| First Author | Kizaki T | Year | 2009 |
| Journal | Mol Immunol | Volume | 46 |
| Issue | 6 | Pages | 1195-203 |
| PubMed ID | 19167076 | Mgi Jnum | J:146143 |
| Mgi Id | MGI:3836828 | Doi | 10.1016/j.molimm.2008.11.005 |
| Citation | Kizaki T, et al. (2009) beta(2)-Adrenergic receptor regulate Toll-like receptor 4-induced late-phase NF-kappaB activation. Mol Immunol 46(6):1195-203 |
| abstractText | 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 IkappaBalpha and abrogated late-phase IkappaBalpha degradation and NF-kappaB activation in response to LPS. Inducible nitric oxide synthase (NOS II) expression was increased continuously during 24h of LPS stimulation in control cells, but decreased in beta(2)AR or beta-arrestin 2-knockdown cells after 6h 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/IkappaBalpha complex through cytoplasmic beta-arrestin 2, and that TRIF-dependent down-regulation of beta(2)AR expression increases the level of cytoplasmic NF-kappaB/IkappaBalpha complex free from beta-arrestin 2, leading to continuous late-phase NF-kappaB activation. |
