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Mechanism by which prostaglandin E2 from Eferocytosis inhibits IL-1R expression and Th17 differentiation

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Author(s):
Allan Botinhon Orlando
Total Authors: 1
Document type: Master's Dissertation
Press: Araraquara. 2018-06-25.
Institution: Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara
Defense date:
Advisor: Alexandra Ivo de Medeiros
Abstract

The expression of inflammatory reactions is characterized by phagocytosis of dead cells, a process called eferocytosis. As a consequence of this process, there is the production of anti-inflammatory mediators, transforming growth factor (TGF-β), prostaglandin E2 (PGE2) and an interleukin-10 (IL-10). However, it is now known that phagocytosis of infected apoptotic cells is one of the responsible for the production of interleukin-6 (IL-6), interleukin-23 (IL-23) and TGF-β lung mediators. The results obtained by our group demonstrate that the phagocytosis of infected apoptotic cells (iCA) with Escherichia coli by dendritic cells promotes, in addition to the production of TGF-β, interleukin-1β (IL-1β) and IL-6, high levels of PGE2. In addition, PGE2, via the prostaglandin E2 receptor (EP4), inhibits differentiation of Th17 lymphocytes by modulating IL-1 receptor (IL-1R) expression in Th lymphocytes. Thus, the objective of this work is to elucidate the mechanism by which PGE2, derived from the ectocytosis of infected apoptotic cells, inhibits the expression of IL-1R and differentiation of Th17 lymphocytes. The results obtained demonstrate that PGE2, via the EP4 receptor, induces the activation of adenylate cyclase / PKA / EPAC, and that this signaling pathway promotes in addition to the inhibition of IL-1R, the inhibition of an important transcription factor involved in the differentiation of Th17 lymphocytes, the STAT3. PGE2 is known to exert its suppressor functions in the differentiation of Th17 cells by the activation of SOCS, as well as to promote the activation of PI3K. However, despite the presence of PGE2 enhancing socs1 expression, inhibition of STAT3 phosphorylation does not appear to be mediated by SOCS1, so little PI3K is involved in inhibiting Th17 cell differentiation. The set of results suggests that the inhibition in differentiation of Th17 lymphocytes by PGE2 during the eferocytosis of infected cells occurs through the activation of the EP4 / adenylate cyclase / PKA / EPAC axis, which results in the direct or indirect inhibition of STAT3 forforylation. (AU)

FAPESP's process: 16/10964-5 - Mechanism by which PGE2 originated from efferocytosis inhibits the expression of Il-1R and Th17 differentiation - Involvement of SOCS3
Grantee:Allan Botinhon Orlando
Support type: Scholarships in Brazil - Master