[5] After binding to the receptor, IL-17 activates several signalling cascades that, in turn, lead to the induction of chemokines.
As a result of these roles, the IL-17 family has been linked to many immune-related/autoimmune diseases including rheumatoid arthritis, asthma, lupus, allograft rejection, anti-tumour immunity and recently psoriasis,[10] multiple sclerosis,[11] and intracerebral hemorrhage.
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.
[15] Consistent with this finding, Chen et al. showed that another molecule, SOCS3, plays an important role in IL-17 production.
Several groups have identified ways to induce IL-17 production both in vitro[17] and in vivo[18][19] by distinct cytokines, called TGF-β and IL-6, without the need for IL-23.
[17][18][19] 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.
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 cystine knot fold is characterized by two sets of paired β-strands stabilized by three disulfide interactions.
[1] Recent work suggests the IL-23/IL-17 pathway plays a major role in the autoimmune disorder psoriasis.
[8][21][22] In this condition, immune cells react to inflammatory molecules released within the skin around the joints and scalp.
[21] 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.
[26][27] Mice injected with monoclonal antibodies targeting IL-17 blocked, or neutralized, down-stream signaling of this cytokine and decreased epidermal hyperplasia.
[26] Similarly, mice genetically modifying to not express IL-23 or IL-17 receptors significantly reduced psoriatic lesion development upon stimulation with the lesion-causing tumor promoter 12-O-tetradecanoylphorbol-13-acetate.
[8] IL-17 promotes psoriasis by contributing to the inflammatory response that damages and overturns the keratinocyte cells of the epidermal layer.
[24] Reduced regulation allows uninhibited proliferation of Th17 cells and production of IL-17 in psoriatic lesions, augmenting IL-17 signaling.
[24][25] 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.
[30][31][32] In January 2015, the FDA approved the use of secukinumab (trade name Cosentyx), an IL-17 inhibiting monoclonal antibody, for the treatment of moderate to severe plaque psoriasis.
[35] Based on emerging evidence from animal models, IL-17 has been suggested as a target for anti-inflammatory therapies to improve recovery post-stroke[36] and to reduce the formation of skin cancer.
[9] 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.
[39] 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.