Agrawal Anshu, Dillon Stephanie, Denning Timothy L, Pulendran Bali
Emory Vaccine Center and Department of Pathology, 954 Gatewood Road, Atlanta, GA 30329, USA.
J Immunol. 2006 May 15;176(10):5788-96. doi: 10.4049/jimmunol.176.10.5788.
Activation of MAPK ERK1/2 has been shown to play an important role in Th1/Th2 polarization and in regulating cytokine production from APCs. The ERK family consists of two members ERK1 and ERK2, which share approximately 84% identity at the amino acid level and can compensate for each other for most functions. Despite these features, ERK1 and ERK2 do serve different functions, but there is very little information on the contribution of individual forms of ERK on innate and adaptive immune responses. In this study, we describe that ERK1(-/-) mice display a bias toward Th1 type immune response. Consistent with this observation, dendritic cells from ERK1(-/-) mice show enhanced IL-12p70 and reduced IL-10 secretion in response to TLR stimulation. Furthermore, serum from ERK1(-/-) mice had 100-fold higher total IgG2b and 10-fold higher total IgG2a and IgG1 Ab isotype titers, and enhanced levels of Ag-specific IgG2b Ab titers, compared with wild-type mice. Consistent with this enhanced Th1 bias, ERK1(-/-) mice showed enhanced susceptibility to myelin oligodendrocyte glycoprotein (MOG)35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE) and developed EAE earlier, and with increased severity, compared with wild-type mice. Importantly, there was a profound skewing toward Th1 responses in ERK1(-/-) mice, with higher IFN-gamma production and lower IL-5 production in MOG35-55-primed T cells, as well as an augmentation in the MOG-specific IgG2a and IgG2b Th1 Ab isotypes. Finally, increased infiltrating cells and myelin destruction was observed in the spinal cord of ERK1(-/-) mice. Taken together, our data suggest that deficiency of ERK1 biases the immune response toward Th1 resulting in increased susceptibility to EAE.
丝裂原活化蛋白激酶细胞外信号调节激酶1/2（MAPK ERK1/2）的激活已被证明在Th1/Th2极化以及调节抗原呈递细胞（APC）的细胞因子产生中发挥重要作用。ERK家族由ERK1和ERK2两个成员组成，它们在氨基酸水平上约有84%的同源性，并且在大多数功能上可以相互补偿。尽管有这些特点，但ERK1和ERK2确实发挥着不同的功能，然而关于ERK的个体形式对先天性和适应性免疫反应的贡献的信息却非常少。在本研究中，我们描述了ERK1基因敲除（-/-）小鼠表现出偏向Th1型免疫反应的倾向。与这一观察结果一致，来自ERK1基因敲除小鼠的树突状细胞在受到Toll样受体（TLR）刺激时，显示出增强的白细胞介素-12p70（IL-12p70）分泌和减少的白细胞介素-10（IL-10）分泌。此外，与野生型小鼠相比，ERK1基因敲除小鼠血清中的总IgG2b水平高100倍，总IgG2a和IgG1抗体亚型滴度高10倍，并且抗原特异性IgG2b抗体滴度水平增强。与这种增强的Th1偏向一致，ERK1基因敲除小鼠对髓鞘少突胶质细胞糖蛋白（MOG）35-55肽诱导的实验性自身免疫性脑脊髓炎（EAE）的易感性增强，并且与野生型小鼠相比，发病更早，病情更严重。重要的是，在ERK1基因敲除小鼠中存在对Th1反应的显著偏向，在经MOG35-55刺激的T细胞中，干扰素-γ（IFN-γ）产生增加，白细胞介素-5（IL-5）产生减少，以及MOG特异性IgG2a和IgG2b Th1抗体亚型增加。最后，在ERK1基因敲除小鼠的脊髓中观察到浸润细胞增加和髓鞘破坏。综上所述，我们的数据表明ERK1的缺乏使免疫反应偏向Th1，导致对EAE的易感性增加。
