Beta2-adrenergic receptor regulate Toll-like receptor 4-induced late-phase NF-kappaB activation

Takako Kizaki, Ken Shirato, Takuya Sakurai, Jun-etsu Ogasawara, Shuji Oh-ishi, Takeshi Matsuoka, Tetsuya Izawa, Kazuhiko Imaizumi, Shukoh Haga, Hideki Ohno
Molecular Immunology 2009, 46 (6): 1195-203
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.

Full Text Links

Find Full Text Links for this Article


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"