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* Department of Internal Medicine, Thoracic Diseases Research Unit, Division of Pulmonary Critical Care,
Department of Immunology,
Department of Biochemistry and Molecular Biology, and
Division of Allergic diseases, Mayo Clinic and Foundation, Rochester, MN 55905
IL-12p70, a heterodimer composed of p35 and p40 subunits, is a key polarizing cytokine produced by maturing dendritic cells (DCs). We report that cigarette smoke extract (CSE), an extract of soluble cigarette smoke components, suppresses both p35 and p40 production by LPS or CD40L-matured DCs. Suppression of IL-12p70 production from maturing DCs was not observed in the presence of nicotine concentrations achievable in CSE or in the circulation of smokers. The suppressed IL-12p70 protein production by CSE-conditioned DCs was restored by pretreatment of DCs or CSE with the antioxidants N-acetylcysteine and catalase. Inhibition of DC IL-12p70 by CSE required activation of ERK-dependent pathways, since inhibition of ERK abrogated the suppressive effect of CSE on IL-12 secretion. Oxidative stress and sustained ERK phosphorylation by CSE enhanced nuclear levels of the p40 transcriptional repressor c-fos in both immature and maturing DCs. Suppression of the p40 subunit by CSE also resulted in diminished production of IL-23 protein by maturing DCs. Using a murine model of chronic cigarette smoke exposure, we observed that systemic and lung DCs from mice "smokers" produced significantly less IL-12p70 and p40 protein upon maturation. This inhibitory effect was selective, since production of TNF-
during DC maturation was enhanced in the smokers. These data imply that oxidative stress generated by cigarette smoke exposure suppresses the generation of key cytokines by maturing DCs through the activation of ERK-dependent pathways. Some of the cigarette smoke-induced inhibitory effects on DC function may be mitigated by antioxidants.
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1 This work was supported by a Parker B. Francis Fellowship Award, an American Lung Association Research Grant, a Flight Attendant Medical Research Institute Grant, and an Annenberg Career Development Award (to R.V.).
P.R.K. designed and performed most of the research, collected, analyzed, and interpreted data, and helped draft the manuscript and figures. T.W.B. designed and performed research. L.P. provided critical input with data analysis and interpretation. A.L. provided critical input with data analysis and interpretation. H.K. contributed vital input regarding study design, data analysis, and interpretation. R.V. performed research, interpreted data, generated figures, wrote the manuscript, and obtained funding for the research performed.
2 Current address: 4100 Lake Drive South East, Grand Rapids, MI 49546.
3 Address correspondence and reprint requests to Dr. Robert Vassallo, Mayo Clinic, Stabile Building 8-54, 200 First Street Southwest, Rochester, MN 55905. E-mail address: vassallo.robert{at}mayo.edu
4 Abbreviations used in this paper: DC, dendritic cell; CSE, cigarette smoke extract; NAC, N-acetylycysteine; siRNA, small interfering RNA.
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