Cyclooxygenase‐independent inhibition of dendritic cell maturation by aspirin

Matasić, Richard; Dietz, Allan B.; Vuk‐Pavlović, Stanimir

doi:10.1046/j.1365-2567.2000.00065.x

Cited by 73 publications

(59 citation statements)

References 43 publications

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“…It has been reported that aspirin inhibits bioactive IL-12 production by macrophages (17) and IL-12p40 secretion by monocyte-derived DC (28). Our results confirm the inhibitory effect of aspirin on IL-12p40 expression.…”

Section: Figuresupporting

confidence: 90%

“…It is also the first study in which DC exposed to aspirin have been tested for homing ability and capacity to sensitize recipients for cell-mediated immune responses. While we were completing this report, Matasic et al (28) observed that aspirin inhibited the maturation of human monocyte-derived DC. There are several differences between this latter study and the present report.…”

Section: Discussionmentioning

confidence: 66%

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Aspirin Inhibits In Vitro Maturation and In Vivo Immunostimulatory Function of Murine Myeloid Dendritic Cells

Hackstein

Morelli

Larregina

et al. 2001

The Journal of Immunology

172

129

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Aspirin is the most commonly used analgesic and antiinflammatory agent. In this study, at physiological concentrations, it profoundly inhibited CD40, CD80, CD86, and MHC class II expression on murine, GM-CSF + IL-4 stimulated, bone marrow-derived myeloid dendritic cells (DC). CD11c and MHC class I expression were unaffected. The inhibitory action was dose dependent and was evident at concentrations higher than those necessary to inhibit PG synthesis. Experiments with indomethacin revealed that the effects of aspirin on DC maturation were cyclooxygenase independent. Nuclear extracts of purified, aspirin-treated DC revealed a decreased NF-κB DNA-binding activity, whereas Ab supershift analysis indicated that aspirin targeted primarily NF-κB p50. Unexpectedly, aspirin promoted the generation of CD11c+ DC, due to apparent suppression of granulocyte development. The morphological and ultrastructural appearance of aspirin-treated cells was consistent with immaturity. Aspirin-treated DC were highly efficient at Ag capture, via both mannose receptor-mediated endocytosis and macropinocytosis. By contrast, they were poor stimulators of naive allogeneic T cell proliferation and induced lower levels of IL-2 in responding T cells. They also exhibited impaired IL-12 expression and did not produce IL-10 after LPS stimulation. Assessment of the in vivo function of aspirin-treated DC, pulsed with the hapten trinitrobenzenesulfonic acid, revealed an inability to induce normal cell-mediated contact hypersensitivity, despite the ability of the cells to migrate to T cell areas of draining lymphoid tissue. These data provide new insight into the immunopharmacology of aspirin and suggest a novel approach to the manipulation of DC for therapeutic application.

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Section: Figuresupporting

confidence: 90%

Section: Discussionmentioning

confidence: 66%

Aspirin Inhibits In Vitro Maturation and In Vivo Immunostimulatory Function of Murine Myeloid Dendritic Cells

Hackstein

Morelli

Larregina

et al. 2001

The Journal of Immunology

172

129

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“…20 We measured p40 in the supernatants of the cells described in Figure 1 and found that the levels of this molecule closely followed the levels of CD83 with a 1-day lag ( Figure 2). The lag might reflect the differences in regulation of gene expression and/or in the post-translational processing inherent in secretion.…”

mentioning

confidence: 84%

Maturation of dendritic cells infected by recombinant adenovirus can be delayed without impact on transgene expression

Dietz

Bulur

et al. 2001

Gene Ther

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Adenovirus-mediated gene transfer to dendritic cells is highly efficient and often used, but the relationship among cell maturation, viral infection and expression of a transferred gene remains unclear. To study this relationship, we introduced a recombinant replication-defective adenovirus encoding the gene for green fluorescent protein to normal human immature myeloid dendritic cells. We induced maturation by the addition of TNF-␣, IL-1␤, IL-6 and prostaglandin E 2 to the medium and assessed cell maturity by the levels of the secreted p40 subunit of IL-12 and of membrane-bound CD83. We quantified the efficiency of gene expression by GFP fluorescence and analyzed the data by a mixed-model analysis of variance; the model explained more than 97% of the effects. CD83 expression and p40 secretion depended solely on incubation time and maturation medium. The cells

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“…LPS can also increase PLA 2 phosphorylation and AA release (31). To study the respective role of each isoform of COX in PGE 2 production and APC functions, we used drugs, such as indomethacin, a COX-1 preference inhibitor (32,33); SC-560, a COX-1-selective inhibitor (34); and NS-398, a COX-2-selective inhibitor (35,36).…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

Cyclooxygenase-2-Issued Prostaglandin E2 Enhances the Production of Endogenous IL-10, Which Down-Regulates Dendritic Cell Functions

Harizi

Juzan

Pitard

et al. 2002

The Journal of Immunology

351

287

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PGE2 is a well-known immunomodulator produced in the immune response by APCs, such as dendritic cells (DCs), the most potent APC of the immune system. We investigated the PGE2 biosynthetic capacity of bone marrow-derived DC (BM-DC) and the effects of PG on the APC. We observed that BM-DC produce PGE2 and other proinflammatory mediators, such as leukotriene B4 and NO, after LPS exposure. Constitutively present in BM-DC, cyclooxygenase (COX)-1 did not contribute significantly to the total pool of PGE2 compared with the LPS-induced COX-2-produced PGE2. Treatment of BM-DC with exogenous PGE2 induced the production of large amounts of IL-10 and less IL-12p70. In addition, selective inhibition of COX-2, but not COX-1, was followed by significant decrements in PGE2 and IL-10, a concomitant restoration of IL-12 production, and an enhancement of DC stimulatory potential. In contrast, we found no demonstrable role for leukotriene B4 or NO. In view of the potential of PGE2 to stimulate IL-10, we examined the possibility that the suppressive effect of PGE2 is mediated via IL-10. We found that exogenous IL-10 inhibits IL-12p70 production in the presence of NS-398, a COX-2 selective inhibitor, while the inhibitory effects of PGE2 were totally reversed by anti-IL-10. We conclude that COX-2-mediated PGE2 up-regulates IL-10, which down-regulates IL-12 production and the APC function of BM-DC.

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Cyclooxygenase‐independent inhibition of dendritic cell maturation by aspirin

Cited by 73 publications

References 43 publications

Aspirin Inhibits In Vitro Maturation and In Vivo Immunostimulatory Function of Murine Myeloid Dendritic Cells

Aspirin Inhibits In Vitro Maturation and In Vivo Immunostimulatory Function of Murine Myeloid Dendritic Cells

Maturation of dendritic cells infected by recombinant adenovirus can be delayed without impact on transgene expression

Cyclooxygenase-2-Issued Prostaglandin E2 Enhances the Production of Endogenous IL-10, Which Down-Regulates Dendritic Cell Functions

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