Tuckermann Jan P, Kleiman Anna, Moriggl Richard, Spanbroek Rainer, Neumann Anita, Illing Anett, Clausen Björn E, Stride Brenda, Förster Irmgard, Habenicht Andreas J R, Reichardt Holger M, Tronche François, Schmid Wolfgang, Schütz Günther
Division of Molecular Biology of the Cell I, German Cancer Research Center, Heidelberg, Germany.
J Clin Invest. 2007 May;117(5):1381-90. doi: 10.1172/JCI28034. Epub 2007 Apr 19.
Glucocorticoids (GCs) are widely used in the treatment of allergic skin conditions despite having numerous side effects. Here we use Cre/loxP-engineered tissue- and cell-specific and function-selective GC receptor (GR) mutant mice to identify responsive cell types and molecular mechanisms underlying the antiinflammatory activity of GCs in contact hypersensitivity (CHS). CHS was repressed by GCs only at the challenge phase, i.e., during reexposure to the hapten. Inactivation of the GR gene in keratinocytes or T cells of mutant mice did not attenuate the effects of GCs, but its ablation in macrophages and neutrophils abolished downregulation of the inflammatory response. Moreover, mice expressing a DNA binding-defective GR were also resistant to GC treatment. The persistent infiltration of macrophages and neutrophils in these mice is explained by an impaired repression of inflammatory cytokines and chemokines such as IL-1beta, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and IFN-gamma-inducible protein 10. In contrast TNF-alpha repression remained intact. Consequently, injection of recombinant proteins of these cytokines and chemokines partially reversed suppression of CHS by GCs. These studies provide evidence that in contact allergy, therapeutic action of corticosteroids is in macrophages and neutrophils and that dimerization GR is required.
糖皮质激素（GCs）尽管有许多副作用，但仍被广泛用于治疗过敏性皮肤病。在此，我们使用Cre/loxP工程化的组织和细胞特异性及功能选择性糖皮质激素受体（GR）突变小鼠，以确定接触性超敏反应（CHS）中GCs抗炎活性的反应性细胞类型和分子机制。GCs仅在激发阶段，即在再次接触半抗原期间，抑制CHS。突变小鼠角质形成细胞或T细胞中GR基因的失活并未减弱GCs的作用，但其在巨噬细胞和中性粒细胞中的缺失消除了炎症反应的下调。此外，表达DNA结合缺陷型GR的小鼠也对GC治疗有抗性。这些小鼠中巨噬细胞和中性粒细胞的持续浸润可通过炎症细胞因子和趋化因子如IL-1β、单核细胞趋化蛋白-1、巨噬细胞炎性蛋白-2和IFN-γ诱导蛋白10的抑制受损来解释。相比之下，TNF-α的抑制保持完整。因此，注射这些细胞因子和趋化因子的重组蛋白可部分逆转GCs对CHS的抑制作用。这些研究提供了证据，表明在接触性过敏中，皮质类固醇的治疗作用在于巨噬细胞和中性粒细胞，并且需要GR二聚化。
