IL-17 (Interleukin-17)

Interleukin 17 family

Interleukin 17 (IL-17) is a potent proinflammatory cytokine produced by activated memory T cells.

This cytokine IL-17  is characterized by its proinflammatory properties, role in recruiting neutrophils, and importance in innate and adaptive immunity. 

The IL-17F gene is located on chromosome 6p12. 

IL-17 plays a key role in inflammation of many autoimmune diseases, such as RA, allergies, asthma, psoriasis, and more, but it also plays a key role in the pathogenesis of these diseases. 

IL-17 plays a role in tumorigenesis and transplant rejection.

Interleukin 17 family (IL17 family) is a family of pro-inflammatory cystine knot cytokines.

IL17 cytokines are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. 

IL-17 activates several signalling cascades that, in turn, lead to the induction of chemokines. 

Acting as chemoattractants, these chemokines recruit the immune cells, such as monocytes and neutrophils to the site of inflammation. 

Promoting inflammation, IL-17 acts in concert with tumor necrosis factor and interleukin-1.

Moreover, an activation of IL-17 signalling is often observed in the pathogenesis of various autoimmune disorders, such as psoriasis.

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, containing four highly conserved cysteine residues.

The most notable role of IL-17 is its involvement in inducing and mediating proinflammatory responses. 

IL-17 is commonly associated with allergic responses. 

IL-17 induces the production of other cytokines: IL-6, G-CSF, GM-CSF, IL-1β, TGF-β, TNF-α. chemokines IL-8, GRO-α, and MCP-1, and prostaglandins (e.g., PGE2) from many cell types (fibroblasts, endothelial cells, epithelial cells, keratinocytes, and macrophages). 

The release of cytokines causes airway remodeling, a characteristic of IL-17 responses, increased chemoattraction of neutrophils but not eosinophils. 

IL-17 function is also essential to a subset of CD4+ T-Cells called T helper 17 (Th17) cells, linking it to many immune/autoimmune related diseases including rheumatoid arthritis, asthma, lupus, allograft rejection, anti-tumor immunity and psoriasis, multiple sclerosis, and intracerebral hemorrhage.

Each member of the IL-17 family has a distinct pattern of cellular expression. 

IL-17A is restricted to a small group of activated T cells, and upregulated during inflammation. 

IL-23 may play a role in promoting survival and/or proliferation of the IL-17 producing T-cells.

IL-17 is unique in that it bears no resemblance to other known interleukins. 

IL-23/IL-17 pathway plays a major role in the autoimmune disorder psoriasis, in which immune cells react to inflammatory molecules released within the skin around the joints and scalp.

This type of  causes the epidermal cells to recycle more rapidly than usual, leads to the formation of red, scaly lesions and chronic skin inflammation.

Biopsies taken from lesions of psoriasis patients show an enrichment of cytotoxic T cells and neutrophils containing IL-17.

IL-17 promotes psoriasis as its inflammatory response 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 immature dendritic cells that  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 and decreases 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.

 IL-8 attracts neutrophils to the site of injury where these cells remove damaged and inflamed keratinocyte cells.

New immature dendritic cells are also recruited by CCL20 via chemotaxis where their activation restarts and amplifies the cycle of inflammation.

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.

IL-17F has been shown to have a pro-inflammatory role in asthma, and is expressed in the airway of asthmatics and its expression level is correlated with disease severity. 

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 being used as for autoimmune diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease.

Secukinumab (trade name Cosentyx), an IL-17 inhibiting monoclonal antibody, for the treatment of moderate to severe plaque psoriasis.

The anti-IL-23 antibody ustekinumab can also be used to effectively treat psoriasis by indirectly reducing IL-17.

The active form of vitamin D has been found to impair production of the IL-17 and IL-17F cytokines by Th17 cells.

The IL-17 receptor family consists of five, broadly distributed receptors (IL-17RA, B, C, D and E).

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.

IL-17RB, binds both IL-17B and IL-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. 

IL-17RE, is known to be expressed in the pancreas, brain, and prostate.

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