Premium
Selective priming to Toll‐like receptor 4 (TLR4), not TLR2, ligands by P. acnes involves up‐regulation of MD‐2 in mice
Author(s) -
Romics Laszlo,
Dolganiuc Angela,
Kodys Karen,
Drechsler Yvonne,
Oak Shilpa,
Velayudham Arumugam,
Mandrekar Pranoti,
Szabo Gyongyi
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20350
Subject(s) - tlr2 , tlr4 , toll like receptor , priming (agriculture) , receptor , toll , chemistry , microbiology and biotechnology , immunology , biology , innate immune system , biochemistry , germination , botany
Lipopolysaccharide (LPS) triggers cytokine production through Toll‐like receptor 4 (TLR4), which shares downstream signaling pathways with TLR2. We investigated the roles of TLR2 and TLR4 in Propionibacterium acnes ( P. acnes )–primed, LPS‐induced liver damage using selective TLR ligands. Stock LPS induced interleukin 8 in both TLR4‐ and TLR2‐expressing human embryonic kidney (HEK) 293 cells. Purified LPS (TLR4 ligand) activated HEK/TLR4 cells, while peptidoglycan and lipoteichoic acid (TLR2 ligands) activated HEK/TLR2 cells, respectively. In mice, P. acnes priming resulted in increased liver messenger RNA (mRNA) and serum levels of tumor necrosis factor α, interleukin 12, and interferon γ (IFN‐γ) by both stock LPS and purified LPS challenges compared with nonprimed controls. In contrast , P. acnes failed to sensitize to TLR2 ligands (peptidoglycan + lipoteichoic acid). In the liver, P. acnes –priming was associated with up‐regulation of TLR4 and MD‐2 proteins, and subsequent LPS challenge further increased MD‐2 and CD14 mRNA levels. The lack of sensitization to TLR2 ligands by P. acnes correlated with no increase in hepatic TLR1 or TLR6 mRNA. In vitro , P. acnes pretreatment desensitized RAW macrophages to a secondary stimulation via both TLR2 and TLR4. However, IFN‐γ could selectively prevent desensitization to TLR4 but not to TLR2 ligands. Furthermore, P. acnes induced production of IFN‐γ in vivo as well as in isolated splenocytes. In vitro , P. acnes –primed Hepa 1‐6 hepatocytes but not RAW macrophages produced increased MD‐2 and CD14 mRNA levels after an LPS challenge. In conclusion , P. acnes priming to selective TLR4‐mediated liver injury is associated with up‐regulation of TLR4 and MD‐2 and is likely to involve IFN‐γ and prevent TLR4 desensitization by P. acnes . (H EPATOLOGY 2004;40:555–564.)