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Involvement of PGE2 in the modulation of IRF4 expression in Th17 cells

Grant number: 15/02657-2
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2015
Effective date (End): December 31, 2015
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Alexandra Ivo de Medeiros
Grantee:Allan Botinhon Orlando
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Associated research grant:11/17611-7 - Effect of efferocytosis by dendritic cells on Th17 differentiation: role of Prostaglandin E2, AP.JP

Abstract

The phagocytosis of infected apoptotic cells, that is, containing internalized PAMP, promotes the production of IL-23, TGF-² and IL-6 by dendritic cells (DC). The role of these soluble mediators in Th17 differentiation was demonstrated by the stimulation of naïve T cells with anti-CD3 and anti-CD28, in the presence of conditioned medium derived from DC incubated with infected apoptotic cells. However, recent data obtained by our group showed that the phagocytosis of apoptotic cells infected with Escherichia coli promotes, in addition to producing Th17 polarizing cytokines, the synthesis of high levels of prostaglandin E2 (PGE2). Our results suggest that different than originally expected, PGE2 appears to have an inhibitory effect on the differentiation of Th17 cells, since that in reduced levels of PGE2, the differentiation of Th17 cells was significantly increased. The involvement of (PGE2) during the process of activation and differentiation of Th1 cells, Treg and Th17 cells has been disclosed in recent years. Recent works in the literature describe both immunostimulatory effect by promoting the differentiation of Th17 cells and expansion, and suppressor by inducing the generation of Treg cells.The interferon regulatory factors (IRFs) are a family of transcription factors that have been described as a key role in T helper cell differentiation. The involvement of IRF4 in Th17 cells differentiation, mediated by IL-6 and TGF- ², was demonstrated in vitro using lymphocytes obtained from IRF4 - / - animals or silencing IRF4. Knowing that IRF4 is a transcription factor involved in the differentiation of Th17 cells and PGE2 is capable of down-regulating the expression and / or translocation of IRF4, the hypothesis is that PGE2, derived from phagocytosis of infected apoptotic cells by dendritic cells, would be able to inhibit the differentiation of "naive" T cells in Th17 by inhibiting IRF4.