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Isorhamnetin inhibits P revotella intermedia lipopolysaccharide‐induced production of interleukin‐6 in murine macrophages via anti‐inflammatory heme oxygenase‐1 induction and inhibition of nuclear factor‐κB and signal transducer and activator of transcription 1 activation
Author(s) -
Jin J. Y.,
Choi E. Y.,
Park H. R.,
Choi J. I.,
Choi I. S.,
Kim S. J.
Publication year - 2013
Publication title -
journal of periodontal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.31
H-Index - 83
eISSN - 1600-0765
pISSN - 0022-3484
DOI - 10.1111/jre.12054
Subject(s) - prevotella intermedia , heme oxygenase , isorhamnetin , lipopolysaccharide , proinflammatory cytokine , microbiology and biotechnology , cytokine , biology , porphyromonas gingivalis , chemistry , immunology , inflammation , biochemistry , heme , kaempferol , genetics , antioxidant , bacteria , enzyme , quercetin
Background and Objective Interleukin‐6 ( IL ‐6) is a key proinflammatory cytokine that has been considered to be important in the pathogenesis of periodontal disease. Therefore, host‐modulatory agents directed at inhibiting IL ‐6 appear to be beneficial in terms of attenuating periodontal disease progression and potentially improving disease susceptibility. In the current study, we investigated the effect of the flavonoid isorhamnetin on the production of IL ‐6 in murine macrophages stimulated with lipopolysaccharide ( LPS) from P revotella intermedia , a pathogen implicated in inflammatory periodontal disease, and its mechanisms of action. Material and Methods Lipopolysaccharide from P . intermedia ATCC 25611 was isolated using the standard hot phenol–water method. Culture supernatants were collected and assayed for IL ‐6. We used real‐time PCR to quantify IL ‐6 and heme oxygenase‐1 ( HO ‐1) mRNA expression. The expression of HO‐1 protein and the levels of signaling proteins were monitored using immunoblot analyses. The DNA ‐binding activity of nuclear factor‐κB ( NF ‐κ B) was analyzed using ELISA ‐based assay kits. Results Isorhamnetin significantly down‐regulated P . intermedia LPS ‐induced production of IL ‐6 as well as its m RNA expression in RAW 264.7 cells. Isorhamnetin up‐regulated the expression of HO‐1 at both gene transcription and translation levels in cells stimulated with P . intermedia LPS . In addition, inhibition of HO‐1 activity by tin protoporphyrin IX blocked the inhibitory effect of isorhamnetin on IL ‐6 production. Isorhamnetin failed to prevent LPS from activating either c‐Jun N ‐terminal kinase or p38 pathways. Isorhamnetin did not inhibit NF ‐κ B transcriptional activity at the level of inhibitory κB‐α degradation. Isorhamnetin suppressed NF ‐κ B signaling through inhibition of nuclear translocation and DNA binding activity of NF ‐κ B p50 subunit and attenuated signal transducer and activator of transcription 1 signaling. Conclusion Although further research is required to clarify the detailed mechanism of action, we propose that isorhamnetin may contribute to blockade of the host‐destructive processes mediated by IL ‐6 and could be a highly efficient modulator of the host response in the treatment of inflammatory periodontal disease. Further research in animal models of periodontitis is required to better evaluate, the potential of isorhamnetin as a novel agent for treating periodontal disease.