The anti-inflammatory regulation of ATP-induced interleukin-1β release by short-chain fatty acids acetate, butyrate, propionate

Abstract

Interleukin-1β (IL-1β) is a pro-inflammatory cytokine, that is mainly secreted by activated monocytes and macrophages. When IL-1β is released, numerous effects are seen, such as the release of cytokines and chemokines which additionally stimulate the bone marrow. A dysregulation of the IL-1β secretion can lead to systemic diseases. Therefore, the release of IL-1β needs to be strictly regulated. The first stimulus by a pathogen-associated molecular pattern (PAMP) such as lipopolysaccharide (LPS), results in the production of the precursor protein pro-interleukin-1β (pro-IL-1β) and the proteins that form the NLRP3-inflammasome. The P2X7 receptor is activated via the second stimulus being for example ATP from damaged cells, which leads to the assembly of the NLRP3-inflammasome and consecutive release of mature IL-1β. In this thesis, experiments were performed on human peripheral blood mononuclear cells (hPBMCs), mouse peripheral blood mononuclear cells (mPBMCs) and mouse bone marrow-derived macrophages (mouse BMDMs). BzATP acted as a potent second signal in hPBMCs, however, contrary to published literature, ATP has seen to be a more potent P2X7 agonist in mPBMCs and mouse BMDMs. Furthermore, not only the P2X7 receptor but also the P2X4 receptor was shown to play a role in the BzATP- or ATP-dependent release of IL-1β in hPBMCs and mouse BMDMs. Recent studies show, that the release of ATP-induced IL-1β can be inhibited via a cholinergic mechanism. In this present work, the cholinergic mechanism is seen to be induced by synthetic FFA agonists and the natural FFA agonists being short-chain fatty acids (SCFAs), in all cells tested. Specifically, the FFA2 has shown to be necessary for the inhibition of the secretion of ATP-dependent IL-1β. This was seen by performing experiments on FFA2 gene-deficient mPBMCs. The exact signal transduction of the anti-inflammatory role shown by SCFAs is in need of further research. Additionally, there is a high potential seen in SCFAs as a therapeutic approach against inflammatory diseases. Therefore, further research in this field is of importance.