TNF ALFA PRODUCTION · Mechanism of anti-inflammatory activity of a phospholipid-like drug

Final Activity Report Summary - TNF ALFA PRODUCTION (Mechanism of anti-inflammatory activity of a phospholipid-like drug)

Tumour necrosis factor (TNF) is a key pro-inflammatory factor that is produced and released by immune cells in response to an infectious organism. Unregulated release of TNF may lead to chronic inflammation in the form of an auto-immune disease, such as rheumatoid arthritis and Crohn disease. TNF is also shown to be involved in the development of other disease states such as sepsis, multiple sclerosis, atherosclerosis, ischemic stroke, inflammation-linked cancer and diabetes. Some inflammatory diseases are successfully treated by TNF blockers, which are protein drugs and thus suffer from several major disadvantages. Attention in inflammation research has therefore focused on the development of small molecular weight inhibitors of TNF production. PCERA-1, a small synthetic compound, was previously found to suppress TNF blood level during inflammation through an unknown mechanism. We hypothesised that PCERA-1 suppressed TNF via a novel pathway. The objective of the proposed research was to elucidate that TNF modulating pathway. We found that the anti-inflammatory activity of PCERA-1 was mediated by a receptor which was highly expressed on the cell surface of a subset of immune cells, called macrophages. Signalling by PCERA-1 was then intra-cellularly transduced by the second messenger CAMP which modulated the activity of the transcription factor CREB. Additional intracellular signalling proteins which participated in PCERA-1 activity were also identified. We furthermore found that PCERA-1 induced the production of a key anti-inflammatory factor, IL-10, in these immune cells. IL-10 production was cooperatively induced by PCERA-1 and the inflammatory stimulus. Finally, we found that PCERA-1 blocked the production of PGE2, a key pro-inflammatory mediator, whose production was the target of most common non-steroidal anti-inflammatory drugs. Thus, by acting on several levels, PCERA-1 could be able to limit the amplitude of inflammation and have a significant effect on its resolution. The information which was obtained by the study deepened our understanding of the molecular mechanisms which regulated inflammation. We expected that further studies would provide us with insights into how to interfere with this process, in order to treat inflammatory auto-immune diseases as well as other inflammation-linked diseases using a novel therapeutic approach.

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