To evaluate the mechanism by which cigarette smoking suppresses pulmonary immune responses, we determined the capacity of alveolar macrophages (AM) to produce interleukin 1 (IL-1 in 32 normal subjects and in 40 patients with pulmonary sarcoidosis. The amount of IL-1 released from LPS-stimulated AM from smokers was significantly decreased compared with that in nonsmokers in both normal and sarcoid groups. The addition of indomethacin to the cultures in 18 normal subjects and in 22 patients with pulmonary sarcoidosis yielded similar results, thus excluding the possibility that this difference resulted from a difference in the amount of cyclooxygenase metabolites released in the culture supernatants. Similar results were obtained by enzyme-linked immunosolvent assay. Because IL-1 is thought to induce the accumulation of T cells at the site of disease and contribute to local cellular and humoral immunity of the lung, our data suggest that the reduced capacity of AM to release IL-1 in smokers affords partial protection against the initiation of immune responses in the lung and the development of granulomatous lung diseases.
T lymphocytes and alveolar macrophages accumulating in the lower respiratory tract of patients with pulmonary sarcoidosis are known to be activated to produce several cytokines, presumably leading to granuloma formation within the lung. We hypothesized that these cells produce colony-stimulating factors (CSFs), which have been shown to affect the proliferation and function of monocyte-/macrophage-lineage cells. To test this hypothesis, we tried to detect mRNA encoding CSFs in cells obtained by bronchoalveolar lavage using a reverse transcription-polymerase chain reaction. Granulocyte-macrophage CSF (GM-CSF) mRNA was detected in five of six patients with pulmonary sarcoidosis, whereas it was detected in none of the five normal controls. Macrophage-CSF mRNA was detected in all subjects examined, and interleukin-3 mRNA in none. These results suggest some relation of GM-CSF to sarcoid lesion formation.
To investigate whether interleukins are involved in the formation of alveolitis in pulmonary sarcoidosis, interleukin-1 (IL-1) production by LPS-stimulated alveolar macrophages (AM) and interleukin-2 (IL-2) production by PHA-stimulated lung and blood T-cells were determined in 35 untreated patients with pulmonary sarcoidosis. The amount of IL-1 produced by AM (BAL IL-1) was significantly increased in patients with pulmonary sarcoidosis compared with that in 18 control subjects. BAL IL-1 showed a significant positive correlation with the intensity of alveolitis assessed by the proportion of lymphocytes in bronchoalveolar lavage fluid (BALF) and the absolute number of lymphocytes per milliliter of BALF. However, the amount of IL-2 produced by lung T-cells (BALT IL-2) showed a significant negative correlation with the intensity of alveolitis. BALT IL-2 was significantly lower than the amount of IL-2 produced by blood T-cells (PBT IL-2). There was no correlation between PBT IL-2 and the intensity of alveolitis. These results suggest that IL-2 contributes to the formation and maintenance of alveolitis in pulmonary sarcoidosis, whereas IL-2 production by lung T-cells is suppressed to down-regulate the enhanced immune processes at the site of disease. The possibility that this hyporesponsiveness of lung T-cells to PHA has resulted from the modulation of the T3-T cell receptor complex remains to be determined.
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