Anti-inflammatory drimane sesquiterpene lactones from an Aspergillus species.
IFN-γ inducible protein 10 (IP-10, CXCL10) is a 10 kDa chemokine, which is secreted from various cell types after exposure to pro-inflammatory stimuli. This chemokine is a ligand for the CXCR3 receptor and regulates immune responses by activating and recruiting leukocytes such as T cells, eosinophils, monocytes, and NK cells to sites of inflammation. Altered expression of CXCL10 has been associated with chronic inflammatory and infectious diseases and therefore CXCL10 represents a promising target for the development of new anti-inflammatory drugs. In a search for inhibitors of CXCL10 promoter activity, three structurally related drimane sesquiterpene lactones (compounds 1-3) were isolated from fermentations of an Aspergillus species. Compounds 1 and 2 inhibited the IFN-γ/TNF-α/IL-1β induced CXCL10 promoter activity in transiently transfected human DLD-1 colon carcinoma cells in a dose-dependent manner with IC50 values of 12.4 μM for 1 and 55 μM for 2, whereas 3 was devoid of any biological activity. Moreover, compounds 1 and 2 reduced CXCL10 mRNA levels and synthesis in IFN-γ/TNF-α/IL-1β stimulated DLD-1 cells.
['Felix|Silke|S|', 'Sandjo|Louis P|LP|', 'Opatz|Till|T|', 'Erkel|Gerhard|G|']
D000894:Anti-Inflammatory Agents, Non-Steroidal D000970:Antineoplastic Agents D001230:Aspergillus D049109:Cell Proliferation D002470:Cell Survival D054357:Chemokine CXCL10 D004305:Dose-Response Relationship, Drug D004354:Drug Screening Assays, Antitumor D006801:Humans D007783:Lactones D000081223:Polycyclic Sesquiterpenes D012333:RNA, Messenger D012717:Sesquiterpenes D013329:Structure-Activity Relationship D014407:Tumor Cells, Cultured
CXCL10 Inflammation Inhibitor Fungal metabolites