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(Chest. 2005;127:251-256.)
© 2005 American College of Chest Physicians

Production of Soluble Tumor Necrosis Factor Receptors and Tumor Necrosis Factor-{alpha} by Alveolar Macrophages in Sarcoidosis and Extrinsic Allergic Alveolitis*

Huaping Dai, MD; Josune Guzman, MD; Baomin Chen, MD and Ulrich Costabel, MD, FCCP

* From the Department of Pneumology and Allergy (Drs. Dai, Chen, and Costabel), Ruhrlandklinik, Medical Faculty, University of Essen, Essen, Germany; and General and Experimental Pathology (Dr. Guzman), Ruhr University, Bochum, Germany.

Correspondence to: Ulrich Costabel, MD, FCCP, Ruhrlandklinik, Tüschener Weg 40, D-45239 Essen, Germany; erj.costabel{at}t-online.de


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Alveolar macrophage (AM)-derived tumor necrosis factor (TNF)-{alpha} plays a pivotal role in the pathogenesis of sarcoidosis and extrinsic allergic alveolitis (EAA). The effects of TNF-{alpha} are mediated by membrane TNF receptor (mTNFR)-1 and mTNFR-2, and can be blocked by soluble TNF receptor (sTNFR)-1 and sTNFR-2.

Methods: We measured the production of the two sTNFRs and TNF-{alpha} in AM culture supernatants from 10 patients with active sarcoidosis, 12 patients with EAA, and 9 control subjects using an enzyme-linked immunosorbent assay method.

Results: Compared with control subjects, the spontaneous and lipopolysaccharide (LPS)-stimulated production of sTNFR-1, sTNFR-2, and TNF-{alpha} was significantly increased in patients with sarcoidosis and EAA. The concentrations of both sTNFRs, but especially of sTNFR-2, were closely related to those of TNF-{alpha}. The LPS-induced increase was 1.5-fold for sTNFR-1, at least fourfold for sTNFR-2, and at least 25-fold for TNF-{alpha} in all study populations.

Conclusion: These results indicate that AMs can release the two sTNFRs in relation to TNF-{alpha}. sTNFR-2 may be more liable to shedding than sTNFR-1. Both sTNFR-1 and sTNFR-2 may be involved in the pathogenesis of sarcoidosis and EAA, possibly as counterregulators of TNF-{alpha}.

Key Words: BAL • extrinsic allergic alveolitis • sarcoidosis • soluble tumor necrosis factor receptor • tumor necrosis factor-{alpha}


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Tumor necrosis factor (TNF)-{alpha} is produced primarily by activated macrophages.12 It is viewed as a pleiotropic cytokine with broad immune regulation functions and is closely related to the development of diseases.34 TNF-{alpha} exerts its diverse biological effects by binding to two specific cell surface receptors (membrane TNF receptor [mTNFR]-1 and mTNFR-2),56 which are expressed on a variety of cells.678 Both receptors can be shed from the cell surface to form soluble TNF receptor (sTNFR)-1 and sTNFR-2,89101112 which can compete with mTNFRs as ligands to TNF and thereby inhibit the effects of TNF. As such, they have been identified to function as natural antagonists of TNF.10131415 However, when sTNFR concentrations are low, they may enhance TNF activity by stabilizing TNF molecules and prolonging the availability of TNF with respect to binding to mTNFRs.1516 The production of sTNFRs seems to be essential for decreasing the TNF activity. sTNFRs have been detected in various body fluids, including serum, plasma, urine, synovial fluid, and BAL fluid with some relation to diseases, including sarcoidosis and extrinsic allergic alveolitis (EAA).817181920212223

It is well known that alveolar macrophage (AM)-derived TNF-{alpha} plays a central role in the development of sarcoidosis and EAA.2425262728 The interrelation between the release of TNF-{alpha} and sTNFRs by AMs in patients with sarcoidosis and EAA is not clear, although a study29 was trying to understand the production of sTNFRs in relation to TNF-{alpha} bioactivity in sarcoidosis. The aim of our study was to analyze simultaneously the spontaneous and lipopolysaccharide (LPS)-induced in vitro production of sTNFRs and TNF-{alpha} by AMs recovered through BAL from patients with sarcoidosis and EAA.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Populations
Sarcoidosis: Ten consecutive patients with active pulmonary sarcoidosis (5 women and 5 men; mean age, 45 ± 2 years [± SEM]; all nonsmokers) were included. No patients were receiving corticosteroids. The diagnosis was established on the basis of compatible clinical and radiographic features, histologic evidence of noncaseating granulomata on transbronchial biopsy or an increased CD4/CD8 ratio (> 3.5) in BAL fluid, and the exclusion of other granulomatous lung diseases. Criteria of disease activity were as follows: (1) recently developed or increasing symptoms such as cough, dyspnea, weakness, fever, and arthralgia; and/or (2) chest radiographic evidence of progressive disease; and/or (3) deterioration of lung function test results. According to chest radiographic staging, five patients had stage I disease, four patients had stage II disease, and one patient had stage III disease. Pulmonary function test results showed a mild decrease in lung volumes (Table 1 ).


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  		Table 1.. General Characteristics of the Study Populations*

 
EAA: This group was composed of 12 consecutive patients with EAA (8 women and 4 men; mean age, 55 ± 2 years; two smokers). Eleven patients were budgerigar fanciers; 1 patient had farmer’s lung. All were untreated at the time of BAL and presented with chronic disease. Mean time since last exposure to BAL was 7 days (range, 1 to 30 days). Diagnostic criteria for EAA were as follows: (1) a history of exposure to organic antigens, (2) clinical signs and symptoms consistent with EAA, (3) radiologic features and/or functional abnormalities characteristic of interstitial lung disease, (4) evidence of serum precipitins against one or more organic antigens, and (5) BAL with increased lymphocytes (> 40%). Pulmonary function test results showed a more pronounced reduction in lung volumes than in patients with sarcoidosis and control subjects (Table 1).

Control Subjects: This group consisted of nine consecutive patients (three women and six men; mean age, 47 ± 5 years; six smokers). They underwent diagnostic bronchoscopy for various reasons (coin lesions, hilar abnormalities, pleural disease, suspicion of recurrent tuberculosis, which was not confirmed). They had no evidence of interstitial lung disease and no history of exposure to antigens known to cause EAA. BAL cytology findings were normal. None of the control subjects had recent therapy or other concomitant illnesses. Written, informed consent was obtained according to institutional guidelines.

Collection of Bronchoalveolar Cells
BAL was performed by instilling a total volume of 200 mL in 10 x 20-mL aliquots into the right middle lobe, with immediate aspiration by gentle suction after each aliquot. The recovered BAL fluid was filtered through two layers of sterile gauze and subsequently centrifuged at 500g for 10 min at 4°C. The cell pellet was washed three times with phosphate buffered saline solution. Total cell counts, cell differentials, and lymphocyte phenotypes were assessed routinely30; data are summarized in Table 2 . Cell viability as determined by Trypan blue exclusion was > 90%.


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  		Table 2.. Cell Counts and Profiles of Lymphocytes in BAL Fluid*

 
Isolation and Culture of AMs
After washing, the cells were suspended to a concentration of 1 x 106/mL in RPMI 1640 medium supplemented with 10% heat-inactivated fetal calf serum, 2 mmol/L L-glutamine, 200 U/mL of penicillin, and 200 µg/mL of streptomycin (Seromed; Biochrom KG; Berlin, Germany). The cell suspension was added at 1 x 106/well to 24-well plastic tissue culture plates (Falkon; Becton Dickinson; Franklin Lakes, NJ) and incubated at 37°C in a 5% CO2-humidified atmosphere for 1 h to permit adhesion of macrophages. The nonadherent cells were then removed by three washings with medium. The purity of the adherent AMs was identified to be > 95% by morphology and nonspecific esterase staining. The adherent AM population was incubated for an additional 24 h in 1 mL of supplemented medium or in 1 mL of medium with 100 ng of lipopolysaccharide (LPS) [Sigma; St. Louis, MO]. At the end of the incubation period, the culture supernatants were harvested, rendered cell-free by centrifugation, and stored at – 80°C until further analysis. Cell viability after 24 h of incubation was always > 90%.

sTNFR-1 and sTNFR-2 Assay
sTNFR-1 and sTNFR-2 concentrations in the AM culture supernatants were measured using commercially available human sTNFR-1 and sTNFR twin enzyme-linked immunosorbent assay (ELISA) kits with a sensitivity of 25 pg/mL and without cross-reactivity between the two assays (HyCult Biotechnology; Uden, Holland) at room temperature. ELISA was performed according to the instructions of the manufacturer. Briefly, sTNFR-1 or sTNFR-2 standards, samples, and controls were added to microtiter plates precoated with antibodies recognizing human sTNFR-1 or sTNFR-2. After 2 h of incubation and four washings, the plates were incubated with the biotinylated second antibodies to human sTNFR-1 or sTNFR-2, then with streptavidin-peroxidase conjugate, each incubation lasting for 1 h, followed by four washings. Next, tetramethylbenzidine substrate solutions were added and developed in the dark for 30 min. The reaction was stopped by adding citric acid solution. The absorbance was read on a spectrophotometer at 450 nm. Finally, the quantities of sTNFR-1 or sTNFR-2 in the samples were determined from individual standard curves and expressed as picograms per milliliter per 106 AMs to correct for the number of total AMs.

TNF-{alpha} Assay
The concentrations of TNF-{alpha} in the AM culture supernatants were quantified using a commercially available human TNF-{alpha} ELISA kit with a detection limit of < 5 pg/mL (Endogen; Woburn, MA). The ELISA was performed according to the instructions of the manufacturer. The concentration of TNF-{alpha} in the samples was expressed as picograms per milliliter per 106 AM.

Statistical Analysis
All data are expressed as mean ± SEM. A Mann-Whitney U test was used to compare the differences between patients with sarcoidosis or EAA and control subjects. Spearman rank order correlation coefficients were used to evaluate correlations. A value of p < 0.05 was considered statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Production of sTNFR-1
As shown in Figure 1 , left, the amount of sTNFR-1 in the culture medium produced spontaneously by AMs after 24 h of incubation was significantly higher in patients with sarcoidosis (70.5 ± 8.7 pg/mL/106 AM; range, 33.6 to 113.4 pg/mL/106 AMs) and in patients with EAA (99.3 ± 15.3 pg/mL/106 AMs; range, 28.3 to 202.0 pg/mL/106 AMs) than in control subjects (16.1 ± 3.9 pg/mL/106 AMs; range, 6.5 to 34.2) [p < 0.01 for both comparisons]. The LPS-induced release of sTNFR-1 from AMs after 24 h was also significantly higher in patients with sarcoidosis (111.9 ± 14.3 pg/mL/106 AMs; range, 59.9 to 210.5 pg/mL/106 AMs) and in patients with EAA (158.2 ± 17.1 pg/mL/106 AMs; range, 83.8 to 316.3 pg/mL/106 AMs) than in control subjects (39.3 ± 11.3 pg/mL/106 AMs; range, 8.5 to 94.0 pg/mL/106 AMs) [p < 0.01, both comparisons]. The LPS-induced increase was modest (1.5-fold) in all study populations.



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  		Figure 1.. Spontaneous and LPS-stimulated production of sTNFR-1 (left) and sTNFR-2 (right) by AMs. **p < 0.01, *p < 0.05 (sarcoidosis or EAA vs control).

 
Production of sTNFR-2
As shown in Figure 1, right, the amount of sTNFR-2 produced spontaneously by AMs after 24 h of incubation was significantly higher in patients with sarcoidosis (274.2 ± 81.3 pg/mL/106 AMs; range, 113.3 to 935.4 pg/mL/106 AMs) and in patients with EAA (540.8 ± 126.1 pg/mL/106 AMs; range, 38.9 to 1,296.0 pg/mL/106 AMs) than in control subjects (63.3 ± 13.6 pg/mL/106 AMs; range, 11.8 to 116.0 pg/mL/106 AMs) [p < 0.01, both comparisons]. After LPS stimulation, the release of sTNFR-2 from AMs after 24 h was also significantly higher in patients with sarcoidosis (1,203.8 ± 137.0 pg/mL/106 AMs; range, 732.0 to 1,870.0 pg/mL/106 AMs) and in patients with EAA (2,384.9 ± 478.3 pg/mL/106 AMs; range, 623.0 to 5,587.0 pg/mL/106 AMs) than in control subjects (686.2 ± 147.3 pg/mL/106 AMs; range, 249.9 to 1,404.5 pg/mL/106 AMs) [p < 0.05 and < 0.01, respectively]. LPS induced a marked increase (at least fourfold) in all study populations when compared with spontaneous production.

Production of TNF-{alpha}
As shown in Figure 2 , the amount of TNF-{alpha} produced spontaneously by AMs after 24 h of incubation was significantly higher in patients with sarcoidosis (160.7 ± 42.0 pg/mL/106 AMs; range, 38.9 to 446.3 pg/mL/106 AMs) and in patients with EAA (145.5 ± 53.5 pg/mL/106 AMs; range, 21.3 to 660.0 pg/mL/106 AMs) than in control subjects (43.2 ± 26.1 pg/mL/106 AMs; range, 1.4 to 245.5 pg/mL/106 AMs) [p < 0.01 and < 0.05, respectively]. The LPS-induced release of TNF-{alpha} from AMs after 24 h was also significantly higher in patients with sarcoidosis (7,332.2 ± 1372.7 pg/mL/106 AMs; range, 2,076.8 to 16,011.0 pg/mL/106 AMs) and in patients with EAA (5,661.4 ± 1,580.9 pg/mL/106 AMs; range, 872.2 to 18,257.1 pg/mL/106 AMs) than in control subjects (1,156.0 ± 345.5 pg/mL/106 AMs; range, 171.0 to 3,319.1 pg/mL/106 AMs) [p < 0.01, both comparisons]. The LPS-induced increase was excessive (at least 25-fold) in all study populations.



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  		Figure 2.. Spontaneous and LPS-stimulated production of TNF-{alpha} by AMs. **p < 0.01, *p < 0.05 (sarcoidosis or EAA vs control).

 
Correlation Between sTNFRs and TNF-{alpha} Produced by AMs
There were positive correlations between sTNFR-1 and TNF-{alpha} levels, either spontaneously produced (r = 0.56, p < 0.005) or after LPS stimulation (r = 0.54, p < 0.005). A closer relationship than for sTNFR-1 was seen between sTNFR-2 and TNF-{alpha} levels, either spontaneously produced (r = 0.68, p < 0.001) or LPS-induced (r = 0.71, p < 0.001). Additionally, the production of sTNFR-1 correlated with sTNFR-2, either spontaneously (r = 0.78, p < 0.001) or after LPS stimulation (r = 0.66, p < 0.001).

The production by AMs of either sTNFR, either spontaneously or following LPS stimulation, correlated with the percentage of BAL lymphocytes (r = 0.72 and r = 0.71 for sTNFR-1, r = 0.79 and r = 0.67 for sTNFR-2, respectively; all p < 0.01). There were no correlations with other BAL cell types.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study demonstrated that the production of sTNFR-1 and sTNFR-2 by AMs in vitro was significantly increased in patients with active sarcoidosis and EAA compared with control subjects, both spontaneously and following LPS stimulation. The in vitro AM release of sTNFRs correlated with BAL lymphocytes in the current study populations, pointing toward a biological relevance of these findings. The enhanced TNF-{alpha} production by AMs in these diseases was confirmed. Interestingly, LPS stimulation produced only a modest increase in sTNFR-1, but an at least fourfold increase in sTNFR-2 and a 25-fold increase in TNF-{alpha}. There was a close correlation between sTNFR-1, especially sTNFR-2 and TNF-{alpha}, and also between each soluble receptor. These results indicate that AMs can release sTNFRs in close relation to TNF-{alpha}, and that sTNFR-2 may be more liable to shed than sTNFR-1.

The concentrations of both sTNFRs but especially those of sTNFR-2 were closely related to those of TNF-{alpha}. It has been shown that sTNFRs are liberated from the cell surface by proteolytic cleavage of TNF receptors. After their generation, these soluble receptors can compete with the cell-bound mTNFRs for TNF-{alpha} and then block the harmful actions of TNF-{alpha}. Moreover, the loss of mTNFRs can lead to a transient TNF refractory state of a cell. Thus, the formation of sTNFRs has been recognized to be a protective mechanism against the deleterious effects of TNF-{alpha}.8101317181920 However, at low concentrations sTNFRs can enhance TNF-{alpha} effects by stabilizing its structure. Therefore, sTNFRs can function as TNF antagonists and TNF stabilizers. sTNFR effects vary depending on their concentrations at the site of TNF-{alpha} action and the ratios of the sTNFR to TNF-{alpha}.14151619

sTNFRs are present at low concentrations in the blood of normal healthy individuals,31 whereas elevated levels of sTNFRs in human biological fluid are found in a variety of TNF-{alpha}–involved inflammatory disorders such as endotoxemia/sepsis, rheumatic diseases, sarcoidosis, and EAA.81014181920212223 These naturally occurring sTNFRs have the potential of neutralizing the bioactivities of TNF-{alpha}.8101418 Higher ratios of sTNFR to TNF-{alpha} are associated with increased probability of survival in meningococcaemia.19 Either sTNFR-1 or sTNFR-2 administration can attenuate the clinical and pathologic reactions caused by LPS-induced TNF-{alpha}.1014

Sarcoidosis and EAA are diseases characterized by pulmonary inflammation and granuloma formation. AM and AM-derived cytokines, in particular TNF-{alpha}, play a crucial role in these processes. TNF-{alpha}, spontaneously released by activated AMs in sarcoidosis and EAA, can enhance the production of interleukin-1, interleukin-6, monocyte-chemoattractant protein-1, and macrophage inflammatory protein-1{alpha},34 all mediators that have been shown to be involved in the development of sarcoidosis and EAA.24252627283233 TNF-{alpha} can promote cellular recruitment and activation in the lungs and thus contribute to the alveolitis characterized by infiltration of mononuclear cells and the formation of granulomas.2425262728 Most of the TNF-{alpha} activities are considered to be mediated by TNFR-1.63435 Interestingly, we observed an up-regulated expression of TNFR-1 on the AM surface in patients with sarcoidosis36 and EAA.37 The increased expression provides more sites for TNF-{alpha} ligation and may enhance the TNF-{alpha}–mediated immune reactions in the disease process of sarcoidosis and EAA.

The TNF-{alpha} action can be attenuated by naturally occurring sTNFRs. However, TNF-{alpha} itself can augment the production of the sTNFRs.38 Elevated sTNFR levels have been reported in plasma and BAL fluid of patients with active sarcoidosis.2021 We have shown lately that also in patients with EAA the sTNFR levels of BAL fluid are increased.22 We report here the increased and concomitant in vitro production of sTNFRs and TNF-{alpha} by AMs in patients with sarcoidosis and in patients with EAA with the chronic form of disease. It is difficult to predict how much can be extrapolated from our data to other types and forms of EAA.

The increased release of sTNFRs may simply reflect the state of AM activation in vivo in our patients, with no particular pathogenetic significance. Nevertheless, there is support from the literature that elevated sTNFR levels function most likely to inhibit excessive TNF-{alpha} effects.14 The inhibitory role of the sTNFRs, at least in the case of release by AMs in our study, seems to be rather limited, however, and not sufficient to suppress all TNF-{alpha} activity, since our data indicate that in response to LPS, there is at least a fivefold greater increase of TNF-{alpha} than of either soluble receptor. The clinical importance of the sTNFRs would be profound, as endogenous sTNFRs are not always sufficient to neutralize the TNF-{alpha} cytotoxicity.141939 Administration of recombinant sTNFRs may prevent the pathologic sequelae caused by exaggerated TNF-{alpha}.

In summary, the two sTNFRs were produced in vitro by AMs in closely relation to TNF-{alpha}. The enhanced production of sTNFRs by AMs from patients with sarcoidosis and EAA may serve to inhibit excessive TNF-{alpha} activity in part, and thus influence the pathologic process. Therefore, sTNFR-1 and sTNFR-2 may be involved in the pathogenesis of sarcoidosis and EAA as potential counterregulators of TNF-{alpha}. Further studies are required to investigate the effect of various concentration of sTNFRs on TNF-{alpha} activity in vitro and the clinical significance of elevated sTNFRs in the two diseases and in other granulomatous disorders.


   Footnotes
 
Abbreviations: AM = alveolar macrophage; EAA = extrinsic allergic alveolitis; ELISA = enzyme-linked immunosorbent assay; LPS = lipopolysaccharide; mTNFR = membrane tumor necrosis factor receptor; sTNFR = serum tumor necrosis factor receptor; TNF = tumor necrosis factor

This work was supported by Arbeitsgemeinschaft zur Förderung der Pneumologie an der Ruhrlandklinik (AFPR) and by Ruhr University Bochum (FORUM).

Received for publication October 2, 2003. Accepted for publication August 10, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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