Alcohol consumption upregulates TLR2 via cGMP
Kofi
�
Alcohol Up-Regulates TLR2 Through a NO/cGMP Dependent Pathway.
Bailey KL, Sisson JH, Romberger DJ, Robinson JE, Wyatt TA.
From the Pulmonary, Critical Care, Sleep & Allergy Section, Department
of Internal Medicine, University of Nebraska Medical Center (KLB, JHS,
DJR, JER, TAW), Omaha Veterans Affairs Medical Center Research Service
(DJR, TAW), and Department of Environmental, Agricultural, and
Occupational Health, College of Public Health, University of Nebraska
Medical Center (DJR, TAW), Omaha, Nebraska.
Background: Heavy alcohol consumption is associated with severe
bronchitis. This is likely related to increased inflammation in the
airways of alcohol abusers. Toll-like receptor 2 (TLR2) is an important
mediator of inflammation in the airway epithelium. TLR2 initiates an
inflammatory cascade in response to gram-positive bacteria. We have
previously shown that alcohol up-regulates TLR2 in the airway
epithelium. However, the mechanism of alcohol-mediated up-regulation of
TLR2 has not been identified. Methods: A human airway epithelial cell
line, 16HBE14o-, was exposed to biologically relevant concentrations of
alcohol (100 mM) in the presence and absence of
N(omega)-Nitro-l-arginine methyl ester hydrochloride, a nitric oxide
(NO) synthase inhibitor; and Rp-8-Br-cGMP-S, an antagonist analogue of
cGMP. TLR2 was measured using real-time PCR and Western blots. In
addition, 16HBE14o- cells were incubated with sodium nitroprusside
(SNP), an NO donor, and 8-Br-cGMP, a cGMP analogue. TLR2 was measured
using real-time PCR. Results: N(omega)-Nitro-l-arginine methyl ester
hydrochloride blocked the alcohol-mediated up-regulation of TLR2. This
indicates that NO plays a key role in alcohol's up-regulation of TLR2.
SNP, a NO donor, up-regulated TLR2. Rp-8-Br-CGMP-S attenuated alcohol's
up-regulation of TLR2, suggesting that NO was working through cGMP/PKG.
8-Br-cGMP up-regulated TLR2, also demonstrating the importance of
cGMP/PKG. Conclusions: Alcohol up-regulates TLR2 through a NO/cGMP/PKG
dependent pathway in the airway epithelium. This is an important
observation in the understanding how alcohol modulates airway
inflammation. In addition, this is the first time that cyclic
nucleotides have been shown to play a role in the regulation of TLR2.
PMID: 19860807