Release of Tumor Necrosis Factor-α From Human Alveolar Macrophages is Decreased in Smokers

doi:10.1378/chest.103.2.479

Chest

Volume 103, Issue 2, February 1993, Pages 479-483

https://doi.org/10.1378/chest.103.2.479 Get rights and content

It is known that smoking affects the development and maintenance of certain types of granulomatous lung diseases. To explore this mechanism(s), we measured tumor necrosis factor (TNF)-$aL concentrations in the culture supernatants of lipopolysaccharide (LPS)-stimulated alveolar macrophages (AMs) in 13 healthy nonsmokers, 13 healthy smokers, 13 nonsmoking sarcoid patients, and 16 smoking sarcoid patients. We found that the capacity of smokers' AMs to release TNF-$aL was significantly decreased both in the normal and sarcoid groups. We also confirmed the previous observation that there was an exaggerated TNF release in patients with pulmonary sarcoidosis. These results indicate a significant role of TNF-$aL in the pathogenetic mechanisms of pulmonary sarcoidosis and suggest the possible involvement of TNF in the mechanisms by which smoking modulates local immune phenomena.

Section snippets

Study Population

The normal population consisted of 26 healthy subjects; 13 were nonsmokers and 13 were smokers. None had a history of lung disease, and none showed evidence of lung disease by physical examination, chest radiograph, and pulmonary function tests. Their detailed demographic data and BAL findings are shown in Table 1.

The diagnosis of pulmonary sarcoidosis was established in 29 untreated patients; 13 were nonsmokers and 16 were smokers. They had a compatible clinical picture without evidence of

RESULTS

We first examined the time course of TNF-$aL release by AMs at the LPS concentration of 20 µg/ml in four patients with pulmonary sarcoidosis (two nonsmokers, two smokers). The AMs were cultured for 12, 24, 48, and 72 h, and TNF-$aL concentrations in the culture supernatants were determined by ELISA. As shown in Figure 1, the release of TNF-$aL increased over time, and plateau levels were reached by 24 h. The levels then remained stable during the following 24 h. Accordingly, a 48-h time point

DISCUSSION

We made two important observations in this study. We first confirmed previous observations that AMs from sarcoid patients have an increased capacity to release TNF-$aL. Tumor necrosis factor was first described in 1975 as a necrosing factor for solid tumors found in the sera of BCG-immunized mice challenged with LPS.¹⁶ Subsequent investigations have shown that the biologic activities of this cytokine extend well beyond the realm of antitumor biology. In the respiratory system, TNF is an

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Smoking Inhibits the Frequency of Bronchovascular Bundle Thickening in Sarcoidosis
2011, Academic Radiology
Citation Excerpt :
Pathophysiologically, it has been suggested that smoking may decrease inflammatory cytokines that contribute to formation of granulomas (15). Tobacco smoke decreases the release of TNF-alpha by alveolar macrophages in normal subjects and in those with sarcoidosis (16). Similarly, nicotine has been shown to inhibit the formation of granulomas in hypersensitivity pneumonitis in a murine model (17).
Smoking has been associated with decreased incidence and prevalence of sarcoidosis, but few studies have evaluated effects of smoking on clinical parameters of the disease. The objectives were to determine the association of smoking with radiographic patterns and to evaluate the associations of these smoking-related radiographic patterns on airflow obstruction in sarcoidosis.
Clinical data and computed tomography (CT) scans of 124 patients with sarcoidosis were reviewed. CT scans were assessed for lymph nodes, nodules, bronchiectasis, bronchovascular bundle thickening, displaced hilum, fibrosis, ground glass, emphysema, pleural changes, and alveolar opacities. CT patterns were compared between patients with and without a history of smoking. The effect of smoking on the associations between radiographic patterns and airflow obstruction was assessed with multivariable analysis.
Smokers had less frequency of bronchovascular bundle thickening than nonsmokers (11/38 subjects [29%] vs 50/86 subjects [58%], P = .003) and more emphysema (7/38 subjects [18%] vs 1/86 subjects [1%], P = .001). Patients who had bronchovascular bundle thickening were less likely to have ever smoked (11/61 subjects [18%] vs 27/63 subjects [43%], P = .003) or be current smokers (4/61 subjects [7%] vs 15/63 subjects [24%], P = .008). Age (P = .003) and bronchovascular bundle thickening (P = .02) were independent predictors of airflow obstruction. There were no differences in smoking history between patients with airflow obstruction versus those without (10/37 subjects [27%] vs 28/87 subjects [32%], P = .63).
In patients with sarcoidosis, smoking is associated with decreased frequency of bronchovascular bundle thickening, an important clinical manifestation of the lung disease. Further, bronchovascular bundle thickening and age are the only independent predictors of airflow obstruction, and smoking does not confound these associations.
The effects of smoking on the lipopolysaccharide response and glucocorticoid sensitivity of alveolar macrophages of patients with asthma
2009, Chest
Citation Excerpt :
Acute cigarette smoke exposure is known to down-regulate the macrophage innate immune response, both in unstimulated8 and LPS-stimulated cells with the notable exception of IL-8.9 Similarly, many other studies have shown that long-term cigarette smoking down-regulates LPS-stimulated inflammatory cytokine production from AMs.10,23–27 In contrast, Koch et al28 showed that long-term cigarette smoking increased LPS-induced IL-8 release in healthy smokers compared with nonsmokers, whereas Cosio et al21 demonstrated an increase in IL-8 and TNF-α in COPD patients and smokers compared to healthy nonsmokers.
Cigarette smoking in asthma patients causes insensitivity to inhaled glucocorticoids. We tested the hypothesis that smoking causes GC insensitivity in alveolar macrophages (AMs) obtained from patients with asthma.
Nineteen asthmatic nonsmokers (ANSs) and 13 asthmatic smokers (ASMs) underwent BAL. AMs were cultured with or without dexamethasone, 0.1 to 1,000 nmol/L, for 2 h before lipopolysaccharide (LPS) [1 μg/mL] stimulation. After 6 h, supernatants were harvested for enzyme-linked immunosorbent assay, and messenger RNA was collected for real-time (RT)-polymerase chain reaction (PCR).
ASMs had higher numbers of AMs per milliliter of BAL fluid than ANSs (1.98 vs 0.75 × 10⁶ cells/mL, respectively; p = 0.007). Cigarette smoking significantly attenuated the LPS response for all three cytokines tested among ANSs vs ASMs (tumor necrosis factor [TNF]-α, 31.6 vs 10.6 ng/mL, respectively (p = 0.01); interleukin [IL]-6, 25.8 vs 10.8 ng/mL, respectively (p = 0.002); IL-8, 62.5 vs 36.1 ng/mL, respectively (p = 0.001)). There was no difference in dexamethasone dose-response curves between ANSs and ASMs (p > 0.05 for all comparisons). The inhibitory concentration of 50% (IC₅₀) for IL-6 was 120.6 vs 83.3, respectively, and for TNF-α it was 4.9 vs 8.6, respectively; an IC₅₀ was not achieved for IL-8. RT-PCR also showed no difference in the suppression of cytokine messenger RNA levels between groups, with IL-8 being the most GC-insensitive cytokine.
Cigarette smoking in patients with asthma increases the number of airway AMs and attenuates their response to LPS, which may have implications in host immune function. Cigarette smoking does not alter the GC sensitivity of AMs in patients with asthma. There was differential cytokine sensitivity, with IL-8 being the least GC-sensitive cytokine. GC-insensitive IL-8 production from AMs may be a mechanism by which neutrophils are attracted into the airways.
Down modulation of IFN-γ signaling in alveolar macrophages isolated from smokers
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The master cytokine, IFN-γ 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-γ (IFN-γR) on alveolar macrophages (AM) of smokers. Here in, we report reduction in the expression of the IFN-γR α-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-γ-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-γ signal transduction in AM from smokers may have an important implication regarding the use of therapeutic IFN-γ in the lungs of patients that develop respiratory disorders as a result of tobacco use.
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This study was supported in part by the Smoking Research Foundation of Japan and by Grants-in-Aid (02404040 and 04454248) for Scientific Research from the Ministry of Education, Science, and Culture of Japan.

Manuscript received February 24; revision accepted July 2.

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Chest

Release of Tumor Necrosis Factor-α From Human Alveolar Macrophages is Decreased in Smokers

Section snippets

Study Population

RESULTS

DISCUSSION

Chest

Chest

J Biol Chem

Release of interleukin-1 by alveolar macrophages of patients with active pulmonary sarcoidosis

Am Rev Respir Dis

Interleukins in pulmonary sarcoidosis: dissociative correlation of lung interleukins 1 and 2 with the intensity of alveolitis

Am Rev Respir Dis

Gamma interferon is spontaneously released by alveolar macrophages and lung T lymphocytes in patients with pulmonary sarcoidosis

J Clin Invest

Expression of granulocyte-macrophage colony-stimulating factor mRNA by inflammatory cells in the sarcoid lung

Am J Respir Cell Mol Biol

Tumor necrosis factor production by human sarcoid alveolar macrophages

Am J Pathol

Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis

J Lab Clin Med

Extrinsic allergic alveolitis: a disease commoner in non-smokers

Thorax

Sarcoidosis: a disease commoner in non-smokers?

Thorax

Chest symptoms and farmer's lung: a community survey

Br J Ind Med

Lymphocyte studies in asymptomatic cigarette smokers: a comparison between lung and peripheral blood

Am Rev Respir Dis

Interleukin 1 production by alveolar macrophages is decreased in smokers

Am Rev Respir Dis

Cigarette smoking decreases interleukin 1 release by human alveolar macrophages

Am J Physiol

Proposal of standardized methods and reference for assaying recombinant human tumor necrosis factor

Jpn J Med Sci Biol

An endotoxin-induced serum factor that causes necrosis of tumors

Proc Natl Acad Sci USA