Introduction Psoriasis is a chronic
Psoriasis is a chronic, recurrent and inflammatory skin disease, and it is characterized by erythema, skin hyperplasia, scales, and hyperproliferation of keratinocyte . It is reported that the psoriasis occurrences are about 3% worldwide , but the number varies depending on ethnicity and geography .
The pathogenesis of psoriasis is associated with many factors, such as genetic polymorphisms, environmental factors and life style. It's reported that diverse populations have unique clinical presentation, genetic susceptibility, treatment response and drug adverse . Although psoriasis was considered as a T cell mediated disease, recent studies shows its association with other T cell subsets such as Th17, Th22 and Treg Pirarubicin during development . Excessive activation of the mitogen-activated protein kinases (MAPK) pathway is a common cause of many diseases including autoimmune diseases and sustention of the extracellular signal-related kinases (ERK) phosphorylation activates T helper 17 cells [6,7]. Therefore, ERK signaling pathway is found to be related to psoriasis [, , ].
Material and methods
Discussions Many studies confirmed that the over-activation of RAF-MEK-ERK signaling pathway plays a central role in human cancers [, , , ]. Furthermore, the close relationship between the ERK pathway and autoimmune disease was also identified. Because of these, ERK inhibitors development attracted many more researchers. For example, BVD-523 (Ulixertinib) clinical trials of phase I/II study in patients with acute myelogenous leukemia or myelodysplastic syndromes has been completed. Also, MK8353's safety, tolerability and efficacy of advanced solid tumors treatment in patients was in process . It has been shown that ERK phosphorylation could activate Th17 cells, and therefore induces inflammatory diseases [7,16]. The inflammatory cytokines TNF-α, IL-2, IL-6, IL-8, IL-18, IL-20 and IL-23 induced or produced by Th17 cell were overexpressed in serum of psoriasis patients and were positively correlated with the psoriasis severity [, , ]. Moreover, the study suggested IL-17 was a psoriasis risk factor for men. The researchers found rapamycin and fingolimod could downregulate pERK level in EAE mice, and further modulate the concentration of IL-17 and TGF-β. Mansouri et al. reported that Th17 cells and its products played an important role in skin diseases process, moreover, clarified IL-17 as a production of Th17 cells was the optimism treatment target for rheumatoid arthritis, psoriatic arthritis, psoriasis and ankylosing spondylitis [, , ]. Drugs targeting IL-17 and IL-12R had been approved for psoriasis therapy. Cytokines, such as IL-6 and IL-12, play an important role in regulating autoimmune diseases. IL-17 could induce keratinocytes to produce IL-6 and defensins, and following that IL-6 was able to initiate the Th17 cell subsets formation from the primary T cells [23,24]. Other cytokines, such as IL-22, IL-6 and IL-20, contributed to induce keratinocyte proliferation; also, TNF-α could elevate keratinocytes to produce more TNF-α, IL-1, and IL-8 [25,26]. It has been reported that IL-6 mediated ERK signaling pathway played a critical role in epidermal differentiation, and IL-12 affected the development of Th1 cells and activation and function of cytotoxic T cells [27,28]. IL-12 and IL-23 inhibitor ustekinumab phase II, randomized, and controlled studies were completed. Regarding to the importance of IL-17A and correlated cytokines IL-6 and IL-12 in psoriasis, we studied the release of all three cytokines in imiquimod-induced mice skin lesions. The results suggested that JSI287 group significantly alleviated the release of IL-17A, IL-6 and IL-12. Transcription factor 1 (ATF1) was significantly up-regulated in mice cervical cancer model, and phosphor-CREB/ATF1 binding to IL-6 promoter influenced IL-6 expression [29,30]. Therefore, we studied CREB and AFI1 gene expression, the data showed that JSI287 downregulated mRNA of ATF1. Therefore, the JSI287 alleviated the syndrome severity for cancer treatment through regulation of ATF1.