Lipopolysaccharide-induced decreased protein S expression in liver cells is mediated by MEK/ERK signaling and NFκB activation: involvement of membrane-bound CD14 and toll-like receptor-4

Abstract

Summary. Background: The vitamin K-dependent protein S (PS), mainly synthesized in hepatocytes and endothelial cells, plays a critical role in the anticoagulant activity of plasma. The decreased plasma level of PS in sepsis is associated with thrombotic tendency, but the mechanism is unclear. Objectives: In the present study, we examined the effect of lipopolysaccharide (LPS) on PS expression in vivo in rat liver, and in vitro in isolated hepatocytes and sinusoidal endothelial cells (SECs) from normal rats. Results: LPS induced a progressive decrease of plasma PS antigen level up to 12 h with a slight recovery at 24 h, and a transient decrease of liver PS mRNA level at 4-8 h with a complete recovery at 24 h. In the in vitro studies, LPS decreased PS antigen and mRNA levels in both hepatocytes and SECs. After LPS treatment, tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6) and interferon-c (IFN-c) transiently increased in plasma. IL-6 increased the protein expression of PS from hepatocytes, while TNF-a decreased it from SECs. LPS increased CD14 in hepatocytes and decreased it in SECs, but did not affect toll-like receptor-4 (TLR-4) expression in both cells. Antirat CD14 and antirat TLR-4 antibodies inhibited LPS-induced NFjB activation, and a NFjB inhibitor suppressed LPS-induced decreased PS expression in both cells. Furthermore, MEK inhibitor blocked LPS-induced decreased PS expression in both cells. Conclusions: These findings suggest that LPS-induced decreased PS expression in hepatocytes and SECs is mediated by MEK/ERK signaling and NFjB activation and that membrane-bound CD14 and TLR-4 are involved in this mechanism. These findings may explain in part the decreased level of plasma PS and thrombotic tendency in sepsis.

Etomidate Mitigates Lipopolysaccharide-Induced CD14 and TREM-1 Expression, NF-κB Activation, and Pro-inflammatory Cytokine Production in Rat Macrophages

“…To understand the potential mechanisms underlying the action of etomidate, we examined the effect of etomidate on the relative levels of CD14 and TREM-1 expression and NF-kB activation in macrophages following LPS stimulation. We found that LPS treatment significantly increased the levels of CD14 and TREM-1 expression and NF-kB activation in macrophages, extending previous observations that LPS stimulates CD14 and TREM-1 expression in hepatocytes and other types of cells [23][24][25][26]. In contrast, treatment with either 2.5 or 5 μM significantly reduced LPS-upregulated CD14 and TREM-1 expression and NF-kB activation in macrophages.…”

Endocytosis of Mycobacterium tuberculosis Heat Shock Protein 60 Is Required to Induce Interleukin-10 Production in Macrophages*

“…We observed a higher NF-B activity when Mtbhsp60 interacted with TLR4 as compared with the TLR2. The predominant induction of NF-B during its interaction with TLR4 could be due to the increased activation of ERK1/2 signaling as indicated elsewhere (93,94). Although many studies have indicated that hsp60 can trigger NF-B and pro-inflammatory responses (48), our studies for the first time indicated that specific interaction of hsp60 of M. tuberculosis with TLR4 resulted in stronger NF-B activity leading to production of pro-inflammatory cytokines like TNF-␣ and IL-12 (29).…”

Altered hepatic inflammatory response in the offspring following prenatal LPS exposure

“…Studies have shown that LPS stimulation decreases the expression of TLR-4 [22,23], and increases the expression of CD14, TNF-␣, IL-1␤, and IL-6 in rodent liver [21,22,24,25]. Moreover, LPS has been shown to activate p42/44 MAPK in cultured hepatocytes in vitro as well as in rodent liver in vivo [26][27][28]. However, it is still unknown how maternal immune activation affects hepatic inflammatory response to LPS stimulation.…”