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
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.