A pro-inflammatory cytokine which is the primary effector of Th17 cells.
Interleukin 17 (IL-17) is a group of cytokines that play a key role in the immune system’s response to infections and inflammation.
They are produced mainly by T helper 17 (Th17) cells and other immune cells such as gamma-delta T cells, natural killer cells, and neutrophils.
IL-17 is involved in the protection against extracellular bacterial and fungal pathogens, and is also known to play a role in autoimmune disorders such as rheumatoid arthritis, psoriasis, anklylosing spondylitis and multiple sclerosis.
IL-17 cytokines interact with specific receptors on target cells and mediate downstream signaling pathways that result in the activation of inflammatory cells and promote inflammation.
They also stimulate the production of other cytokines, chemokines, and inflammatory mediators that work together to promote the body’s immune response.
Interleukin 17 family (IL17 family) is a family of pro-inflammatory cystine knot cytokines.
They are produced by a group of T helper 17 cells in response to their stimulation with IL-23.
The protein encoded by IL17A is a founding member of IL-17 family,
The biologically active IL-17 interacts with type I cell surface receptor IL-17R.
There are at least three variants of IL-17R referred to as IL17RA, IL17RB, and IL17RC.
After binding to the receptor, IL-17 activates several signalling cascades that, in turn, lead to the induction of chemokines.
Chemokines act as chemoattractants and recruit the immune cells, such as monocytes and neutrophils to the site of inflammation.
Typically, these signaling events follow an invasion of the body by pathogens.
Promoting the inflammation, IL-17 acts in concert with tumor necrosis factor and interleukin-1.
An activation of IL-17 signalling is often observed in the pathogenesis of various autoimmune disorders, such as psoriasis.
Family members
The IL-17 family in humans comprises IL17A, IL17B, IL17C, IL17D, IL17E and IL17F.
IL-17E is also known as IL-25.
All members of the IL-17 family have a similar protein structure.
Their protein sequences contain four highly conserved cysteine residues.
Numerous immune regulatory functions have been reported for the
IL-17 family of cytokines induce many immune signaling molecules,
most notably 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-6, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α), chemokines (including IL-8, GRO-α, and MCP-1), and prostaglandins (e.g., PGE2) from many cell types (fibroblasts, endothelial cells, epithelial cells, keratinocytes, and macrophages).
IL-17 acts with IL-22 to induce expression of antimicrobial peptide by keratinocytes.
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 CD4+ T-Cells called T helper 17 (Th17) cells.
The IL-17 family has been linked to many immune/autoimmune related diseases: including rheumatoid arthritis, asthma, lupus, allograft rejection, anti-tumour immunity, psoriasis, multiple sclerosis, and intracerebral hemorrhage.
The gene for human IL-17A is 1874 base pairs long.
IL-17 is cloned from CD4+ T cells.
Each member of the IL-17 family has a distinct pattern of cellular expression.
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 promoter regions of both IL-17A and IL-17F increasing their gene activity.
IL-17 production can be induced cytokines by TGF-β and IL-6, without the need for IL-23.
IL-23 may play a role in promoting survival and/or proliferation of the IL-17 producing T-cells.
IL-17(A) is a 155-amino acid protein that is a disulfide-linked, homodimeric, secreted glycoprotein with a molecular mass of 35 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.
The IL-23/IL-17 pathway plays a major role in the autoimmune disorder psoriasis.
In psoriasis immune cells react to inflammatory molecules released within the skin around the joints and scalp.
This response causes the epidermal cells to recycle more rapidly than usual, which leads to the formation of red, scaly lesions and chronic skin inflammation.
Analysis of biopsies taken from lesions of psoriasis patients show an enrichment of cytotoxic T cells and neutrophils containing IL-17.
An excessive infiltration of pro-inflammatory immune cells and IL-17 cytokines are associated with the development of psoriasis.
IL-17 promotes psoriasis by contributing to the inflammatory response that damages and overturns the keratinocyte cells of the epidermal layer.
Inflammation begins with keratinocyte cells entering the final stages of their cell cycle, which activates immature dendritic cells (DC).
Cytokines released from DCs stimulate dying keratinocytes to secrete TNF-alpha, IL-1 and IL-6 leading to the chemotaxis of T cells, natural killer cells and monocytes to the epidermis.
These cells release IL-23 which induce Th17 cells to produce IL-17.
IL-17 interaction with IL-17RA receptors, abundant on the keratinocyte cell surface, incite epidermal cells to increase expression of IL-6, antimicrobial peptides, IL-8 and CCL20.
Increased concentration of IL-6 alters the epidermal environment by decreasing the ability of T regulatory cells to control the behavior of Th17 cells.
Reduced regulation allows uninhibited proliferation of Th17 cells and production of IL-17 in psoriatic lesions, augmenting IL-17 signaling.
Antimicrobial peptides and IL-8 attract neutrophils to the site of injury where these cells remove damaged and inflamed keratinocyte cells.
IL-17 and additional cytokines released from the influx of neutrophils, T and dendritic cells mediate effects on localized leukocytes and keratinocytes that supports the progression of psoriasis by inciting chronic inflammation.
The IL-17F gene is located on chromosome 6p12.
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 expressed in the airway of asthmatics and its expression level is correlated with disease severity.
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 may have a crucial role in allergic airway inflammation and have important therapeutic implications in asthma.
IL-17 inhibitors are possible treatments for autoimmune diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease.
The IL-17 receptor family consists of five, broadly distributed receptors (IL-17RA, B, C, D and E) that present with individual ligand specificities.
IL-17RA 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.