Interleukin 17
Encyclopedia
Interleukin-17 is the founding member of a group of cytokine
s called the IL-17 family. IL-17A, was originally identified as a transcript
from a rodent
T-cell hybridoma
by Rouvier et al. in 1993. Known as CTLA8 in rodents, IL-17 shows high homology to viral IL-17 encoded by an open reading frame
of the T lymphotropic rhadinovirus
Herpesvirus saimiri.
Interleukin 17 is a cytokine that acts as a potent mediator in delayed – type reactions by increasing chemokine production in various tissues to recruit monocytes and neutrophils to the site of inflammation, similar to Interferon gamma. IL- 17 is produced by T helper cells and is induced by IL – 23 which results in destructive tissue damage in delayed – type reactions. Interleukin 17 as a family functions as a proinflammatory cytokine that responds to the invasion of the immune system by extracellular pathogens and induces destruction of the pathogen’s cellular matrix. Interleukin 17 acts synergistically with tumor necrosis factor
and interleukin-1.
To elicit its functions, IL-17 binds to a type I cell surface receptor called IL-17R
of which there are at least three variants IL17RA
, IL17RB
, and IL17RC
.
), and IL-17F. All members of the IL-17 family have a similar protein
structure, with four highly conserved cysteine
residues critical to their 3-dimensional
shape, yet they have no sequence similarity to any other known cytokines. Phylogenetic analysis reveals that among IL-17 family members, the IL-17F isoforms 1 and 2 (ML-1) have the highest homology to IL-17A (sharing 55 and 40% amino acid
identity to IL-17A respectively), followed by IL-17B (29%), IL-17D (25%), IL-17C (23%), and IL-17E being most distantly related to IL-17A (17%). These cytokines are all well conserved in mammal
s, with as much as 62–88% of amino acids conserved between the human and mouse homologs.
, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α), chemokines (including IL-8
, GRO-α, and MCP-1), and prostaglandins (e.g., PGE
2) from many cell types (fibroblasts, endothelial cells, epithelial cells, keratinocytes, and macrophages). The release of cytokines causes many functions, such as airway remodeling, a characteristic of IL-17 responses. The increased expression of chemokines attracts other cells including neutrophils but not eosinophils. IL-17 function is also essential to a subset of CD4
+ T-Cells called T helper 17
(Th17) cells. As a result of these roles, the IL-17 family has been linked to many immune/autoimmune related diseases including rheumatoid arthritis
, asthma
, lupus
, allograft rejection and anti-tumour immunity.
for human IL-17 is 1874 base pair
s long and was cloned from CD4+ T cells. Each member of the IL-17 family has a distinct pattern of cellular expression
. The expression of IL-17A and IL-17F appear to be restricted to a small group of activated T cells, and upregulated during inflammation
. IL-17B is expressed in several peripheral tissues and immune tissues. IL-17C is also highly upregulated in inflammatory
conditions, although in resting conditions is low in abundance. IL-17D is highly expressed in the nervous system
and in skeletal muscle
and IL-17E is found at low levels in various peripheral tissues.
Much progress has been made in the understanding of the regulation of IL-17. At first, Aggarwal et al. showed that production of IL-17 was dependent on IL-23
. Later, a Korean group discovered that STAT3
and NF-κB signalling pathways are required for this IL-23-mediated IL-17 production. Consistent with this finding, Chen et al. showed that another molecule, SOCS3
, plays an important role in IL-17 production. In the absence of SOCS3, IL-23-induced STAT3 phosphorylation
is enhanced, and phosphorylated STAT3 binds to the promotor regions of both IL-17A and IL-17F increasing their gene activity. In contrast, some scientists believe IL-17 induction is independent of IL-23. Several groups have identified ways to induce IL-17 production both in vitro and in vivo by distinct cytokines, called TGF-β and IL-6
, without the need for IL-23. Although IL-23 is not required for IL-17 expression in this situation, IL-23 may play a role in promoting survival and/or proliferation of the IL-17 producing T-cells. Recently, Ivanov et al. found that the thymus
specific nuclear receptor
, ROR-γ
, directs differentiation of IL-17-producing T cells.
-linked, homodimeric, secreted glycoprotein
with a molecular mass of 35 kDa. Each subunit of the homodimer is approximately 15-20 KDa. The structure of IL-17 consists of a signal peptide
of 23 amino acids (aa) followed by a 123-aa chain region characteristic of the IL-17 family. An N-linked glycosylation
site on the protein was first identified after purification of the protein revealed two bands, one at 15 KDa and another at 20 KDa. Comparison of different members of the IL-17 family revealed four conserved cysteines that form two disulfide bond
s. IL-17 is unique in that it bears no resemblance to other known interleukin
s. Furthermore, IL-17 bears no resemblance to any other known proteins or structural domains.
The crystal structure of IL-17F, which is 50% homologous to IL-17A, revealed that IL-17F is structurally similar to the cysteine knot family of proteins that includes the neurotrophin
s. The cysteine knot fold is characterized by two sets of paired β-strands stabilized by three disulfide interactions. However, in contrast to the other cysteine knot proteins, IL-17F lacks the third disulfide bond. Instead, a serine
replaces the cysteine at this position. This unique feature is conserved in the other IL-17 family members. IL-17F also dimerizes in a fashion similar to nerve growth factor
(NGF) and other neurotrophins.
s.
The IL-17 receptor family consists of five, broadly distributed receptors that present with individual ligand specificities. Within this family of receptors, IL-17R is the best-described. IL-17R binds both IL-17A and IL-17F and is expressed in multiple tissues: vascular endothelial cells, peripheral T cells, B cell lineages, fibroblast, lung, myelomonocytic cells, and marrow stromal cells.
Another member of this receptor family, IL-17RB, binds both IL-17B and IL-17E. Furthermore, it is expressed in the kidney, pancreas, liver, brain, and intestine. IL-17RC is expressed by the prostate, cartilage, kidney, liver, heart, and muscle, and its gene may undergo alternate splicing to produce a soluble receptor in addition to its cell membrane-bound form. In similar manner, the gene for IL-17RD may undergo alternative splicing to yield a soluble receptor. This feature may allow these receptors to inhibit the stimulatory effects of their yet-undefined ligands. The least-described of these receptors, IL-17RE, is known to be expressed in the pancreas, brain, and prostate.
Signal transduction by these receptors is as diverse as their distribution. These receptors do not exhibit a significant similarity in extracellular or intracellular amino acid sequence when compared to other cytokine receptors. Transcription factors such as TRAF6
, JNK
, Erk1/2, p38, AP-1 and NF-κB have been implicated in IL-17 mediated signaling in a stimulation-dependent, tissue-specific manner. Other signaling mechanisms have also been proposed, but more work is needed to fully elucidate the true signaling pathways used by these diverse receptors.
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
s called the IL-17 family. IL-17A, was originally identified as a transcript
Transcript
Transcript may refer to:* Transcript , a copy of a student's permanent academic record* Transcription , the process of creating an equivalent RNA copy of a sequence of DNA* Transcript , a record of all court proceedings...
from a rodent
Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing....
T-cell hybridoma
Hybridoma
Hybridoma technology is a technology of forming hybrid cell lines by fusing a specific antibody-producing B cell with a myeloma cell that is selected for its ability to grow in tissue culture and for an absence of antibody chain synthesis...
by Rouvier et al. in 1993. Known as CTLA8 in rodents, IL-17 shows high homology to viral IL-17 encoded by an open reading frame
Open reading frame
In molecular genetics, an open reading frame is a DNA sequence that does not contain a stop codon in a given reading frame.Normally, inserts which interrupt the reading frame of a subsequent region after the start codon cause frameshift mutation of the sequence and dislocate the sequences for stop...
of the T lymphotropic rhadinovirus
Rhadinovirus
Rhadinoviruses are a genus of herpesviruses that include the Human herpesvirus 8 , also known as Kaposi's sarcoma-associated herpesvirus , which causes Kaposi's sarcoma, primary effusion lymphoma and multicentric Castleman's disease. Other names for the Rhadinovirus genus include Rhadinoviridae...
Herpesvirus saimiri.
Interleukin 17 is a cytokine that acts as a potent mediator in delayed – type reactions by increasing chemokine production in various tissues to recruit monocytes and neutrophils to the site of inflammation, similar to Interferon gamma. IL- 17 is produced by T helper cells and is induced by IL – 23 which results in destructive tissue damage in delayed – type reactions. Interleukin 17 as a family functions as a proinflammatory cytokine that responds to the invasion of the immune system by extracellular pathogens and induces destruction of the pathogen’s cellular matrix. Interleukin 17 acts synergistically with tumor necrosis factor
Tumor necrosis factor
Tumor necrosis factor is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction...
and interleukin-1.
To elicit its functions, IL-17 binds to a type I cell surface receptor called IL-17R
Interleukin-17 receptor
Interleukin-17 receptor is a cytokine receptor which binds interleukin 17. Functional IL-17R is a heteromeric complex consisting of at least IL17RA and IL17RC....
of which there are at least three variants IL17RA
IL17RA
Interleukin 17 receptor A, also known as IL17RA and CDw217 , is a human gene....
, IL17RB
IL17RB
Interleukin-17 receptor B is a protein that in humans is encoded by the IL17RB gene....
, and IL17RC
IL17RC
Interleukin-17 receptor C is a protein that in humans is encoded by the IL17RC gene....
.
Family members
In addition to IL-17A, members of the IL-17 family include IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25Interleukin 25
Interleukin-25 is a protein that in humans is encoded by the IL25 gene.- Function :IL-25 is a cytokine that shares the sequence similarity with IL17. This cytokine can induce NF-κB activation, and stimulate the production of IL8. Both this cytokine and IL17B are ligands for the cytokine receptor...
), and IL-17F. All members of the IL-17 family have a similar protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
structure, with four highly conserved cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residues critical to their 3-dimensional
Three-dimensional space
Three-dimensional space is a geometric 3-parameters model of the physical universe in which we live. These three dimensions are commonly called length, width, and depth , although any three directions can be chosen, provided that they do not lie in the same plane.In physics and mathematics, a...
shape, yet they have no sequence similarity to any other known cytokines. Phylogenetic analysis reveals that among IL-17 family members, the IL-17F isoforms 1 and 2 (ML-1) have the highest homology to IL-17A (sharing 55 and 40% amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
identity to IL-17A respectively), followed by IL-17B (29%), IL-17D (25%), IL-17C (23%), and IL-17E being most distantly related to IL-17A (17%). These cytokines are all well conserved in mammal
Mammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s, with as much as 62–88% of amino acids conserved between the human and mouse homologs.
Function
Numerous immune regulatory functions have been reported for the IL-17 family of cytokines, it is presumed due to their induction of many immune signaling molecules. The most notable role of IL-17 is it involvement in inducing and mediating proinflammatory responses. IL-17 is commonly associated with allergic responses. IL-17 induces the production of many other cytokines (such as IL-6Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α), chemokines (including IL-8
IL-8
IL-8 can refer to:* Interleukin 8, a chemokine of the immune system* Illinois' 8th congressional district* Illinois Route 8...
, GRO-α, and MCP-1), and prostaglandins (e.g., PGE
Prostaglandin E
Prostaglandin E is a family of naturally occurring prostaglandins and may be used pharmaceutically in medicine.Types include:* Prostaglandin E1 also termed Alprostadil* Prostaglandin E2 also termed DinoprostoneIt is created from prostaglandin E synthase....
2) from many cell types (fibroblasts, endothelial cells, epithelial cells, keratinocytes, and macrophages). The release of cytokines causes many functions, such as airway remodeling, a characteristic of IL-17 responses. The increased expression of chemokines attracts other cells including neutrophils but not eosinophils. IL-17 function is also essential to a subset of CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
+ T-Cells called T helper 17
T helper 17 cell
T helper 17 cells are a subset of T helper cells producing interleukin 17 discovered in 2007. They are considered developmentally distinct from Th1 and Th2 cells and excessive amounts of the cell are thought to play a key role in autoimmune disease such as multiple sclerosis , but also...
(Th17) cells. As a result of these roles, the IL-17 family has been linked to many immune/autoimmune related diseases including rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
, asthma
Asthma
Asthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
, lupus
Lupus erythematosus
Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...
, allograft rejection and anti-tumour immunity.
Role in asthma
The IL-17F gene was discovered in 2001, and is located on chromosome 6p12. Notably, among this family, IL-17F has been well characterized both in vitro and in vivo, and has been shown to have a pro-inflammatory role in asthma. IL-17F is clearly expressed in the airway of asthmatics and its expression level is correlated with disease severity. Moreover, a coding region variant (H161R) of the IL-17F gene is inversely associated with asthma and encodes an antagonist for the wild-type IL-17F. IL-17F is able to induce several cytokines, chemokines and adhesion molecules in bronchial epithelial cells, vein endothelial cells, fibroblasts and eosinophils. IL-17F utilizes IL-17RA and IL-17RC as its receptors, and activates the MAP kinase related pathway. IL-17F is derived from several cell types such as Th17 cells, mast cells and basophils, and shows a wide tissue expression pattern including lung. Overexpression of IL-17F gene in the airway of mice is associated with airway neutrophilia, the induction of many cytokines, an increase in airway hyperreactivity, and mucus hypersecretion. Hence, IL-17F may have a crucial role in allergic airway inflammation, and have important therapeutic implications in asthma.Gene expression
The geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
for human IL-17 is 1874 base pair
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...
s long and was cloned from CD4+ T cells. Each member of the IL-17 family has a distinct pattern of cellular expression
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
. The expression of IL-17A and IL-17F appear to be restricted to a small group of activated T cells, and upregulated during inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
. IL-17B is expressed in several peripheral tissues and immune tissues. IL-17C is also highly upregulated in inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
conditions, although in resting conditions is low in abundance. IL-17D is highly expressed in the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
and in skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
and IL-17E is found at low levels in various peripheral tissues.
Much progress has been made in the understanding of the regulation of IL-17. At first, Aggarwal et al. showed that production of IL-17 was dependent on IL-23
Interleukin 23
Interleukin-23 subunit alpha is a protein that in humans is encoded by the IL23A gene. IL-23 is produced by dendritic cells and macrophages...
. Later, a Korean group discovered that STAT3
STAT protein
The STAT protein regulates many aspects of growth, survival and differentiation in cells...
and NF-κB signalling pathways are required for this IL-23-mediated IL-17 production. Consistent with this finding, Chen et al. showed that another molecule, SOCS3
SOCS3
Suppressor of cytokine signaling 3 is a protein that in humans is encoded by the SOCS3 gene.-Interactions:SOCS3 has been shown to interact with PTPN11, Glycoprotein 130, Erythropoietin receptor, Janus kinase 2, RAS p21 protein activator 1 and Insulin-like growth factor 1 receptor.-Regulation:There...
, plays an important role in IL-17 production. In the absence of SOCS3, IL-23-induced STAT3 phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
is enhanced, and phosphorylated STAT3 binds to the promotor regions of both IL-17A and IL-17F increasing their gene activity. In contrast, some scientists believe IL-17 induction is independent of IL-23. Several groups have identified ways to induce IL-17 production both in vitro and in vivo by distinct cytokines, called TGF-β and IL-6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...
, without the need for IL-23. Although IL-23 is not required for IL-17 expression in this situation, IL-23 may play a role in promoting survival and/or proliferation of the IL-17 producing T-cells. Recently, Ivanov et al. found that the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
specific nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
, ROR-γ
RAR-related orphan receptor gamma
RAR-related orphan receptor gamma is a protein that in humans is encoded by the RORC gene. RORγ is member of the nuclear receptor family of transcription factors.- Gene expression :...
, directs differentiation of IL-17-producing T cells.
Structure
IL-17(A) is a 155-amino acid protein that is a disulfideDisulfide
In chemistry, a disulfide usually refers to the structural unit composed of a linked pair of sulfur atoms. Disulfide usually refer to a chemical compound that contains a disulfide bond, such as diphenyl disulfide, C6H5S-SC6H5....
-linked, homodimeric, secreted glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
with a molecular mass of 35 kDa. Each subunit of the homodimer is approximately 15-20 KDa. The structure of IL-17 consists of a signal peptide
Signal peptide
A signal peptide is a short peptide chain that directs the transport of a protein.Signal peptides may also be called targeting signals, signal sequences, transit peptides, or localization signals....
of 23 amino acids (aa) followed by a 123-aa chain region characteristic of the IL-17 family. An N-linked glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
site on the protein was first identified after purification of the protein revealed two bands, one at 15 KDa and another at 20 KDa. Comparison of different members of the IL-17 family revealed four conserved cysteines that form two disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
s. IL-17 is unique in that it bears no resemblance to other known interleukin
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
s. Furthermore, IL-17 bears no resemblance to any other known proteins or structural domains.
The crystal structure of IL-17F, which is 50% homologous to IL-17A, revealed that IL-17F is structurally similar to the cysteine knot family of proteins that includes the neurotrophin
Neurotrophin
Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.They belong to a class of growth factors, secreted proteins that are capable of signaling particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the...
s. The cysteine knot fold is characterized by two sets of paired β-strands stabilized by three disulfide interactions. However, in contrast to the other cysteine knot proteins, IL-17F lacks the third disulfide bond. Instead, a serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
replaces the cysteine at this position. This unique feature is conserved in the other IL-17 family members. IL-17F also dimerizes in a fashion similar to nerve growth factor
Nerve growth factor
Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...
(NGF) and other neurotrophins.
Therapeutic target
Because of its involvement in autoimmune conditions, IL-17 inhibitors are being investigated as possible treatments, eg. vidofludimus in phase IIB for rheumatoid arthritis and inflammatory bowel disease.Receptors
See also Interleukin-17 receptorInterleukin-17 receptor
Interleukin-17 receptor is a cytokine receptor which binds interleukin 17. Functional IL-17R is a heteromeric complex consisting of at least IL17RA and IL17RC....
s.
The IL-17 receptor family consists of five, broadly distributed receptors that present with individual ligand specificities. Within this family of receptors, IL-17R is the best-described. IL-17R binds both IL-17A and IL-17F and is expressed in multiple tissues: vascular endothelial cells, peripheral T cells, B cell lineages, fibroblast, lung, myelomonocytic cells, and marrow stromal cells.
Another member of this receptor family, IL-17RB, binds both IL-17B and IL-17E. Furthermore, it is expressed in the kidney, pancreas, liver, brain, and intestine. IL-17RC is expressed by the prostate, cartilage, kidney, liver, heart, and muscle, and its gene may undergo alternate splicing to produce a soluble receptor in addition to its cell membrane-bound form. In similar manner, the gene for IL-17RD may undergo alternative splicing to yield a soluble receptor. This feature may allow these receptors to inhibit the stimulatory effects of their yet-undefined ligands. The least-described of these receptors, IL-17RE, is known to be expressed in the pancreas, brain, and prostate.
Signal transduction by these receptors is as diverse as their distribution. These receptors do not exhibit a significant similarity in extracellular or intracellular amino acid sequence when compared to other cytokine receptors. Transcription factors such as TRAF6
TRAF
TNF receptor associated factors also known as TRAFs are a family of proteins primarily involved in the regulation of inflammation, antiviral responses and apoptosis....
, JNK
Janus kinase
Janus kinase is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 & 2 , but were ultimately published as "Janus kinase"...
, Erk1/2, p38, AP-1 and NF-κB have been implicated in IL-17 mediated signaling in a stimulation-dependent, tissue-specific manner. Other signaling mechanisms have also been proposed, but more work is needed to fully elucidate the true signaling pathways used by these diverse receptors.