C-type lectin DC-SIGN modulates toll-like receptor signaling via Raf-1 kinase-dependent acetylation of transcription factor NF-κB

被引:509
作者
Gringhuis, Sonja I. [1 ]
den Dunnen, Jeroen [1 ]
Litjens, Manja [1 ]
Hof, Bert van het [1 ]
van Kooyk, Yvette [1 ]
Geijtenbeek, Teunis B. H. [1 ]
机构
[1] Vrije Univ Amsterdam, Med Ctr, Dept Mol Cell Biol & Immunol, NL-1007 MB Amsterdam, Netherlands
关键词
D O I
10.1016/j.immuni.2007.03.012
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Adaptive immune responses by dendritic cells (DCs) are critically controlled by Toll-like receptor (TLR) function. Little is known about modulation of TLR-specific signaling by other pathogen receptors. Here, we have identified a molecular signaling pathway induced by the C-type lectin DC-SIGN that modulates TLR signaling at the level of the transcription factor NF-kappa B. We demonstrated that pathogens trigger DC-SIGN on human DCs to activate the serine and threonine kinase Raf-1, which subsequently leads to acetylation of the NF-kappa B subunit p65, but only after TLR-induced activation of NF-kappa B. Acetylation of p65 both prolonged and increased IL10 transcription to enhance anti-inflammatory cytokine responses. We demonstrated that different pathogens such as Mycobacterium tuberculosis, M. leprae, Candida albicans, measles virus, and human immunodeficiency virus-1 interacted with DC-SIGN to activate the Raf-1-acetylation-dependent signaling pathway to modulate signaling by different TLRs. Thus, this pathway is involved in regulation of adaptive immunity by DCs to bacterial, fungal, and viral pathogens.
引用
收藏
页码:605 / 616
页数:12
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