Department of Biological Science, College of Medical and Life Sciences, Silla University, 140 Baegyang-daero, 700beon-gil, Sasang-gu, Busan 617-736, Republic of Korea.
Department of Periodontology, School of Dentistry, Pusan National University, 49 Busandaehak-ro, Mulgeum-eup, Yangsan, Gyeongsangnam-do 626-870, Republic of Korea; Dental Research Institute, Pusan National University Dental Hospital, Yangsan, Gyeongsangnam-do, Republic of Korea; Dental and Life Science Institute, Pusan National University, Yangsan, Gyeongsangnam-do, Republic of Korea.
Int Immunopharmacol. 2021 Jan;90:107190. doi: 10.1016/j.intimp.2020.107190. Epub 2020 Nov 19.
Carbon monoxide (CO) is increasingly being appreciated as an important mediator that has pleiotropic biological properties and appears to have a possible therapeutic application for a variety of disorders. Nevertheless, whether this gaseous molecule may be utilized as a therapeutic intervention for periodontal disease is unclear. Here, we examined the potential beneficial effect of CO-releasing molecule-2 (CORM-2), a tricarbonyldichlororuthenium(II) dimer, against the elaboration of proinflammatory mediators by murine macrophages challenged with lipopolysaccharide (LPS) isolated from Prevotella intermedia, a pathogenic bacterium implicated in inflammatory periodontal disease. We found that NO and IL-1β production, iNOS protein expression and mRNA expressions of iNOS and IL-1β were significantly down-regulated when LPS-challenged RAW264.7 cells were exposed to CORM-2. In addition, HO-1 expression was upregulated by CORM-2 in cells activated with P. intermedia LPS, and the inhibitory influence of CORM-2 upon NO production was attenuated by tin protoporphyrin IX, an inhibitor of HO activity. PPAR-γ did not function in the attenuation of NO and IL-1β by CORM-2. JNK and p38 phosphorylation caused by LPS was not altered by CORM-2. CORM-2 reduced NF-κB reporter activity and IκB-α degradation elicited by P. intermedia LPS. Additionally, CORM-2 inhibited LPS-induced phosphorylation of STAT1/3. In conclusion, CORM-2 suppresses NO and IL-1β production caused by P. intermedia LPS. CORM-2 exerts its effect by a mechanism involving anti-inflammatory HO-1 induction and attenuation of NF-κB and STAT1/3 activation, independently of PPAR-γ as well as JNK and p38. CORM-2 may hold promise as host response modulation agent for periodontal disease, though further research is indicated to verify the therapeutic effect.
一氧化碳（CO）作为一种重要的介质，具有多种生物学特性，对于多种疾病可能具有潜在的治疗应用，这一点越来越受到重视。然而，这种气态分子是否可用于治疗牙周病尚不清楚。在这里，我们研究了一氧化碳释放分子-2（CORM-2）对脂多糖（LPS）诱导的小鼠巨噬细胞产生促炎介质的潜在有益作用，LPS 是一种与炎症性牙周病有关的致病细菌中间普氏菌中分离得到的。我们发现，当 LPS 刺激的 RAW264.7 细胞暴露于 CORM-2 时，NO 和 IL-1β 的产生、iNOS 蛋白表达以及 iNOS 和 IL-1β 的 mRNA 表达显著下调。此外，CORM-2 可诱导 HO-1 在被中间普氏菌 LPS 激活的细胞中表达，而 HO 活性抑制剂 tin 原卟啉 IX 可减弱 CORM-2 对 NO 产生的抑制作用。PPAR-γ 并未参与 CORM-2 对 NO 和 IL-1β 的抑制作用。CORM-2 并未改变 LPS 引起的 JNK 和 p38 的磷酸化。CORM-2 降低了由中间普氏菌 LPS 引起的 NF-κB 报告基因活性和 IκB-α 的降解。此外，CORM-2 抑制了 LPS 诱导的 STAT1/3 磷酸化。总之，CORM-2 抑制了中间普氏菌 LPS 引起的 NO 和 IL-1β 的产生。CORM-2 通过一种涉及抗炎性 HO-1 诱导和抑制 NF-κB 和 STAT1/3 激活的机制发挥作用，与 PPAR-γ 以及 JNK 和 p38 无关。CORM-2 可能作为治疗牙周病的宿主反应调节因子有一定前景，但需要进一步研究来验证其治疗效果。
