Macrophages and derived-TNF-α promote lipopolysaccharide-induced upregulation of endogenous β-glucuronidase in the epithelial cells of the bile duct: A possible facilitator of hepatolithiasis formation - 07/01/23
Highlights |
• | M2 macrophages regulate the LPS-induced expression of endogenous β-GD. |
• | TNF-α secreted by macrophages further promote the increase in the expression of endogenous β-GD possibly via the NF-κB/PCNA signalling cascade. |
Abstract |
Background |
Hepatolithiasis is prevalent in Southeast Asian regions, and the role of endogenous β-glucuronidase (β-GD) in the formation of hepatolithiasis is being gradually recognised. Revealing the regulation mechanism of the expression of endogenous β-GD will provide new therapeutic strategies for intervening in the formation of hepatolithiasis.
Methods |
Liver specimens from patients with hepatolithiasis were examined by immunohistochemistry to assess the expression of macrophage markers including CD68, CD80, and CD206, as well as that of TNF-α and endogenous β-GD, compared with that in normal liver samples. HiBEpiC cells were co-cultured directly or indirectly with induced M2 macrophages or directly stimulated with TNF-α, and the expression of the endogenous β-GD was examined. A PKC inhibitor, chelerythrine, and an NF-κB inhibitor, pyrrolidine dithiocarbamate (PDTC), were used to elucidate the possible regulation mechanism.
Results |
The expression of macrophage markers including CD68 and CD206, as well as that of TNF-α and endogenous β-GD significantly increased in liver specimens from patients with hepatolithiasis compared with that in normal liver samples. The expression of CD68, CD206 and TNF-α was positively correlated with that of endogenous β-GD. When HiBEpiC cells were co-cultured directly or indirectly with M2 macrophages, following stimulation with lipopolysaccharide (LPS), the expression of endogenous β-GD was significantly higher in the indirect co-culture group than that in the direct co-culture group, or in HiBEpiC cells or M2 macrophages cultured alone. Further experiments revealed that following stimulation with LPS, TNF-α secretion increased in both the indirect and direct co-culture groups compared with that in HiBEpiC cells cultured alone. TNF-α increased the expression of endogenous β-GD in HiBEpiC cells, in a dose- and time-dependent manner. In addition, TNF-α significantly increased the expression levels of p-P65 and proliferating cell nuclear antigen (PCNA), and PDTC effectively inhibited the TNF-α-induced expression of PCNA and β-GD.
Conclusions |
Infiltration of macrophages, especially M2 macrophages, may be involved in the hepatolithiasis formation. LPS activates the macrophages, inducing the secretion of TNF-α, which can further increase the expression of endogenous β-GD in the epithelial cells of the bile duct, possibly via the NF-κB/PCNA signalling cascade.
Le texte complet de cet article est disponible en PDF.Keywords : Hepatolithiasis, Macrophage, β-glucuronidase, TNF-α, NF-κB
Abbreviations : β-GD, LPS, PMA, PCNA, TLR4, TNF-α
Plan
Vol 47 - N° 1
Article 102062- janvier 2023 Retour au numéro
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