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Mechanism by which PGE2 originated from efferocytosis inhibits the expression of Il-1R and Th17 differentiation - Involvement of SOCS3

Grant number: 16/10964-5
Support type:Scholarships in Brazil - Master
Effective date (Start): September 01, 2016
Effective date (End): February 28, 2018
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 efferocytosis (phagocytosis of apoptotic cells) promotes the synthesis of anti-inflammatory mediators, such as transforming growth factor (TGF ²), prostaglandin E2 (PGE2) and interleukin-10 (IL-10), important for differentiation of regulatory T cells (Treg). However, the phagocytosis of infected apoptotic cells directs the synthesis of anti and pro-inflammatory cytokines such as TGF², IL-6 and IL-23 known to promote the induction of T helper 17 (Th17). Results obtained recently by our group showed that the phagocytosis of infected apoptotic cells with Escherichia coli by dendritic cells promotes in addition of TGF², IL-6 and IL-1², the synthesis of high levels of PGE2. Furthermore, we found that PGE2 through EP4 receptor inhibits the differentiation of Th17 lymphocytes by modulating the expression of IL-1 receptor expression by Th lymphocytes.However, the mechanism by which PGE2 via EP4 inhibits IL-1R expression in lymphocytes Th17 remains unknown. Studies suggest that activation of STAT 3 (Signal transducer and activator of transcription-3) by the IL-6 signaling is one of the major pathways involved in the expression of IL-1R and differentiation of Th17. Moreover, it has been demonstrated that PGE2 in monocytes increases the expression and activity of the STAT3 inhibitors, SOCS3 (Suppressor of cytokine signaling 3), and decreases the expression of IRF4 (Interferon Regulatory Factor 4) an important transcription factor in the differentiation of Th17. Therefore the hypothesis of this project is that PGE2 via EP4, induces expression of SOCS3, which prevents the activation of STAT3, affecting the expression of IL-1 receptor, as well as transcription factors involved in the differentiation of Th17 as IRF4 and ROR³t.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
DEJANI, NAIARA NAIANA; ORLANDO, ALLAN BOTINHON; NINO, VICTORIA EUGENIA; PENTEADO, LETICIA DE AQUINO; VERDAN, FELIPE FORTINO; RIBEIRO BAZZANO, JULIA MIRANDA; CODO, ANA CAMPOS; GUERTA SALINA, ANA CAROLINA; SARAIVA, AMANDA CORREIA; AVELAR, MATHEUS ROSSI; SPOLIDORIO, LUIS CARLOS; SEREZANI, C. HENRIQUE; MEDEIROS, ALEXANDRA IVO. Intestinal host defense outcome is dictated by PGE(2) production during efferocytosis of infected cells. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 115, n. 36, p. E8469-E8478, SEP 4 2018. Web of Science Citations: 3.
PENTEADO, LETICIA DE AQUINO; DEJANI, NAIARA NAIANA; VERDAN, FELIPE FORTINO; ORLANDO, ALLAN BOTINHON; NINO, VICTORIA EUGENIA; DIAS, FERNANDA DE NUZZI; GUERTA SALINA, ANA CAROLINA; MEDEIROS, ALEXANDRA IVO. Distinctive role of efferocytosis in dendritic cell maturation and migration in sterile or infectious conditions. IMMUNOLOGY, v. 151, n. 3, p. 304-313, JUL 2017. Web of Science Citations: 5.
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
ORLANDO, Allan Botinhon. Mecanismo pelo qual Prostaglandina E2 oriunda da eferocitose inibe a expressão do IL-1R e a diferenciação de Th17. 2018. 109 f. Master's Dissertation - Universidade Estadual Paulista "Júlio de Mesquita Filho" Faculdade de Ciências Farmacêuticas..

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