TLR4/MYD88-dependent, LPS-induced synthesis of PGE(2) by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells
Contribuinte(s) |
UNIVERSIDADE DE SÃO PAULO |
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Data(s) |
20/10/2012
20/10/2012
2008
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Resumo |
Antigen-presenting cells (APCs) control T-cell responses by multiple mechanisms, including the expression of co-stimulatory molecules and the production of cytokines and other mediators that control T-cell proliferation, survival and differentiation. Here, we demonstrate that soluble factor(s) produced by Toll-like receptor (TLR)-activated APCs suppress activation-induced cell death (AICD). This effect was observed in non-stimulated APCs, but it was significantly increased after lipopolysaccharide (LPS) treatment. Using different KO mice, we found that the LPS-induced protective factor is dependent on TLR4/MyD88. We identified the protective factor as prostaglandin E-2(PGE(2)) and showed that both APC-derived supernatants and PGE(2) prevented CD95L upregulation in T cells in response to TCR/CD3 stimulation, thereby avoiding both AICD and activated T cell killing of target macrophages. The PGE(2) receptors, EP2 and EP4, appear to be involved since pharmacological stimulation of these receptors mimics the protective effect on T cells and their respective antagonists interfere with the protection induced by either APCs derived or synthetic PGE(2). Finally, the engagement of EP2 and EP4 synergistically activates protein kinase A (PKA) and exchange protein directly activated by cAMP pathways to prevent AICD. Taken together, these results indicate that APCs can regulate T-cell levels of CD95L by releasing PGE2 in response to LPS through a TLR4/MyD88-dependent pathway, with consequences for both T cell and their own survival. Ministry of Education (CAPES, Brazil) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) FAPESP Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Brazilian Research Council (CNPq-Brazil) |
Identificador |
CELL DEATH AND DIFFERENTIATION, v.15, n.12, p.1901-1909, 2008 1350-9047 http://producao.usp.br/handle/BDPI/28326 10.1038/cdd.2008.128 |
Idioma(s) |
eng |
Publicador |
NATURE PUBLISHING GROUP |
Relação |
Cell Death and Differentiation |
Direitos |
restrictedAccess Copyright NATURE PUBLISHING GROUP |
Palavras-Chave | #T lymphocyte #death receptor #apoptosis #prostaglandin E-2 #Toll-like receptor #AICD #ACTIVATION-INDUCED APOPTOSIS #ABL-MEDIATED RESISTANCE #NF-KAPPA-B #PROSTAGLANDIN E-2 #BCR-ABL #DIABETES-MELLITUS #ADAPTIVE IMMUNITY #IN-VIVO #DEATH #RECEPTOR #Biochemistry & Molecular Biology #Cell Biology |
Tipo |
article original article publishedVersion |