Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid
Gram-positive bacterial products such as peptidoglycan (PGN) and lipoteichoic acid (LTA) are potent stimulators of innate inflammatory responses. We previously reported that lipopolysaccharide (LPS), a major biologically active agent of gram-negative bacteria, induces a proinflammatory response via...
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Veröffentlicht in: | Laboratory investigation 2006-07, Vol.86 (7), p.676-686 |
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Zusammenfassung: | Gram-positive bacterial products such as peptidoglycan (PGN) and lipoteichoic acid (LTA) are potent stimulators of innate inflammatory responses. We previously reported that lipopolysaccharide (LPS), a major biologically active agent of gram-negative bacteria, induces a proinflammatory response via the Toll-like receptor (TLR) 4 in hepatic stellate cells (HSCs). Here we investigated the mechanism of proinflammatory action by PGN and LTA in activated human HSCs. Following treatment with either TNF-α or IL-1β, expression of TLR2 and CD14 was determined by real-time PCR and Western blotting. NF-κB activation was assessed by NF-κB-driven luciferase assay and electrophoretic mobility shift assay. Interleukin-8 (IL-8) from culture supernatant was measured by ELISA. Activated human HSCs express TLR2 and CD14, which are receptors for PGN and LTA signaling. TNF-α and IL-1β significantly upregulated the expression of TLR2 mRNA and protein in HSCs. PGN and LTA induced NF-κB activation and stimulated production of IL-8 in HSCs. Pretreatment with TNF-α or IL-1β augmented NF-κB activation and IL-8 production in response to PGN or LTA. Both PGN- and LTA-induced NF-κB activation and IL-8 secretion were completely inhibited by anti-TLR2 blocking antibody (T2.5). These findings suggest that TNF-α or IL-1β primed HSCs enhance the production of IL-8 in response to PGN and LTA through augmentation of the TLR2 system. |
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ISSN: | 0023-6837 1530-0307 |
DOI: | 10.1038/labinvest.3700422 |