is encoded by the IRS1 gene. It is a 131 kDa protein with amino acid sequence of 1242 residues. It contains a single pleckstrin homology (PH) domain at the N-terminus and a PTB domain ca. 40 residues downstream of this, followed by a poorly conserved C-terminus tail. Together with IRS2, IRS3 (pseudogene) and IRS4, it is homologous to the Drosophila protein chico, whose disruption extends the median lifespan of flies up to 48%. Similarly, Irs1 mutant mice experience moderate life extension and delayed age-related pathologies.
CCAAT/enhancer-binding protein beta is a protein that in humans is encoded by the CEBPB gene.
Leukotriene B4 receptor 2, also known as BLT2, BLT2 receptor, and BLTR2, is an Integral membrane protein that is encoded by the LTB4R2 gene in humans and the Ltbr2 gene in mice.
5-Hydroxyeicosatetraenoic acid (5-HETE, 5(S)-HETE, or 5S-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(S)-HETE to 5-oxo-eicosatetraenoic acid (5-oxo-ETE), 5(S),15(S)-dihydroxyeicosatetraenoic acid (5(S),15(S)-diHETE), or 5-oxo-15-hydroxyeicosatetraenoic acid (5-oxo-15(S)-HETE).
GATA3 is a transcription factor that in humans is encoded by the GATA3 gene. Studies in animal models and humans indicate that it controls the expression of a wide range of biologically and clinically important genes.
Antileukoproteinase, also known as secretory leukocyte protease inhibitor (SLPI), is an enzyme that in humans is encoded by the SLPI gene. SLPI is a highly cationic single-chain protein with eight intramolecular disulfide bonds. It is found in large quantities in bronchial, cervical, and nasal mucosa, saliva, and seminal fluids. SLPI inhibits human leukocyte elastase, human cathepsin G, human trypsin, neutrophil elastase, and mast cell chymase. X-ray crystallography has shown that SLPI has two homologous domains of 53 and 54 amino acids, one of which exhibits anti-protease activity. The other domain is not known to have any function.
S100 calcium-binding protein A10 (S100A10), also known as p11, is a protein that is encoded by the S100A10 gene in humans and the S100a10 gene in other species. S100A10 is a member of the S100 family of proteins containing two EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells. They regulate a number of cellular processes such as cell cycle progression and differentiation. The S100 protein is implicated in exocytosis and endocytosis by reorganization of F-actin.
Annexin A4 is a protein that in humans is encoded by the ANXA4 gene.
OX-2 membrane glycoprotein, also named CD200 is a human protein encoded by the CD200 gene. CD200 gene is in human located on chromosome 3 in proximity to genes encoding other B7 proteins CD80/CD86. In mice CD200 gene is on chromosome 16.
Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.
MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old White woman. MCF-7 is the acronym of Michigan Cancer Foundation-7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-workers. The Michigan Cancer Foundation is now known as the Barbara Ann Karmanos Cancer Institute.
Prostaglandin inhibitors are drugs that inhibit the synthesis of prostaglandin in human body. There are various types of prostaglandins responsible for different physiological reactions such as maintaining the blood flow in stomach and kidney, regulating the contraction of involuntary muscles and blood vessels, and act as a mediator of inflammation and pain. Cyclooxygenase (COX) and Phospholipase A2 are the major enzymes involved in prostaglandin production, and they are the drug targets for prostaglandin inhibitors. There are mainly 2 classes of prostaglandin inhibitors, namely non- steroidal anti- inflammatory drugs (NSAIDs) and glucocorticoids. In the following sections, the medical uses, side effects, contraindications, toxicity and the pharmacology of these prostaglandin inhibitors will be discussed.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.
