| RRC ID |
6617
|
| 著者 |
Kizaki T, Shirato K, Sakurai T, Ogasawara JE, Oh-ishi S, Matsuoka T, Izawa T, Imaizumi K, Haga S, Ohno H.
|
| タイトル |
Beta2-adrenergic receptor regulate Toll-like receptor 4-induced late-phase NF-kappaB activation.
|
| ジャーナル |
Mol Immunol
|
| Abstract |
Stimulation of Toll-like receptor 4 (TLR4) by lipopolysaccharide (LPS) triggers myeloid differentiation factor 88 (MyD88)-dependent early-phase NF-kappaB activation and Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent late-phase NF-kappaB activation. In a previous study, we have shown that beta(2)-adrenergic receptor (beta(2)AR) functions as a negative regulator of NF-kappaB activation through beta-arrestin 2 in the macrophage cell line RAW264 and that down-regulation of beta(2)AR expression in response to LPS is essential for NF-kappaB activation and expression of its target gene, inducible nitric oxide synthase (NOS II). Here, we demonstrate that beta(2)AR plays an important role in TRIF-dependent late-phase NF-kappaB activation. LPS-stimulated down-regulation was induced in MyD88-knockdown cells, but not in TRIF-knockdown cells, suggesting that beta(2)AR expression was down-regulated by the TRIF-dependent pathway. On the other hand, depletion of beta(2)AR or beta-arrestin 2 expression by siRNA decreased cytoplasmic IkappaB alpha and abrogated late-phase IkappaB alpha degradation and NF-kappaB activation in response to LPS. Inducible nitric oxide synthase (NOS II) expression was increased continuously during 24 h of LPS stimulation in control cells, but decreased in beta(2)AR or beta-arrestin 2-knockdown cells after 6 h of LPS stimulation. These findings suggest that beta(2)AR functions not only as a negative regulator of NF-kappaB activation, but also as a stabilizing factor of the NF-kappaB/IkappaB alpha complex through cytoplasmic beta-arrestin 2, and that TRIF-dependent down-regulation of beta(2)AR expression increases the level of cytoplasmic NF-kappaB/IkappaB alpha complex free from beta-arrestin 2, leading to continuous late-phase NF-kappaB activation.
|
| 巻・号 |
46(6)
|
| ページ |
1195-203
|
| 公開日 |
2009-3-1
|
| DOI |
10.1016/j.molimm.2008.11.005
|
| PII |
S0161-5890(08)00756-6
|
| PMID |
19167076
|
| MeSH |
Adaptor Proteins, Vesicular Transport / immunology
Adaptor Proteins, Vesicular Transport / metabolism
Animals
Arrestins / genetics
Arrestins / immunology
Arrestins / metabolism
Cell Line
Down-Regulation
Gene Knockdown Techniques
Lipopolysaccharides / pharmacology
Macrophages / metabolism
Mice
Myeloid Differentiation Factor 88 / genetics
NF-kappa B / metabolism*
Nitric Oxide Synthase Type II / metabolism
Receptors, Adrenergic, beta-2 / immunology
Receptors, Adrenergic, beta-2 / physiology*
Signal Transduction
Toll-Like Receptor 4 / immunology
Toll-Like Receptor 4 / physiology*
beta-Arrestin 2
beta-Arrestins
|
| IF |
3.641
|
| 引用数 |
24
|
|
WOS 分野
|
IMMUNOLOGY
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
RAW 264(RCB0535) |
