Amphiregulin, also known as AREG, is a protein synthesized as a transmembrane glycoprotein with 252 aminoacids and it is encoded by the AREG gene. [5] [6] [7] in humans. [8]
Amphiregulin, also known as AREG, is a protein synthesized as a transmembrane glycoprotein with 252 aminoacids and it is encoded by the AREG gene. [5] [6] [7] in humans. [8]
The protein encoded by this gene is a member of the epidermal growth factor (EGF) family. [5]
It is a critical autocrine growth factor as well as a mitogen for astrocytes, Schwann cells, and fibroblasts. It is ligand for epidermal growth factor (EGF) and it is related to transforming growth factor alpha (TGF-alpha). This protein interacts with the Epidermal growth factor receptor (EGFR) to promote the growth of normal epithelial cells.
AREG is a critical factor in estrogen action and ductal development of the mammary glands. [9] [10] [11] [12] [13] Amphiregulin has been found to be essential for mammary ductal development, as evidenced by absence of ductal growth in amphiregulin knockout mice. [12] This is similar to the phenotypes of EGFR and ERα knockout mice, which also show absence of ductal growth. [12] Amphiregulin is expressed in many parts of body such as ovaries, placenta, pancreas, breasts, lungs and spleen. Expression of amphiregulin can be induced by TGF-α, TNF-α, interleukin 1, and prostaglandins. [14] [15]
Generally, amphiregulin is considered to be a part of type 2 mediated resistance and tolerance, the latter of which occurs by promoting the reestablishment of tissue integrity after damage that is due to acute or chronic inflammation. Its involvement in tissue repair can be explained by its dual role, as amphiregulin can induce mitogenic signals, but it can also lead to cell differentiation of epithelial cells. [16]
While epithelial-derived amphiregulin can promote tissue repair, several immune cells are found to express it in cases of tissue damage, so amphiregulin is part of the crosstalk between immune and epithelial cells. [16] [17]
A population of immune cells that is found to increase its amphiregulin expression after tissue damage, is the innate lymphoid cell 2 (ILC2) population. This has been observed in several organs, such as the lung, the intestine, and the skin. The expression of amphiregulin by ILC2s can be induced by interleukin 33 (IL-33). [18] Also, in skin derived ILC2s, amphiregulin expression was regulated by the interaction of killer-cell lectin-like receptor G1 (KLRG1) with E-cadherin. [19] After intestinal damage, activated intestinal ILC2s produce amphiregulin which enhances the production of mucin by epithelial cells, increases the expression of Claudin-1 and promotes the activity of goblet cells. These functions of amphiregulin lead to increased junction strength, as well as the strengthening of the mucus layer. [18]
Tissue resident regulatory T cells (Tregs) can also express amphiregulin to promote tissue repair. In the skeletal muscle, the IL-33 receptor (ST2) expressing Tregs have a distinct T-cell receptor (TCR) repertoire, [20] and TCR signals don’t seem to be required for amphiregulin production, but this process can be dependent on the IL-33/ST2 (or IL-33 receptor) pathway and the expression of interleukin 18 receptor (IL-18R) on tissue resident Tregs. [21] Also, amphiregulin that is expressed from these Tregs can further enhance their function, forming an autocrine positive feedback loop. [22] Amphiregulin-expressing tissue resident Tregs have been observed in the lung, where most of them are CD44 hi CD62L lo and they express higher levels of CD103, programmed cell death protein 1 (PD-1), glucocorticoid-induced TNFR-related protein (GITR), cytotoxic T-lymphocyte antigen 4 (CTLA-4) and KLRG1. [21] They have been found in injured muscles, where this population has been associated with eosinophil influx, and the production of amphiregulin could enhance the colony-forming efficiency and myogenic differentiation of skeletal muscle satellite cells in vitro, increasing muscle healing. [16] In the inflamed colon, Gata3 +Helios+ Tregs express high levels of amphiregulin too. [23] Moreover, Tregs that express amphiregulin, along with keratinocyte growth factor (KGF), CD39 and CD73, act on parenchymal cells to promote tissue repair and regeneration. [21]
Some unconventional T cells have been associated with the promotion of tissue repair by amphiregulin in a direct or in an indirect manner. After intestinal damage, mucosal-associated invariant T (MAIT) cells produce amphiregulin that leads to epithelial cell turnover and enhances the activity of goblet cells. Also, a pro-repair response by amphiregulin produced by ILC2s and Tregs, that is dependent on IL-33 signaling, is induced by gamma delta (γδ) T cells that produce interleukin 17A (IL-17A). This correlation between IL-17A-producing γδ T cells and amphiregulin has been observed in the lungs and in the oral mucosa. [18]
Mutations in this encoded protein are associated with a psoriasis-like skin phenotype. [24] [5] Higher circulating levels of amphiregulin are associated with AGVHD progression. [25] [26] [27]
Overexpression of amphiregulin is connected with cancer of the breast, prostate, colon, pancreas, lung, spleen, and bladder. [28] [29] [12]
It seems that expression of AREG is connected with proliferation of fibroblasts and production of proinflammatory cytokines interleukin 8 and vascular endothelial growth factor (VEGF). [30]
Chronic elevation of amphiregulin levels has been associated with fibrosis in several organs. ILC2s are drivers of liver, skin, and pulmonary fibrosis, and their expression of interleukin 13 (IL-13) and amphiregulin is implicated in this process. [16] Pathogenic memory Th2 cells that express amphiregulin are also involved in pulmonary fibrosis. Exposure to house dust mite leads to the increase of amphiregulin-expressing pathogenic memory Th2 cells. This increase might be related to the IL-33/ST2 signaling, as blocking this pathway causes less production of amphiregulin. The function of amphiregulin in airway fibrosis is related to eosinophils that express EGFR, in which amphiregulin binds to, resulting in the upregulation of inflammatory genes, including Spp1 that encodes osteopontin. The expression of osteopontin by eosinophils shapes the pathogenesis of pulmonary fibrosis. [31] Moreover, macrophage-derived amphiregulin is involved in the transforming growth factor beta (TGF-β)-induced fibrosis too, as it has been found to activate latent TGF-β through the activation of integrin-αV complex. [16] [32] [33] In the liver, ongoing necrosis leads to the activation of hepatic ILC2s which release amphiregulin along with IL-13. The release of them activates the hepatic stellate cells that transform into myofibroblasts, and ultimately promotes liver fibrosis. [19]
Amphiregulin is part of cellular response type 2. [34] It was found that the cell source of amphiregulin is innate lymphoid cells 2 (ILC2) which are dependent on interleukin 33. ILC2 expressed amphiregulin after tissue damage of the intestines and activation by IL-33. Moreover, endogenous AREG with IL-33 decreased the intestinal inflammation in mice with normal count of T-lymphocytes and in deficient mice. [35]
A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word mamma, "breast". The mammary glands are arranged in organs such as the breasts in primates, the udder in ruminants, and the dugs of other animals. Lactorrhea, the occasional production of milk by the glands, can occur in any mammal, but in most mammals, lactation, the production of enough milk for nursing, occurs only in phenotypic females who have gestated in recent months or years. It is directed by hormonal guidance from sex steroids. In a few mammalian species, male lactation can occur. With humans, male lactation can occur only under specific circumstances.
Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with paracrine signaling, intracrine signaling, or classical endocrine signaling.
The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.
The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.
The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.
Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence identity to IL-4 and is capable of IL-4 independent signaling. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.
A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell.
Interleukin 11 is a protein that in humans is encoded by the IL11 gene.
Hepatocyte growth factor (HGF) or scatter factor (SF) is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts on haemopoietic progenitor cells and T cells. It has been shown to have a major role in embryonic organ development, specifically in myogenesis, in adult organ regeneration, and in wound healing.
Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of proteins that in humans is encoded by the HBEGF gene.
Epiregulin (EPR) is a protein that in humans is encoded by the EREG gene.
Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.
Teratocarcinoma-derived growth factor 1 is a protein that in humans is encoded by the TDGF1 gene. The protein is an extracellular, membrane-bound signaling protein that plays an essential role in embryonic development and tumor growth. Mutations in this gene are associated with forebrain defects. Pseudogenes of this gene are found on chromosomes 2, 3, 6, 8, 19 and X. Alternate splicing results in multiple transcript variants.
The Interleukin-2 receptor alpha chain is a protein involved in the assembly of the high-affinity Interleukin-2 receptor, consisting of alpha (IL2RA), beta (IL2RB) and 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.
Breast development, also known as mammogenesis, is a complex biological process in primates that takes place throughout a female's life.
Interleukin 1 receptor-like 1, also known as IL1RL1 and ST2, is a protein that in humans is encoded by the IL1RL1 gene.
Innate lymphoid cells (ILCs) are the most recently discovered family of innate immune cells, derived from common lymphoid progenitors (CLPs). In response to pathogenic tissue damage, ILCs contribute to immunity via the secretion of signalling molecules, and the regulation of both innate and adaptive immune cells. ILCs are primarily tissue resident cells, found in both lymphoid, and non- lymphoid tissues, and rarely in the blood. They are particularly abundant at mucosal surfaces, playing a key role in mucosal immunity and homeostasis. Characteristics allowing their differentiation from other immune cells include the regular lymphoid morphology, absence of rearranged antigen receptors found on T cells and B cells, and phenotypic markers usually present on myeloid or dendritic cells.
Liver regeneration is the process by which the liver is able to replace damaged or lost liver tissue. The liver is the only visceral organ with the capacity to regenerate. The liver can regenerate after partial hepatectomy or injury due to hepatotoxic agents such as certain medications, toxins, or chemicals. Only 51% of the original liver mass is required for the organ to regenerate back to full size. The phenomenon of liver regeneration is seen in all vertebrates, from humans to fish. The liver manages to restore any lost mass and adjust its size to that of the organism, while at the same time providing full support for body homeostasis during the entire regenerative process. The process of regeneration in mammals is mainly compensatory growth or hyperplasia because while the lost mass of the liver is replaced, it does not regain its original shape. During compensatory hyperplasia, the remaining liver tissue becomes larger so that the organ can continue to function. In lower species such as fish, the liver can regain both its original size and mass.
ILC2 cells, or type 2 innate lymphoid cells are a type of innate lymphoid cell. Not to be confused with the ILC. They are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells lack antigen specific B or T cell receptor because of the lack of recombination activating gene. ILC2s produce type 2 cytokines and are involved in responses to helminths, allergens, some viruses, such as influenza virus and cancer.
Th22 cells are subpopulation of CD4+ T cells that produce interleukin-22 (IL-22). They play a role in the protective mechanisms against variety of bacterial pathogens, tissue repair and wound healing, and also in pathologic processes, including inflammations, autoimmunity, tumors, and digestive organs damages.