Macrophages and neutrophils are the targets for immune suppression by glucocorticoids in contact allergy

被引:213
作者
Tuckermann, Jan P.
Kleiman, Anna
Moriggl, Richard
Spanbroek, Rainer
Neumann, Anita
Illing, Anett
Clausen, Bjoern E.
Stride, Brenda
Foerster, Irmgard
Habenicht, Andreas J. R.
Reichardt, Holger M.
Tronche, Francois
Schmid, Wolfgang
Schuetz, Guenther
机构
[1] German Canc Res Ctr, Div Mol Biol Cell 1, D-69120 Heidelberg, Germany
[2] Fritz Lipmann Inst, Leibniz Inst Age Res, Div Tissue Specif Hormone Act, Jena, Germany
[3] Univ Jena, Inst Vasc Med, D-6900 Jena, Germany
[4] Ludwig Boltzmann Inst Canc Res, Vienna, Austria
[5] Univ Amsterdam, Acad Med Ctr, Dept Cell Biol & Histol, NL-1012 WX Amsterdam, Netherlands
[6] EMBL, Heidelberg, Germany
[7] Univ Dusseldorf, Inst Umweltmed Forsch, D-4000 Dusseldorf, Germany
[8] Univ Gottingen, Dept Cellular & Mol Immunol, D-3400 Gottingen, Germany
[9] Coll France, UMR7148 CNRS, F-75231 Paris, France
基金
奥地利科学基金会;
关键词
D O I
10.1172/JCI28034
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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 and inflammatory 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-1 beta, 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.
引用
收藏
页码:1381 / 1390
页数:10
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