Heme oxygenase-1 signals are involved in preferential inhibition of pro-inflammatory cytokine release by surfactin in cells activated with Porphyromonas gingivalis lipopolysaccharide.
Porphyromonas gingivalis is considered the major pathogen of periodontal disease, which leads to chronic inflammation in oral tissues. P. gingivalis-produced lipopolysaccharide (LPS) is a key factor in the development of periodontitis. It is established that surfactin produced by Bacillus subtilis confers anti-inflammatory properties. However, the underlying mechanisms responsible for surfactin-induced anti-inflammatory actions in the context of periodontitis are poorly understood. In this study, we investigated whether surfactin affected P. gingivalis LPS-induced pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-12, and determined that it significantly inhibited their production. Surfactin-mediated inhibition was mainly due to blocked activation of P. gingivalis LPS-triggered nuclear factor-κB. We also examined whether the regulatory effect of surfactin on P. gingivalis LPS-stimulated human THP-1 macrophages was mediated by the induction of heme oxygenase-1 (HO-1) signals, and determined that surfactin also induced HO-1 mRNA and protein expression via activation of Nrf-2. Additionally, we found that small interfering RNA-mediated knock-down of Nrf-2 significantly inhibited surfactin-induced HO-1 expression. Furthermore, inhibition of phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) significantly decreased surfactin-induced HO-1 expression, which is consistent with the suggestion that surfactin-induced HO-1 expression occurs via PI3K/Akt, ERK, and Nrf-2. Treatment with a selective inhibitor of HO-1 reversed the surfactin-mediated inhibition of pro-inflammatory cytokines, suggesting that surfactin induces anti-inflammatory effects by activating Nrf-2-mediated HO-1 induction via PI3K/Akt and ERK signaling. Collectively, these observations support the potential of surfactin as a candidate in strategies to prevent caries, periodontitis, or other inflammatory diseases.
Park
Sun Young
SY
Pusan National University, Busan, Republic of Korea.
Kim
Young Hun
YH
Kim
Eun-Kyoung
EK
Ryu
Eun Yeon
EY
Lee
Sang-Joon
SJ
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D055666:Lipopeptides / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D016966:Porphyromonas gingivalis / Q000737:chemistry*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
D016207:Cytokines; D055666:Lipopeptides; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D010456:Peptides, Cyclic; D012333:RNA, Messenger; C009365:surfactin peptide; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases