TLR4/MYD88-dependent, LPS-induced synthesis of PGE2 by macrophages or dendritic cells prevents anti-CD3-mediated CD95L upregulation in T cells.

Weinlich R, Bortoluci KR, Chehab CF, Serezani CH, Ulbrich AG, Peters-Golden M, Russo M, Amarante-Mendes GP
Cell Death Differ. 2008 15 (12): 1901-9

PMID: 18820644 · DOI:10.1038/cdd.2008.128

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 PGE(2) in response to LPS through a TLR4/MyD88-dependent pathway, with consequences for both T cell and their own survival.

MeSH Terms (22)

Animals CD3 Complex Cell Death Cyclic AMP-Dependent Protein Kinases Cytoprotection Dendritic Cells Dinoprostone Fas Ligand Protein Guanine Nucleotide Exchange Factors Lipopolysaccharides Macrophage Activation Macrophages Mice Myeloid Differentiation Factor 88 Receptors, Prostaglandin E Receptors, Prostaglandin E, EP2 Subtype Receptors, Prostaglandin E, EP4 Subtype Signal Transduction Subcellular Fractions T-Lymphocytes Toll-Like Receptor 4 Up-Regulation

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