Kupffer cell activation by different microbial lysates: Toll‐like receptor‐2 plays pivotal role on thromboxane A₂ production in mice and humans

Abstract

Thromboxane (TX) A 2 has been identified as an important intrahepatic vasoconstrictor upon Kupffer cell (KC) activation during infections such as spontaneous bacterial peritonitis (SBP). The study aimed to investigate the role of TLRs in the TXA 2 increase in liver nonparenchymal cells and their related mechanisms. Here, we identified TLR-2 as a common pathway for different microbials: microbial lysates including Gram-positive bacteria, Gram-negative bacteria, and fungi all increased TXA 2 secretion via activation of TLR-2 in human KCs, accompanied by increased expression and phosphorylation of Myd88related pathway. Of all TLR agonists, only TLR-1,-2, and-4 agonists increased TXA 2 in human KCs. These results were further confirmed by mouse liver nonparenchymal cells. Comparing the effects of TLR-1,-2, and-4 antagonists, only TLR-2 antagonist showed inhibitory effects with all tested microbial lysates. Pretreatment with TLR-2 antagonist in human KCs blocked the secretion of IL-10, CXCL-10, TNF-α, and IL-6 induced by Grampositive and Gram-negative bacterial stimulation. IL-23 and IL-1β were only induced by Gram-negative bacteria. Thus, TLR-2 might be a potential marker and an attractive target for future treatment of patients with SBP. In addition, IL-23 and IL-1β might distinguish early between Gram-positive and Gram-negative SBP.

Eicosanoids and other oxylipins in liver injury, inflammation and liver cancer development

“…LPS induction leads to the upregulation of COX2 concurrent with PGE2 synthase 1 (PGES1) in liver resident macrophages, the Kupffer cells ( Bezugla et al, 2006 ). Consistently, LPS induces the robust production of PGE2 and TXA2 in the liver ( Bowers et al, 1985 ; Bezugla et al, 2006 ; Miller et al, 2007 ; Miao et al, 2016 ; Zhang et al, 2020a ). Thus, the induction of COX2 appears to contribute to the inflammatory response and is also considered to have generally cytoprotective effects that are attributed primarily to PGE2 ( Figure 4 ).…”

Bilobalide attenuates lipopolysaccharide‑induced HepG2 cell injury by inhibiting TLR4‑NF‑κB signaling via the PI3K/Akt pathway

“…Toll-like receptors (TLRs) are considered to be important components of the innate immune response (11). They are expressed by both hepatocytes and Kupffer cells and serve important roles in hepatic inflammation (12)(13)(14). LPS, as a TLR ligand, can bind to TLRs and trigger the release of multiple inflammatory mediators, leading to activation of the inflammatory cascade and liver injury (15).…”