Down modulation of IFN-γ signaling in alveolar macrophages isolated from smokers

Division of Pulmonary and Critical Care Medicine, Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Toxicology and Applied Pharmacology (Impact Factor: 3.71). 04/2009; 237(1):22-8. DOI: 10.1016/j.taap.2009.02.021
Source: PubMed


The master cytokine, IFN-gamma possesses a wide spectrum of biological effects and is crucial for development of the highly activated macrophage phenotype characteristically found during inflammation. However, no data exists regarding the potential influence of cigarette smoke on the status of the expression of the cell surface receptor for IFN-gamma (IFN-gammaR) on alveolar macrophages (AM) of smokers. Here in, we report reduction in the expression of the IFN-gammaR alpha-chain on AM of cigarette smokers, when compared with non-smokers. Ensuing from the loss of receptor expression on the AM of smokers there was a decrease in IFN-gamma-mediated cell signaling. This included a decrease in the phosphorylation of signal transducer and activator of transcription (STAT)-1 and induction of interferon regulatory factor (IRF)-1. Further, diminished activation/induction of transcription factors did not appear to result from induction of known members of the 'suppressors of cytokine signaling (SOCS)' family. Decreased IFN-gamma signal transduction in AM from smokers may have an important implication regarding the use of therapeutic IFN-gamma in the lungs of patients that develop respiratory disorders as a result of tobacco use.

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    • "A recently published study found that mice infected with M. tuberculosis (M.tb.) and later exposed to tobacco smoke had reduced Interferon-gamma (IFN-γ) responses following T-cell stimulation [16]. This is in accordance with other recent studies in humans showing that exposure to tobacco smoke reduces IFN-γ production in epithelial cells after antigenic challenge [17] and impairs IFN-γ mediated signaling [18-20] and vaccine efficacy [21,22]. These findings suggest a negative effect of smoking on the immune defense which in theory might affect the performance of immunodiagnostic tests, such as the IGRAs. "
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    ABSTRACT: Background False negative and indeterminate Interferon Gamma Release Assay (IGRA) results are a well documented problem. Cigarette smoking is known to increase the risk of tuberculosis (TB) and to impair Interferon-gamma (IFN-γ) responses to antigenic challenge, but the impact of smoking on IGRA performance is not known. The aim of this study was to evaluate the effect of smoking on IGRA performance in TB patients in a low and high TB prevalence setting respectively. Methods Patients with confirmed TB from Denmark (DK, n = 34; 20 smokers) and Tanzania (TZ, n = 172; 23 smokers) were tested with the QuantiFERON-TB Gold In tube (QFT). Median IFN-γ level in smokers and non smokers were compared and smoking was analysed as a risk factor for false negative and indeterminate QFT results. Results Smokers from both DK and TZ had lower IFN-γ antigen responses (median 0.9 vs. 4.2 IU/ml, p = 0.04 and 0.4 vs. 1.6, p < 0.01), less positive (50 vs. 86%, p = 0.03 and 48 vs. 75%, p < 0.01) and more false negative (45 vs. 0%, p < 0.01 and 26 vs. 11%, p = 0.04) QFT results. In Tanzanian patients, logistic regression analysis adjusted for sex, age, HIV and alcohol consumption showed an association of smoking with false negative (OR 17.1, CI: 3.0-99.1, p < 0.01) and indeterminate QFT results (OR 5.1, CI: 1.2-21.3, p = 0.02). Conclusions Cigarette smoking was associated with false negative and indeterminate IGRA results in both a high and a low TB endemic setting independent of HIV status.
    BMC Infectious Diseases 12/2012; 12(1):379. DOI:10.1186/1471-2334-12-379 · 2.61 Impact Factor
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    • "The degeneration of normal mucociliary processes in the COPD airways due to accumulated lifetime cigarette-smoke exposure contributes to the colonization of NTHI in the lower respiratory tract. It is now well accepted that cigarettesmoke alters the immune response in the airways and even impacts adversely on systemic immunity (Domagala-Kulawik, 2008; Mehta et al., 2008; Dhillon et al., 2009; Stämpfli and Anderson, 2009). This alteration negatively influences the innate immune response to bacterial infection, which further dysregulates inflammatory cascades in the respiratory mucosa. "
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    ABSTRACT: Non-typeable Haemophilus influenzae (NTHI) colonizes the lower respiratory tract of patients with chronic obstructive pulmonary disease and also causes exacerbations of the disease. The 16-kDa lipoprotein P6 has been widely studied as a potential vaccine antigen due to its highly conserved expression amongst NTHI strains. Although P6 is known to induce potent inflammatory responses, its role in the pathogenesis of NTHI infection in vivo has not been examined. Additionally, the presence of an amino-terminal lipid motif on P6 serves to activate host Toll-like receptor 2 (TLR2) signaling. The role of host TLR2 and NTHI expression of the lipoprotein P6 on the induction of airway inflammation and generation of adaptive immune responses following chronic NTHI stimulation was evaluated with TLR2-deficient mice and a P6-deficient NTHI strain. Absence of either host TLR2 or bacterial P6 resulted in diminished levels of immune cell infiltration within lungs of mice exposed to NTHI. Pro-inflammatory cytokine secretion was also reduced in lungs that did not express TLR2 or were exposed to NTHI devoid of P6. Induction of specific antibodies to P6 was severely limited in TLR2-deficient mice. Although mice exposed to the P6-deficient NTHI strain were capable of generating antibodies to other surface antigens of NTHI, these levels were lower compared to those observed in mice exposed to P6-expressing NTHI. Therefore, cognate interaction between host TLR2 and bacterial P6 serves to enhance lung inflammation and elicit robust adaptive immune responses during NTHI exposure. Strategies to limit NTHI inflammation while simultaneously promoting robust immune responses may benefit from targeting the TLR2:P6 signaling axis.
    Frontiers in Immunology 04/2011; 2:10. DOI:10.3389/fimmu.2011.00010
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    • "Altered interferon responses after cigarette smoke exposure may not be limited to epithelial cells. For example, macrophage and fibroblast cell lines exposed to cigarette smoke preparations in media and alveolar macrophages isolated from individuals that smoke cigarettes have reduced responsiveness to interferons [47,52,54-56]. Thus, cigarette smoke appears to affect multiple components of interferon-dependent antiviral defense. "
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    ABSTRACT: Although individuals exposed to cigarette smoke are more susceptible to respiratory infection, the effects of cigarette smoke on lung defense are incompletely understood. Because airway epithelial cell responses to type II interferon (IFN) are critical in regulation of defense against many respiratory viral infections, we hypothesized that cigarette smoke has inhibitory effects on IFN-gamma-dependent antiviral mechanisms in epithelial cells in the airway. Primary human tracheobronchial epithelial cells were first treated with cigarette smoke extract (CSE) followed by exposure to both CSE and IFN-gamma. Epithelial cell cytotoxicity and IFN-gamma-induced signaling, gene expression, and antiviral effects against respiratory syncytial virus (RSV) were tested without and with CSE exposure. CSE inhibited IFN-gamma-dependent gene expression in airway epithelial cells, and these effects were not due to cell loss or cytotoxicity. CSE markedly inhibited IFN-gamma-induced Stat1 phosphorylation, indicating that CSE altered type II interferon signal transduction and providing a mechanism for CSE effects. A period of CSE exposure combined with an interval of epithelial cell exposure to both CSE and IFN-gamma was required to inhibit IFN-gamma-induced cell signaling. CSE also decreased the inhibitory effect of IFN-gamma on RSV mRNA and protein expression, confirming effects on viral infection. CSE effects on IFN-gamma-induced Stat1 activation, antiviral protein expression, and inhibition of RSV infection were decreased by glutathione augmentation of epithelial cells using N-acetylcysteine or glutathione monoethyl ester, providing one strategy to alter cigarette smoke effects. The results indicate that CSE inhibits the antiviral effects of IFN-gamma, thereby presenting one explanation for increased susceptibility to respiratory viral infection in individuals exposed to cigarette smoke.
    Respiratory research 05/2010; 11(1):64. DOI:10.1186/1465-9921-11-64 · 3.09 Impact Factor
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