Aspirin inhibits in vitro maturation and in vivo immunostimulatory function of murine myeloid dendritic cells

Citation
H. Hackstein et al., Aspirin inhibits in vitro maturation and in vivo immunostimulatory function of murine myeloid dendritic cells, J IMMUNOL, 166(12), 2001, pp. 7053-7062
Citations number
54
Categorie Soggetti
Immunology
Journal title
JOURNAL OF IMMUNOLOGY
ISSN journal
00221767 → ACNP
Volume
166
Issue
12
Year of publication
2001
Pages
7053 - 7062
Database
ISI
SICI code
0022-1767(20010615)166:12<7053:AIIVMA>2.0.ZU;2-M
Abstract
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 (DQ. CD Ile and MHC class I e xpression were unaffected. The inhibitory action was dose dependent and was evident at concentrations higher than those necessary to inhibit PG synthe sis. 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-kappaB DNA-binding activity, w hereas Ab supershift analysis indicated that aspirin targeted primarily NF- ICB p50. Unexpectedly, aspirin promoted the generation of CD11c(+) DC, due to apparent suppression of granulocyte development. The morphological and u ltrastructural appearance of aspirin-treated cells was consistent with imma turity. Aspirin-treated DC were highly efficient at Ag capture, via both ma nnose 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 I L-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 trin itrobenzenesulfonic acid, revealed an inability to induce normal cell-media ted contact hypersensitivity, despite the ability of the cells to migrate t o 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.