An antiinflammatory role for IKKbeta through the inhibition of "classical" macrophage activation.
An antiinflammatory role for IKKbeta through the inhibition of "classical" macrophage activation.
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IKKbeta 通过抑制“经典”巨噬细胞激活发挥抗炎作用。
DOI：
10.1084/jem.20080124
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发表时间：
2008-06-09
期刊：
影响因子：
--
通讯作者：
Lawrence T
中科院分区：
文献类型：
--
作者：
Fong CH;Bebien M;Didierlaurent A;Nebauer R;Hussell T;Broide D;Karin M;Lawrence T
核因子κB （NF-κB）通路在炎症和免疫中起核心作用。在对促炎细胞因子和病原体相关分子模式的反应中，NF-κB的激活是由IκB激酶(IKK)β控制的。利用Cre/lox介导的基因靶向IKKβ，我们发现了IKKβ在B组链球菌感染过程中的组织特异性作用。虽然在气道上皮细胞中IKKβ的缺失具有抑制炎症和降低先天免疫的预期作用，但在髓系谱系中IKKβ的缺失意外地赋予了对感染的抵抗，这与巨噬细胞中白细胞介素(IL)-12、诱导型一氧化氮合酶（NOS2）和主要组织相容性复合体（MHC） II类的表达增加有关。我们还描述了IKKβ在巨噬细胞中抑制信号转导和转录激活因子（Stat）1信号传导中的未知作用，这对IL-12、NOS2和MHC II类表达至关重要。这些研究表明，在感染期间，IKKβ通过与Stat1通路的负性串扰抑制“经典”活化或M1巨噬细胞表型。这可能代表了一种在感染期间防止巨噬细胞过度活跃并有助于炎症解决的机制。这证实了IKKβ在巨噬细胞活化调控中的新作用，在慢性炎性疾病、感染和癌症中具有重要意义。
The nuclear factor κB (NF-κB) pathway plays a central role in inflammation and immunity. In response to proinflammatory cytokines and pathogen-associated molecular patterns, NF-κB activation is controlled by IκB kinase (IKK)β. Using Cre/lox-mediated gene targeting of IKKβ, we have uncovered a tissue-specific role for IKKβ during infection with group B streptococcus. Although deletion of IKKβ in airway epithelial cells had the predicted effect of inhibiting inflammation and reducing innate immunity, deletion of IKKβ in the myeloid lineage unexpectedly conferred resistance to infection that was associated with increased expression of interleukin (IL)-12, inducible nitric oxide synthase (NOS2), and major histocompatibility complex (MHC) class II by macrophages. We also describe a previously unknown role for IKKβ in the inhibition of signal transducer and activator of transcription (Stat)1 signaling in macrophages, which is critical for IL-12, NOS2, and MHC class II expression. These studies suggest that IKKβ inhibits the “classically” activated or M1 macrophage phenotype during infection through negative cross talk with the Stat1 pathway. This may represent a mechanism to prevent the over-exuberant activation of macrophages during infection and contribute to the resolution of inflammation. This establishes a new role for IKKβ in the regulation of macrophage activation with important implications in chronic inflammatory disease, infection, and cancer.
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影响因子：
64.8
作者：
Lawrence, T;Bebien, M;Karin, M
通讯作者：
Karin, M
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I
影响因子：
4.4
作者：
Mueller, Uwe;Stenzel, Werner;Alber, Gottfried
通讯作者：
Alber, Gottfried
影响因子：
4.4
作者：
Gadjeva, M;Tomczak, MF;Horwitz, BH
通讯作者：
Horwitz, BH
DOI：
10.1073/pnas.0406143101
发表时间：
2004-10-05
影响因子：
11.1
作者：
Liu, GY;Doran, KS;Nizet, V
通讯作者：
Nizet, V