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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 (O40633).
The protein encoded by this gene is a proinflammatory cytokine produced by activated T cells. This cytokine regulates the activities of NF-kappaB and mitogen-activated protein kinases. This cytokine can stimulate the expression of IL6 and cyclooxygenase-2 (PTGS2/COX-2), as well as enhance the production of nitric oxide (NO).
IL-17A, often referred to as IL-17, was originally discovered at transcriptional level by Rouvier et al. in 1993 from a rodent T-cell hybridoma, derived from the fusion of a mouse cytotoxic T cell clone and a rat T cell lymphoma. Human and mouse IL-17A were cloned a few years later by Yao and Kennedy. Lymphocytes including CD4+, CD8+, gamma-delta T (γδ-T), invariant NKT and innate lymphoid cells (ILCs) are primary sources of IL-17A. Non-T cells, such as neutrophils, have also been reported to produce IL-17A under certain circumstances. IL-17A producing T helper cells (Th17 cells) are a distinct lineage from the Th1 and Th2 CD4+ lineages and the differentiation of Th17 cells requires STAT3 and RORC. IL-17 receptor A (IL-17RA) was first isolated and cloned from mouse EL4 thymoma cells and the bioactivity of IL-17A was confirmed by stimulating the transcriptional factor NF-kappa B activity and interleukin-6 (IL-6) secretion in fibroblasts. IL-17RA pairs with IL-17RC to allow binding and signaling of IL-17A, IL-17F, and IL-17AF.
High levels of this cytokine are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis and multiple sclerosis.
Multiple sclerosis (MS) is a neurological disease caused by immune cells, which attack and destroy the myelin sheath that insulates neurons in the brain and spinal cord. This disease and its animal model experimental autoimmune encephalomyelitis (EAE) have historically been associated with the discovery of Th17 cells. More current experiments on this animal model have also revealed that a key function of IL-17A in central nervous system (CNS) autoimmunity was to recruit IL-1β-secreting myeloid cells. These cells play a vital role in priming pathogenic Th17 cells, thus promoting the development of autoimmune disease. However, elevated expression of IL-17A in MS lesions as well as peripheral blood had been documented before the identification of Th17 cells. Human Th17 cells have been shown to efficiently transmigrate across the blood-brain barrier in multiple sclerosis lesions, promoting central nervous system inflammation.
Psoriasis is an auto-inflammatory skin disease characterized by circumscribed, crimson red, silver-scaled, plaque-like inflammatory lesions. Initially, psoriasis was considered to be a Th1-mediated disease since elevated levels of IFN-γ, TNF-α, and IL-12 was found in the serum and lesions of psoriasis patients. However, the finding of IL-17-producing cells as well as IL17A transcripts in the lesions of psoriatic patients suggested that Th17 cells may synergize with Th1 cells in driving the pathology in psoriasis. The levels of IL-17A in the synovium correlate with tissue damage, whereas levels of IFN-γ correlate with protection. IL-17A inhibitors have been widely used in treating psoriasis and psoriatic arthritis, although the newer drug bimekizumab that directly targets both IL-17A and IL-17F (thus also IL-17AF) has shown promise to be more effective in treating psoriasis by blocking all three known ligands of the IL-17RA/IL-17RC complex.
Th17 cells is also strongly associated rheumatoid arthritis (RA), a chronic disorder with symptoms include chronic joint inflammation, autoantibody production, which lead to the destruction of cartilage and bone. Direct clinical significance of IL-17A in RA comes from recent clinical trials which found that two anti-IL-17A antibodies, namely secukinumab and ixekizumab significantly benefit these patients. However, IL-17A inhibitors show worse response rates in RA than current frontline disease-modifying antirheumatic drugs (DMARD) for RA such as corticosteroids and TNFα inhibitors.
Th17 cells and IL-17 have also been linked to Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel diseases (IBD). Th17 cells infiltrate massively to the inflamed tissue of IBD patients and both in vitro and in vivo studies have shown that Th17-related cytokines may initiate and amplify multiple pro-inflammatory pathways. Elevated IL-17A levels in IBD have been reported by several groups. Nonetheless, Th17 signature cytokines, such as IL-17A and IL-22, may target gut epithelial cells and promote the activation of regulatory pathways and confer protection in the gastrointestinal tract. To this end, recent clinical trials targeting IL-17A in IBD were negative and actually showed increased adverse events in the treatment arm. This data raised the question regarding the role of IL-17A in IBD pathogenesis and suggested that the elevated IL-17A might be beneficial for IBD patients.
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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 (O40633).
The protein encoded by this gene is a proinflammatory cytokine produced by activated T cells. This cytokine regulates the activities of NF-kappaB and mitogen-activated protein kinases. This cytokine can stimulate the expression of IL6 and cyclooxygenase-2 (PTGS2/COX-2), as well as enhance the production of nitric oxide (NO).
IL-17A, often referred to as IL-17, was originally discovered at transcriptional level by Rouvier et al. in 1993 from a rodent T-cell hybridoma, derived from the fusion of a mouse cytotoxic T cell clone and a rat T cell lymphoma. Human and mouse IL-17A were cloned a few years later by Yao and Kennedy. Lymphocytes including CD4+, CD8+, gamma-delta T (γδ-T), invariant NKT and innate lymphoid cells (ILCs) are primary sources of IL-17A. Non-T cells, such as neutrophils, have also been reported to produce IL-17A under certain circumstances. IL-17A producing T helper cells (Th17 cells) are a distinct lineage from the Th1 and Th2 CD4+ lineages and the differentiation of Th17 cells requires STAT3 and RORC. IL-17 receptor A (IL-17RA) was first isolated and cloned from mouse EL4 thymoma cells and the bioactivity of IL-17A was confirmed by stimulating the transcriptional factor NF-kappa B activity and interleukin-6 (IL-6) secretion in fibroblasts. IL-17RA pairs with IL-17RC to allow binding and signaling of IL-17A, IL-17F, and IL-17AF.
High levels of this cytokine are associated with several chronic inflammatory diseases including rheumatoid arthritis, psoriasis and multiple sclerosis.
Multiple sclerosis (MS) is a neurological disease caused by immune cells, which attack and destroy the myelin sheath that insulates neurons in the brain and spinal cord. This disease and its animal model experimental autoimmune encephalomyelitis (EAE) have historically been associated with the discovery of Th17 cells. More current experiments on this animal model have also revealed that a key function of IL-17A in central nervous system (CNS) autoimmunity was to recruit IL-1β-secreting myeloid cells. These cells play a vital role in priming pathogenic Th17 cells, thus promoting the development of autoimmune disease. However, elevated expression of IL-17A in MS lesions as well as peripheral blood had been documented before the identification of Th17 cells. Human Th17 cells have been shown to efficiently transmigrate across the blood-brain barrier in multiple sclerosis lesions, promoting central nervous system inflammation.
Psoriasis is an auto-inflammatory skin disease characterized by circumscribed, crimson red, silver-scaled, plaque-like inflammatory lesions. Initially, psoriasis was considered to be a Th1-mediated disease since elevated levels of IFN-γ, TNF-α, and IL-12 was found in the serum and lesions of psoriasis patients. However, the finding of IL-17-producing cells as well as IL17A transcripts in the lesions of psoriatic patients suggested that Th17 cells may synergize with Th1 cells in driving the pathology in psoriasis. The levels of IL-17A in the synovium correlate with tissue damage, whereas levels of IFN-γ correlate with protection. IL-17A inhibitors have been widely used in treating psoriasis and psoriatic arthritis, although the newer drug bimekizumab that directly targets both IL-17A and IL-17F (thus also IL-17AF) has shown promise to be more effective in treating psoriasis by blocking all three known ligands of the IL-17RA/IL-17RC complex.
Th17 cells is also strongly associated rheumatoid arthritis (RA), a chronic disorder with symptoms include chronic joint inflammation, autoantibody production, which lead to the destruction of cartilage and bone. Direct clinical significance of IL-17A in RA comes from recent clinical trials which found that two anti-IL-17A antibodies, namely secukinumab and ixekizumab significantly benefit these patients. However, IL-17A inhibitors show worse response rates in RA than current frontline disease-modifying antirheumatic drugs (DMARD) for RA such as corticosteroids and TNFα inhibitors.
Th17 cells and IL-17 have also been linked to Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of inflammatory bowel diseases (IBD). Th17 cells infiltrate massively to the inflamed tissue of IBD patients and both in vitro and in vivo studies have shown that Th17-related cytokines may initiate and amplify multiple pro-inflammatory pathways. Elevated IL-17A levels in IBD have been reported by several groups. Nonetheless, Th17 signature cytokines, such as IL-17A and IL-22, may target gut epithelial cells and promote the activation of regulatory pathways and confer protection in the gastrointestinal tract. To this end, recent clinical trials targeting IL-17A in IBD were negative and actually showed increased adverse events in the treatment arm. This data raised the question regarding the role of IL-17A in IBD pathogenesis and suggested that the elevated IL-17A might be beneficial for IBD patients.