Yusuf Nabiha, Nasti Tahseen H, Huang Chun-Ming, Huber Brad S, Jaleel Tarannum, Lin Hui-Yi, Xu Hui, Elmets Craig A
Department of Dermatology and Skin Diseases Research Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
J Immunol. 2009 Jan 1;182(1):675-83. doi: 10.4049/jimmunol.182.1.675.
Proteomic analysis of murine skin has shown that a variety of heat shock proteins (HSPs) are constitutively expressed in the skin. Using murine allergic contact hypersensitivity as a model, we investigated the role of two heat shock proteins, HSP27 and HSP70, in the induction of cutaneous cell-mediated immune responses. Immunohistochemical examination of skin specimens showed that HSP27 was present in the epidermis and HSP70 was present in both the epidermis and dermis. Inhibition of HSP27 and HSP70 produced a reduction in the 1-fluoro-2,4-dinitrobenzene contact hypersensitivity response and resulted in the induction of Ag-specific unresponsiveness. Treatment of dendritic cell cultures with recombinant HSP27 caused in the up-regulation of IL-1beta, TNF-alpha, IL-6, IL-12p70, and IL-12p40 but not IL-23p19, which was inhibited when Abs to HSP27 were added. The 1-fluoro-2,4-dinitrobenzene-conjugated dendritic cells that had been treated with HSP27 had an increased capacity to initiate contact hypersensitivity responses compared with control dendritic cells. This augmented capacity required TLR4 signaling because neither cytokine production by dendritic cells nor the increased induction of contact hypersensitivity responses occurred in TLR4-deficient C3H/HeJ mice. Our findings indicate that a cascade of events occurs following initial interaction of hapten with the skin that includes increased activity of HSPs, their interaction with TLR4, and, in turn, increased production of cytokines that are known to enhance Ag presentation by T cells. The results suggest that HSPs form a link between adaptive and innate immunity during the early stages of contact hypersensitivity.
对小鼠皮肤的蛋白质组学分析表明，多种热休克蛋白（HSPs）在皮肤中组成性表达。以小鼠过敏性接触超敏反应为模型，我们研究了两种热休克蛋白HSP27和HSP70在诱导皮肤细胞介导的免疫反应中的作用。皮肤标本的免疫组织化学检查显示，HSP27存在于表皮中，HSP70存在于表皮和真皮中。抑制HSP27和HSP70可使1-氟-2,4-二硝基苯接触超敏反应降低，并导致抗原特异性无反应性的诱导。用重组HSP27处理树突状细胞培养物可导致IL-1β、TNF-α、IL-6、IL-12p70和IL-12p40上调，但不导致IL-23p19上调，添加抗HSP27抗体时这种上调受到抑制。与对照树突状细胞相比，用HSP27处理过的1-氟-2,4-二硝基苯偶联树突状细胞引发接触超敏反应的能力增强。这种增强的能力需要TLR4信号传导，因为在TLR4缺陷的C3H/HeJ小鼠中，树突状细胞既不产生细胞因子，接触超敏反应的诱导也不增加。我们的研究结果表明，在半抗原与皮肤初次相互作用后会发生一系列事件，包括热休克蛋白活性增加、它们与TLR4相互作用，进而增加已知可增强T细胞抗原呈递的细胞因子的产生。结果表明，在接触超敏反应的早期阶段，热休克蛋白在适应性免疫和先天性免疫之间形成了联系。
