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Tobacco Smoking Inhibits Expression of Proinflammatory Cytokines and Activation of IL-1R-Associated Kinase, p38, and NF-B in Alveolar Macrophages Stimulated with TLR2 and TLR4 Agonists¹

Haiyan Chen^*, Mark J. Cowan, Jeffrey D. Hasday, Stefanie N. Vogel^* and Andrei E. Medvedev^2,*

^* Department of Microbiology and Immunology and Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Maryland, Baltimore, Baltimore, MD 21201

Tobacco smoking has been associated with impaired pulmonary functions and increased incidence of infections; however, mechanisms that underlie these phenomena are poorly understood. In this study, we examined whether smokers’ alveolar macrophages (AM) exhibit impaired sensing of bacterial components via TLR2 and TLR4 and determined the effect of smoking on expression levels of TLR2, TLR4 and coreceptors, and activation of signaling intermediates. Smokers’ AMs exhibited reduced gene expression and secretion of proinflammatory cytokines (TNF-, IL-1, IL-6) and chemokines (RANTES and IL-8) upon stimulation with TLR2 and TLR4 agonists, S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-Lys4-OH trihydrochloride (Pam₃Cys), and LPS, whereas expression of anti-inflammatory cytokines (IL-10 and IL-1 receptor antagonist) was not affected. TLR3 activation with polyinosinic-polycytidylic acid led to comparable or even higher cytokine responses in smokers’ AMs, indicating that smoking-induced suppression does not affect all TLRs. Comparable expression of cytokines and chemokines was detected in PBMC and purified monocytes obtained from smokers and nonsmokers, demonstrating that the suppressive effect of smoking is restricted to the lung. TLR2/4-inducible IL-1R-associated kinase-1 (IRAK-1) and p38 phosphorylation and NF-B activation was suppressed in smokers’ AMs, whereas TLR2, TLR4, CD14, MD-2 mRNA levels, and TLR4 protein expression were not altered. These data suggest that changes in expression and/or activities of signaling intermediates at the postreceptor level account for smoking-induced immunosuppression. Thus, exposure of AMs to tobacco smoke induces a hyporesponsive state similar to endotoxin tolerance as manifested by inhibited TLR2/4-induced expression of proinflammatory cytokines, chemokines, and impaired activation of IRAK-1, p38, and NF-B, resulting in suppressed expression of proinflammatory mediators.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from Philip Morris USA and Philip Morris International (to A.E.M.), University of Maryland Other Tobacco Related Diseases/Maryland Restitution Fund grants (to A.E.M.), and National Institutes of Health Grants AI-059524 (to A.E.M.) and AI-44936 (to S.N.V.).

² Address correspondence and reprint requests to Dr. Andrei E. Medvedev, Department of Microbiology and Immunology, School of Medicine, University of Maryland, Baltimore, 660 West Redwood Street, Room 324, Baltimore, MD 21201. E-mail address: amedvedev{at}som.umaryland.edu

³ Abbreviations used in this paper: COPD, chronic pulmonary obstructive disease; AM, alveolar macrophages; PAMP, pathogen-associated molecular patterns; TIR, Toll-IL-1R; TRIF, TIR domain-containing adapter inducing IFN-; IRAK, IL-1R-associated kinase; IL-1RA, IL-1R antagonist; poly(1:C), polyinosinic-polycytidylic acid; Pam3Cys, S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-(S)-Ser-Lys4-OH trihydrochloride.

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