Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA 30303, USA.
Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA.
Int J Mol Sci. 2018 Nov 8;19(11):3511. doi: 10.3390/ijms19113511.
Phosphodiesterase 4B (PDE4B) plays an important role in inflammation. Recently we have reported that roflumilast as a PDE4-selective inhibitor, synergizes with nontypeable (NTHi) to up-regulate PDE4B expression in vitro and in vivo. Clinical evidence and our previous results suggest that synergistic induction of PDE4B could be counterproductive for suppressing inflammation or may contribute to tolerance to roflumilast. We thus investigated if dexamethasone inhibits the synergistic induction of PDE4B by roflumilast and NTHi as well as inflammation. Here, dexamethasone markedly suppressed the synergistic induction of PDE4B in human lung epithelial cells and in vivo. We also found that dexamethasone further suppressed NTHi-induced inflammatory response in vitro and in vivo. Moreover, Compound A, as a dissociating non-steroidal glucocorticoid receptor (GR) ligand, inhibited the synergistic induction of PDE4B, thereby suggesting the requirement of dexamethasone-mediated GR activation in the suppression of PDE4B expression. Taken together, our data suggest that dexamethasone may help attenuate inflammation and tolerance through suppressing the PDE4B expression in chronic obstructive pulmonary disease (COPD) patients using roflumilast.
磷酸二酯酶 4B（PDE4B）在炎症中发挥重要作用。最近，我们报道罗氟司特作为一种 PDE4 选择性抑制剂，与非典型性（NTHi）协同作用，在体外和体内上调 PDE4B 的表达。临床证据和我们之前的结果表明，PDE4B 的协同诱导可能不利于抑制炎症，或者可能导致对罗氟司特的耐受。因此，我们研究了地塞米松是否抑制罗氟司特和 NTHi 协同诱导的 PDE4B 以及炎症。在这里，地塞米松显著抑制了人肺上皮细胞和体内的 PDE4B 协同诱导。我们还发现，地塞米松进一步抑制了 NTHi 在体外和体内诱导的炎症反应。此外，作为一种分离的非甾体糖皮质激素受体（GR）配体的化合物 A 抑制了 PDE4B 的协同诱导，这表明地塞米松介导的 GR 激活在抑制 PDE4B 表达中是必需的。综上所述，我们的数据表明，地塞米松可能通过抑制慢性阻塞性肺疾病（COPD）患者中罗氟司特的 PDE4B 表达，有助于减轻炎症和耐受。
