• 2018-07
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  • br Materials and methods br Results br Discussion


    Materials and methods
    Discussion DUSP1 is a member of the subfamily of the Dusl specific phosphatases (DUSPs). High levels of DUSP1 observed in lung, liver and placenta, and low levels have been found in the BCECF-AM and kidney. DUSP1 has been shown to be elevated in various diseases [18]. DUSP1 was increased in the late stages of breast cancer, gastric adenocarcinoma and the liver in patients with chronic hepatitis C virus [8]. However, a reduction DUSP1 expression was reported in lentiviral models of Huntington\'s disease [31]. In this study, our data revealed that DUSP1 was clearly reduced in psoriasis patients, which is accordance with the results of Palagummi et al. [25]. Additionally, DUSP1 was also decreased in HaCaT cells exposure to M5. Thus, there may be a role for DUSP1 in the development of psoriasis. Keratinocyte proliferation has been occur in various benign and malignant skin conditions, including psoriasis, actinic keratosis and seborrheic keratosis [4]. It has been reported that overexpression of DUSP1 blocks the proliferation of osteoblasts [13]. In our study, cells were treated with M5 to mimic the proliferation and apoptosis observed in psoriasis; we found that enhancing DUSP1 expression suppressed proliferation in HaCaT cells. Moreover, overexpression of DUSP1 inhibited the protein expression of cyclin D1 and Rb, implying an anti-proliferation role of DUSP1 in HaCaT cells. Additionally, suppression of DUSP1 expression resulted in a reduction in oxidative stress-induced cell death [15]. In this study, we showed that enhancing DUSP1 expression resulted in an augment of cell apoptosis rate, c-caspase 3 expression and the Bax/Bcl-2 ratio in HaCaT cells in the presence of M5. DUSP1, as a phosphatase can inactivate MAP kinase, ERKs, p38 MAPKs and JNKs [24]. Elk-1 is a downstream transcriptional target of MAPK/ERK, and inhibition of the MAPK/ERK cascade prevents Elk-1 phosphorylation [10]. The Egr-1 promoter contains five serum response elements (SREs). A ternary complex factor Elk-1 is essential for SRE-mediated activity [33]. Activation of the ERK signaling induced the biosynthesis of Egr-1 [28]. In this study, we demonstrated that enhancing DUSP1 expression reduced the protein expression of p-ERK, p-Elk-1 and Egr-1. Report revealed that Egr-1 is significantly increased in the skin lesions of patients with psoriasis [11,20]. Furthermore, the ChIP assay revealed that p-Elk-1 can bind to the promoter of Egr-1 in HaCaT cells, and DUSP1 reduced this binding effect. These data indicate that DUSP1 negatively regulates the ERK/Elk-1/Egr-1 signaling pathway in HaCaT cells. Egr-1 overexpression stimulated keratinocyte proliferation [14,17]. Furthermore, Egr-1 knockdown increases the PA-induced cleavage of caspase 3 and poly(ADP-ribose) polymerase (PARP) [7]. It would therefore be of interest to determine whether the ERK/Elk-1/Egr-1 pathway is involved in the regulation of DUSP1-mediated proliferation and apoptosis in HaCaT cells. Our data confirmed that enhancing Egr-1 abrogated the roles of DUSP1 in the proliferation and apoptosis of HaCaT cells, suggesting that DUSP1 regulates proliferation and apoptosis in HaCaT cells through the ERK/Elk-1/Egr-1 pathway.
    Conflict of interest
    Introduction Cardiovascular disease (CVD) is the major cause of death worldwide, and the principal contributing factor to the CVD pathology is atherosclerosis, which is characterized by the accumulation of low-density lipoprotein (LDL) and inflammatory cells, mainly macrophages and T cells (McLaren et al., 2011). Atherosclerosis is a well-known chronic, inflammatory disorder disease (Ross, 1999). Both innate and adaptive the immune responses modulate the development of atherosclerosis, such as lesion initiation and progression, and potentially devastating thrombotic complications. Inflammatory response disorders could also impair reverse cholesterol transport (RCT) which helps remove the cholesterol deposited in artery lesions. Aside from macrophages, T cells are known to play an important role in regulating the development of atherosclerosis (McLaren et al., 2011). Some studies have found that immuno-deficient mice, lack of T-cell and conventional B-cell populations, that carry a severe combined immunodeficiency mutation (SCID) when crossed with ApoE- or LDLR-deficient mice have a progeny with less advanced atherosclerosis progression (Daugherty et al., 1997). Transfer of CD4+ T cells from ApoE-deficient mice to ApoE-deficient SCID mice resulted in significantly enhanced atherosclerosis progression (Zhou et al., 2000). Additionally, treatment with effector T cells (Teff) derived from systemic lupus erythematous (SLE)–susceptible mice stimulated atherosclerosis in of Rag/LDLR-deficient mice (Wilhelm et al., 2015).