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CD83-stimulated monocytes suppress T-cell immune responses through production of prostaglandin E2.

ABSTRACT: CD83 is commonly known as a specific marker for mature dendritic cells. It has been shown to be important for CD4(+) T-cell development in the thymus. However, its function in the peripheral immune system remains enigmatic. Here, we show that CD83 inhibits proliferation and production of IL-2 and IFN-? by T cells, and the inhibitory effect of CD83 is mediated by monocytes. Prostaglandin E2 (PGE(2)), but not IL-10 or TGF-?, was up-regulated specifically by CD83 in monocytes. Consistent with high levels of PGE(2), expression of COX-2 also was increased upon CD83 treatment. NF-?B activation also is required for induction of PGE(2) by CD83. Finally, application of the COX-2-selective inhibitor NS-398 fully prevented CD83-triggered inhibition of T-cell responses. Our study establishes an immune-regulatory mechanism by CD83 via stimulation of PGE(2) production in monocytes.

SUBMITTER: Chen L

PROVIDER: S-EPMC3219128 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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CD83-stimulated monocytes suppress T-cell immune responses through production of prostaglandin E2.

Chen Liwen L Zhu Yibei Y Zhang Guangbo G Gao Chao C Zhong Weixue W Zhang Xueguang X

Proceedings of the National Academy of Sciences of the United States of America 20111107 46

CD83 is commonly known as a specific marker for mature dendritic cells. It has been shown to be important for CD4(+) T-cell development in the thymus. However, its function in the peripheral immune system remains enigmatic. Here, we show that CD83 inhibits proliferation and production of IL-2 and IFN-γ by T cells, and the inhibitory effect of CD83 is mediated by monocytes. Prostaglandin E2 (PGE(2)), but not IL-10 or TGF-β, was up-regulated specifically by CD83 in monocytes. Consistent with high ...[more]

PMID: 22065790

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Project description:Rationale: Cationic nanocarriers present with well-known toxicities, including inflammatory toxicity, which limit their clinical application. How the cationic nanocarrier-induced inflammatory response is negatively regulated is unknown. Herein, we found that following a sublethal dose of cationic nanocarriers, the induced inflammatory response is characterized by early neutrophil infiltration and spontaneous resolution within 1 week. Methods: C57BL/6 mice were intravenously injected with a dosage of 1-100 mg/kg cationic DOTAP liposomes as well as other cationic materials. Cell necrosis was detected by flow cytometry. Release of mitochondrial DNA was quantified by qPCR via Taqman probes. Signal proteins were detected by Western blotting. PGE2 production in the supernatant was quantitated using an enzyme immunoassay (EIA). The infiltrated inflammatory cells were observed in WT mice, Ccr2-/- mice, Sting-/- mice and Tlr9-/- mice. Results: The early stage (24-48 h) inflammatory neutrophil infiltration was followed by an increasing percentage of monocytes; and, compared with WT mice, Ccr2-/- mice presented with more severe pulmonary inflammation. A previously uncharacterized population of regulatory monocytes expressing both inflammatory and immunosuppressive cytokines was identified in this model. The alteration in monocyte phenotype was directly induced by mtDNA release from cationic nanocarrier-induced necrotic cells via a STING- or TLR9-dependent pathway. Neutrophil activation was specifically inhibited by PGE2 from Ly6C+ inflammatory monocytes, and intravenous injections of dual-phenotype monocytes beneficially modified the immune response; this inhibitory effect was abolished after treatment with indomethacin. Moreover, we provide clear evidence that mitochondrial DNA activated Ly6C+ monocytes and increased PGE2 production through TLR9- or STING-mediated MAPK-NF-?B-COX2 pathways. Conclusion: Our findings suggest that Ly6C+ monocytes and mtDNA-induced Ly6C+ monocyte PGE2 production may be part of a feedback mechanism that contributes to the resolution of cationic nanocarrier-induced inflammatory toxicity and may have important implications for understanding nanoparticle biocompatibility and designing better, safer drug delivery systems.

Dataset Information

CD83-stimulated monocytes suppress T-cell immune responses through production of prostaglandin E2.

Publications

CD83-stimulated monocytes suppress T-cell immune responses through production of prostaglandin E2.

Similar Datasets

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