Fungal Metabolite Terrein Suppresses IL-6/sIL-6R-Induced CSF1 Secretion in Gingival Fibroblasts

Objectives: It is important to regulate inflammatory responses caused by bacterial infection for periodontal therapy. In order to reduce inflammation, it has been of interests to utilize natural products, such as lipid mediators and biological metabolites, "Terrein" was isolated from Aspergillus terreus as a secondary bioactive fungal metabolite; one of the functions is anti-inflammatory effects. We have already reported that synthetic (+)-terrein suppresses IL-6 signaling cascade, especially STAT3 / ERK1/2, and secretion of vascular endothelial growth factor (VEGF) in gingival fibroblasts (GFs). However, precise function of (+)-terrein is still unknown. In this study, we examined the target molecule of (+)-terrein and the effect on IL-6-induced protein secretion in GFs.
Methods: Primary culture of GFs was used (institutional review board approval #661, and signed informed consent were obtained from donors). Synthetic (+)-terrein was used as described previously. GFs were pre-treated with (+)-terrein (10 µM) for 30 min, then stimulated with IL-6/sIL-6R (50 ng/ml each) for 12 h. Accumulation of mRNA was analyzed using PCR Array (84 genes, Growth Factors, Qiagen). Results were confirmed by real-time PCR using the same RNA sample and by ELISA using supernatant after 24 h culture. Phosphorylation of IL-6-cascade molecules (Akt, SHP2, and JAK1) was analyzed by Western blotting.
Results: Synthetic (+)-terrein suppressed IL-6/sIL-6R-induced mRNA accumulations and protein secretion of colony stimulating factor-1 (CSF1) in addition to VEGF. Furthermore, (+)-terrein suppressed IL-6/sIL-6R-induced protein phosphorylation of Akt, SHP2 and JAK1.
Conclusions: JAK1 controls the signaling of many cytokines including IL-6 with transactivating and phosphorylating the latter’s cytoplasmic domain by binding to a cytokine receptor such as gp130. Our results suggested that (+)-terrein has a potential to regulate JAK1 and to induce the resolution of inflammation by suppressing IL-6/sIL-6R-induced secretion of CSF1 and VEGF.
This study was supported by JSPS KAKENHI Grant-in-Aid for Scientific Research (C) (220549860).