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Alveolar macrophage cytotoxic activity is inhibited by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a carcinogenic component of cigarette smoke

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Abstract

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a carcinogenic compound of cigarette smoke that generates electrophilic intermediates capable of damaging DNA. Recently, we have shown that NNK can modulate mediator production by alveolar macrophages (AM) and bronchial and alveolar epithelial cells, suggesting that cigarette smoke can alter lung immune response. Thus, we investigated the effect of NNK and cigarette smoke extract (CSE) on AM capacity to eliminate tumoral cells. Rat AM cell line, NR8383, was treated with NNK (500 μM) or CSE (3%) and stimulated with lipopolysaccharide (10 ng/ml). The release of cytotoxic mediators, tumor necrosis factor (TNF) and reactive oxygen species (ROS), was measured in cell-free supernatants using ELISA and superoxide anion production. TNF- and ROS-dependent cytotoxicity were studied using a 51Chromium-release assay and WEHI-164 and P-815 cell lines. Treatment of AM with NNK and CSE for 18 h significantly inhibited AM TNF release. CSE exposure resulted in a significant increase of ROS production, whereas NNK did not. TNF-dependent cytotoxic activity of NR8383 and freshly isolated rat AM was significantly inhibited after treatment with NNK and CSE. Interestingly, although ROS production was stimulated by CSE and not affected by NNK, CSE inhibited AM ROS-dependent cytotoxicity. These results suggest that NNK may be one of the cigarette smoke components responsible for the reduction of pulmonary cytotoxicity. Thus, NNK may have a double pro-carcinogenic effect by contributing to DNA adduct formation and inhibiting AM cytotoxicity against tumoral cells.

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Abbreviations

AM:

Alveolar macrophage

COPD:

Chronic obstructive pulmonary disease

CSE:

Cigarette smoke extract

COX:

Cyclooxygenase

FBS:

Fetal bovine serum

IL:

Interleukin

LPS:

Lipopolysaccharide

NNK:

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone

NO:

Nitric oxide

Pen-Strep:

Penicillin–Streptomycin

PGE2 :

Prostaglandin E2

ROS:

Reactive oxygen species

TNF:

Tumor necrosis factor

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Acknowledgment

The authors thank Dr. Yvon Cormier and Dr. Paul H. Naccache for critical review of the manuscript. This study was supported by the Canadian Institutes of Health Research. L.I.P. has a studentship from FRSQ.

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Authors and Affiliations

  1. Centre de Recherche, Hôpital Laval, Institut Universitaire de Cardiologie et de Pneumologie de l’Université Laval, 2725 Chemin Ste-Foy, G1V 4G5, Quebec, QC, Canada

    Léa-Isabelle Proulx & Elyse Y. Bissonnette

  2. Centre de recherche en Immunologie et Rhumatologie du CHUL, Quebec, QC, Canada

    Guillaume Paré

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  1. Léa-Isabelle Proulx
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  2. Guillaume Paré
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  3. Elyse Y. Bissonnette
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Correspondence to Elyse Y. Bissonnette.

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Proulx, LI., Paré, G. & Bissonnette, E.Y. Alveolar macrophage cytotoxic activity is inhibited by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a carcinogenic component of cigarette smoke. Cancer Immunol Immunother 56, 831–838 (2007). https://doi.org/10.1007/s00262-006-0243-6

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