interleukin-8 and celastrol

Graves' disease is an autoimmune disease of the thyroid gland, which is characterized by hyperthyroidism, diffuse goiter and Graves' ophthalmopathy (GO). Although several therapeutic strategies for the treatment of GO have been developed, the effectiveness and the safety profile of these therapies remain to be fully elucidated. Therefore, examination of novel GO therapies remains an urgent requirement. Celastrol, a triterpenoid isolated from traditional Chinese medicine, is a promising drug for the treatment of various inflammatory and autoimmune diseases. CCK‑8 and apoptosis assays were performed to investigate cytotoxicity of celastrol and effect on apoptosis on orbital fibroblasts. Reverse transcription‑polymerase chain reaction, western blotting and ELISAs were performed to examine the effect of celastrol on interleukin (IL)‑1β‑induced inflammation in orbital fibroblasts from patients with GO. The results demonstrated that celastrol significantly attenuated the expression of IL‑6, IL‑8, cyclooxygenase (COX)‑2 and intercellular adhesion molecule‑1 (ICAM‑1), and inhibited IL‑1β‑induced increases in the expression of IL‑6, IL‑8, ICAM‑1 and COX‑2. The levels of prostaglandin E2 in orbital fibroblasts induced by IL‑1β were also suppressed by celastrol. Further investigation revealed that celastrol suppressed the IL‑1β‑induced inflammatory responses in orbital fibroblasts through inhibiting the activation of nuclear factor (NF)‑κB. Taken together, these results suggested that celastrol attenuated the IL‑1β‑induced pro‑inflammatory pathway in orbital fibroblasts from patients with GO, which was associated with the suppression of NF-κB activation.

Topics: Anti-Inflammatory Agents; Apoptosis; Cell Survival; Cyclooxygenase 2; Dinoprostone; Enzyme Activation; Female; Fibroblasts; Gene Expression; Graves Disease; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; NF-kappa B; Pentacyclic Triterpenes; Signal Transduction; Triterpenes

Pristimerin, a naturally occurring quinonemethide triterpenoid compound, is known to exert a variety of pharmacological activities. In the present study, we investigated the molecular actions of pristimerin against LPS-induced inflammatory responses in human monocytic THP-1 cells. The results showed that pristimerin inhibited the production of TNF-α and IL-8 in a dose-dependent manner. To explore the possible mechanisms underlying these inhibitions by pristimerin, we examined the intracellular ROS level and the NF-κB protein signaling pathway. Pristimerin clearly scavenged LPS-induced intracellular ROS production. In addition, pristimerin prevented LPS-induced NF-κB activation through the inhibition of phosphorylation of IKKα/β, phosphorylation and degradation of IκBα, as well as phosphorylation and nuclear translocation of NF-κB p65. These findings suggest that pristimerin down-regulates the expression of pro-inflammatory mediators through blocking of NF-κB activation by inhibiting interconnected ROS/IKK/NF-κB signaling pathways.

Topics: Antineoplastic Agents; Cells, Cultured; Down-Regulation; Humans; I-kappa B Kinase; I-kappa B Proteins; Inflammation; Interleukin-8; Lipopolysaccharides; NF-kappa B; NF-KappaB Inhibitor alpha; Pentacyclic Triterpenes; Phosphorylation; Reactive Oxygen Species; Signal Transduction; Transcription Factor RelA; Triterpenes; Tumor Necrosis Factor-alpha