Carcinogenesis Advance Access published online on February 4, 2004
Carcinogenesis, doi:10.1093/carcin/bgh103
© 2004 by Oxford University Press
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CARCINOGENESIS
1 Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l'Université Laval
* Corresponding author. E-mail: elyse.bissonnette{at}med.ulaval.ca.
Received 28 July 2003
; revised 20 January 2004
; accepted 26 January 2004
NNK, a nicotine derived nitrosamine, is a potent lung carcinogen that generates electrophilic intermediates capable of damaging DNA. The effects of NNK on the immune response, which may facilitate lung carcinogenesis, are poorly understood. Alveolar macrophages (AM), a key cell in the maintenance of lung homeostasis, metabolize NNK via two major metabolic activation pathways:
Cytokine production by alveolar macrophages is down regulated by the
-methylhydroxylation pathway of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)
2 Faculté de Pharmacie, Université Laval
-methylhydroxylation and -methylenehydroxylation. We have previously shown that NNK inhibits the production of interleukin-12 (IL-12) and tumor necrosis factor (TNF), but stimulates the production of IL-10 and prostaglandin E2 (PGE2) by AM. In the present study, we investigated the contribution of each activation pathway in the modulation of AM function. We used two precursors, 4-[(acetoxymethyl)-nitrosamino]-1-(3-pyridyl)-1-butanone (NNKOAc) and N-nitro(acetoxymethyl)methylamine (NDMAOAc), which generate the reactive electrophilic intermediates (4-(3-pyridyl)-4-oxo-butanediazohydroxyde and methanediazohydroxyde, respectively) in high yield and exclusively. Rat AM cell line, NR8383, was stimulated and treated with different concentrations of NNKOAc or NDMAOAc (12, 25, and 50 µM). Mediator release was measured in cell-free supernatants. NNKOAc significantly inhibited the production of IL-10, IL-12, TNF, and NO but increased the release of PGE2 and COX-2 expression suggesting that the -methylhydroxylation pathway might be responsible for NNK modulation of AM cytokine release. In contrast, NDMAOAc did not modulate AM mediator production. However, none of these precursors, alone or in combination, could explain the stimulation of AM IL-10 production by NNK. Our results suggest that the methylhydroxylation of NNK leading to DNA pyridyloxobutylation also modulates cytokine production in NNK-treated AM.
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