Abstract：
We have previously reported that swellings caused by haptens, such as 2,4,6-trinitrochlorobenzene (TNCB), may be associated with the extracellular signal-regulated kinase (ERK)-induced proliferation pathway. However, the involvement of the Spred/Sprouty family as critical negative regulators of the Ras/Raf/ERK signaling pathway at disease sites is not well-established. Thus, in the present study, the effects of hapten-challenge on the expression levels of genes and proteins associated with the Spred/Sprouty family in the ear of mice were investigated. The activation of ERK and epidermal growth factor receptor (EGFR) tyrosine kinase was inhibited by their selective inhibitors, namely, U0126 and PD168393, respectively. Twenty-four hours after the final challenge by the haptens TNCB, 2,4-dinitrofluorobenzene, or oxazolone, ear thickness was augmented by challenge with all haptens and the gene expression levels of Spred1, Spred2, Sprouty1, and Sprouty2 in swelling induced by all haptens were significantly decreased. Furthermore, Spred2, Sprouty1, and Sprouty2 genes were decreased in the epidermis and dermis of the TNCB-challenged ear. In conclusion, it is possible that the mechanism of hapten-challenge-induced skin thickening involves not only the enhancement of cell proliferative functions via the activation of ERK by EGFR tyrosine kinase activation but also the decreases expression of Spred/Sprouty family members.
摘要：
我们以前报道过由半抗原引起的肿胀，如2,4,6-三硝基氯苯（TNCB），可能与细胞外信号调节激酶（ERK）诱导的增殖途径有关。然而,Spred/Sprouty家族作为Ras/Raf/ERK信号通路的关键负调节因子在疾病部位的参与尚未得到证实.因此，在本研究中，研究了半抗原攻击对小鼠耳朵中与Spred/Sprouty家族相关的基因和蛋白质表达水平的影响。ERK和表皮生长因子受体（EGFR）酪氨酸激酶的激活被它们的选择性抑制剂抑制，即,分别为U0126和PD168393。在半抗原TNCB的最后一次挑战24小时后，2,4-二硝基氟苯,或者恶唑酮,所有半抗原的攻击都增加了耳朵的厚度，并且所有半抗原诱导的肿胀中Spred1，Spred2，Sprouty1和Sprouty2的基因表达水平均显着降低。此外，Spred2，Sprouty1和Sprouty2基因在TNCB攻击的耳朵的表皮和真皮中减少。总之,半抗原攻击诱导的皮肤增厚的机制可能不仅涉及通过EGFR酪氨酸激酶激活激活ERK来增强细胞增殖功能，而且还涉及Spred/Sprouty家族成员表达的降低。
