Studies On Interleukin-6 Receptor Antagonists From Microbial Metabolites

Interleukin 6 (IL-6) is a kind of important cytokine. The research discovered that IL-6 displays a broad range biological activities on many kinds of cells, such as lymphocytes, hematopoietic stem cells, liver cells, tumor cells and neuronal cells, Additionally, IL-6 participate in many pathology processes of disease like inflammation, rheumatoid arthritis, tumor, Castleman's disease and autoimmune diseases. Especially, it is reported that the level of IL-6 is very high in the cell of myeloma. IL-6 plays its role on target cells through a double-stranded receptor complex consisting of IL-6R and a signal transduction subunit (gp130). IL-6R is one of transmembrane glycoprotein which has two types of natural receptors: gp130 binding with membrane and soluble IL-6R. Both of them play essential role during the process of IL-6 signal transduction.With the recombinant IL-6R as target, an ELISA assay for screening antagonists of IL-6R was developed by us. And three fungi strains named 2572, 2421 and 713 respectively were found to exhibit activity in this assay. Using several chromatography methods, three compounds, 2572A, 2421A and 713A were separated and purified from the cultured broth of Fungi 2572, 2421 and 713 respectively. The molecular formular and structure of them were elucidated by UV, IR, MS, ¹HNMR, ¹³C-NMR, DEPT, ¹H-¹H COSY, HMQC, HMBC spectra. 2572A and 2421A were identified as 6-epi-5'-hydroxymycosporulone and riboflavin respectively. 713A was a new compound. Three compounds were screened for their IL-6 antagonist effects. 2572A and 713A showed good activity, 2421A exhibited weak IL-6R antagonist (IL-6Ra) activity. But they all didn't show notable inhibition to HCT-8, Bel-7402 and BGC823 tumor strains. Though 2572A and 2421A were known compounds, it was the first research report about their IL-6Ra activities.