Interleukin 17F (IL-17F) is signaling protein that is in human which is encoded by the ''IL17F''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

and is considered a

pro-inflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include int ...

. This protein belongs to the

interleukin 17 Interleukin 17 family (IL17 family) is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identifi ...

family and is mainly produced by the

T helper 17 T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. Howe ...

cells after their stimulation with

interleukin 23 Interleukin 23 (IL-23) is a heterodimeric cytokine composed of an IL-12B (IL-12p40) subunit (which is shared with IL-12) and an IL-23A (IL-23p19) subunit. IL-23 is part of the IL-12 family of cytokines. The functional receptor for IL-23 (t ...

. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and

epithelial cells Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

. The ''IL17F'' gene is located on chromosome 6p12 and was discovered in 2001. This cytokine can be secreted as disulfide-linked

homodimer In biochemistry, a protein dimer is a macromolecular complex or protein multimer, multimer formed by two protein monomers, or single proteins, which are usually Non-covalent interaction, non-covalently bound. Many macromolecules, such as proteins ...

heterodimer In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...

Function and signaling

IL-17F is involved in the development of

inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...

and host defense against infection by inducing the expression of genes that encode other proinflammatory cytokines, such as

tumor necrosis factor Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...

interleukin 1 The Interleukin-1 family (IL-1 family) is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. Discovery Discovery of these cytokines began with studies on t ...

interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...

and some members of the

colony-stimulating factor Colony-stimulating factors (CSFs) are secreted glycoproteins that bind to receptor proteins on the surfaces of committed progenitors in the bone marrow, thereby activating intracellular signaling pathways that can cause the cells to proliferate ...

family. IL-17F can also induce expression of

chemokine Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addit ...

s, such as

CXCL1 The chemokine (C-X-C motif) 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 infecti ...

CXCL5 C-X-C motif chemokine 5 (CXCL5 or ENA78) is a protein that in humans is encoded by the ''CXCL5'' gene. Function The protein encoded by this gene, CXCL5 is a small cytokine belonging to the CXC chemokine family that is also known as epithelia ...

interleukin 8 Interleukin 8 (IL-8 or chemokine (C-X-C motif) ligand 8, CXCL8) is a chemokine produced by macrophages and other cell types such as epithelial cells, airway smooth muscle cells and endothelial cells. Endothelial cells store IL-8 in their stor ...

CCL7 Chemokine (C-C motif) ligand 7 (CCL7) is a small cytokine that was previously called monocyte-chemotactic protein 3 (MCP3). CCL7 is a small protein that belongs to the CC chemokine family and is most closely related to CCL2 (previously called M ...

and others, thereby promoting inflammation and

neutrophil Neutrophils are a type of phagocytic white blood cell and part of innate immunity. More specifically, they form the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. Their functions vary in differe ...

recruitment. IL-17F signaling can also lead to

antimicrobial peptide Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for ...

and

matrix metalloproteinase Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs be ...

production. The target cells of IL-17F are epithelial cells,

fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...

keratinocyte Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...

s, synoviocytes and

endothelial cells The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

. These cells express IL-17RA and IL-17RC, which are the receptors IL-17F binds. IL-17F shows a broad tissue expression pattern, including the lungs, where it may be associated with the pathogenesis of asthma. IL-17F employs Act1 and

TRAF6 TRAF6 is a TRAF human protein. Function The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF rece ...

as its signal transducers to induce the expression of the pro-inflammatory cytokines and chemokines in many different cell types. IL-17F signaling also activates the

MAP kinase A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammato ...

pathway and leads to the activation of

NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...

, MAPK-AP-1 and C/EBP. IL-17F is highly (55%) homologous to

interleukin-17A Interleukin-17A is a protein that in humans is encoded by the ''IL17A'' gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene (). Function The protein encoded by this gene is a proinflammatory cytoki ...

(IL-17A). These two molecules bind to the same receptors and are very likely to have similar biological functions. IL-17A and IL-17F are often co-expressed. However, IL-17F is a weaker inducer of pro-inflammatory cytokine expression and is produced by a wider range of cell types than IL-17A. Another difference lies in the binding affinities for their receptors: IL-17A binds more strongly to IL-17RA, IL-17F to IL-17RC. The interleukin 17 family members are among the effector cytokines of

Th17 T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. Howe ...

immune response. This immune response protects hosts from pathogens at epithelial and mucosal tissues including the

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...

, and

intestine The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The tract is the largest of the body's systems, after the cardiovascular system. T ...

. The Th17-type immune response is directed primarily against extracellular bacteria. IL-17F as an effector cytokine of Th17 cells is involved in host defense against bacterial infections. It has many mechanisms by which it helps resist

bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

. IL-17F has the ability to stimulate the production of

defensin Defensins are small cysteine-rich cationic proteins across cellular life, including vertebrate and invertebrate animals, plants, and fungi. They are host defense peptides, with members displaying either direct Antimicrobial, antimicrobial activit ...

s and other

antimicrobial peptides Antimicrobial peptides (AMPs), also called host defence peptides (HDPs) are part of the innate immune response found among all classes of life. Fundamental differences exist between Prokaryote, prokaryotic and eukaryota, eukaryotic cells that may ...

; it can also resist bacteria through production of pro-inflammatory cytokines and chemokines that attract

s and other effector cells.

Clinical significance

IL-17F is a proinflammatory cytokine associated with many diseases. It very often plays crucial role in

autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...

s. One of the diseases associated with IL-17F is

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by patches of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small localized patches to complete b ...

. Levels of IL-17F, as well as the levels of IL-17A, are increased in psoriatic skin and in synovial cells in psoriatic arthritis. IL-17F is capable of inducing cartilage matrix release and can inhibit the synthesis of new cartilage matrix. The

monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodie ...

bimekizumab Bimekizumab, sold under the brand name Bimzelx ( ), is a humanized anti-IL17A, anti-IL-17F, and anti-IL17AF monoclonal antibody that is used to treat plaque psoriasis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, and hi ...

against IL-17A and IL-17F is approved in Europe for the treatment of psoriasis; it may also be useful in the treatment of

ankylosing spondylitis Ankylosing spondylitis (AS) is a type of arthritis from the disease spectrum of axial spondyloarthritis. It is characterized by long-term inflammation of the joints of the spine, typically where the spine joins the pelvis. With AS, eye and bow ...

. IL-17F plays an important role in

asthma Asthma is a common long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wh ...

and allergic airway inflammation. IL-17F has been well characterized both ''in vitro'' and ''in vivo'' to have a pro-inflammatory role in asthma. IL-17F was originally found in bronchoalveolar lavage cells from patients with allergic asthma upon ragweed allergen stimulation. The expression level of IL-17F correlates with the severity of the disease. Overexpression of this cytokine in the airway is associated with

neutrophilia Neutrophilia (also called neutrophil leukocytosis or occasionally neutrocytosis) is leukocytosis of neutrophils, that is, a high number of neutrophils in the blood. Because neutrophils are the main type of granulocytes, mentions of granulocytosis ...

, secretion of many cytokines, increased

airway The respiratory tract is the subdivision of the respiratory system involved with the process of conducting air to the alveoli for the purposes of gas exchange in mammals. The respiratory tract is lined with respiratory epithelium as respiratory ...

activity and mucus hypersecretion. IL-17F is also involved in the pathogenesis of intestinal inflammation. Expression of IL-17F in colon is associated with

inflammatory bowel disease Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, with Crohn's disease and ulcerative colitis (UC) being the principal types. Crohn's disease affects the small intestine and large intestine ...

, and this inducible IL-17F expression is significantly higher in

Crohn's disease Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea, fever, abdominal distension, and weight loss. Complications outside of the ...

than in

ulcerative colitis Ulcerative colitis (UC) is one of the two types of inflammatory bowel disease (IBD), with the other type being Crohn's disease. It is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary sympto ...

. Increased expression of IL-17F is also found in neuronal inflammation—specifically, in active lesion sites in experimental autoimmune encephalitis, an animal model of

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

. IL-17F together with IL-17A contributes to

chronic inflammation Chronic systemic inflammation is the result of release of pro-inflammatory cytokines from immune-related cells and the chronic activation of the innate immune system. It can contribute to the development or progression of certain conditions such ...

. IL-17F may also be involved in

tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abn ...

and associated with the

tumor microenvironment The tumor microenvironment is a complex ecosystem surrounding a tumor, composed of cancer cells, stromal tissue (including blood vessels, immune cells, fibroblasts and signaling molecules) and the extracellular matrix. Mutual interaction between ...

(TME), as pro-tumor and anti-tumor functions have been ascribed to the related protein IL-17A has. However, a role for IL-17F in tumor development has not been well described.

References

{{reflist Genes on human chromosome 6 Interleukins