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Am. J. Respir. Cell Mol. Biol., Volume 20, Number 1, January 1999 122-128

Hydrogen Peroxide Enhances Shedding of Type I Soluble Tumor Necrosis Factor Receptor from Pulmonary Epithelial Cells

Toshihiko Hino, Hidenori Nakamura, Shuichi Abe, Hiroshi Saito, Minoru Inage, Kyoko Terashita, Shuichi Kato, and Hitonobu Tomoike

The First Department of Internal Medicine, Yamagata University School of Medicine, Yamagata, Japan


    Abstract

Abstract
Introduction
Materials and Methods
Results
Discussion
References

Reactive oxygen intermediates (ROIs) are among the important mediators in the pathogenesis of lung diseases in which tumor necrosis factor (TNF) plays a pivotal role. However, the effects of ROIs on the TNF- TNF receptor system remain unclear. Effects of hydrogen peroxide on the shedding of soluble tumor necrosis factor receptor (sTNF-R) were investigated in a pulmonary epithelial cell line (A549) using enzyme-linked immunoassay. A549 cells spontaneously released type I sTNF-R (sTNF-RI) into the culture medium. Hydrogen peroxide accelerated the release of sTNF-RI from the A549 cells time- and dose- dependently. Stimulated release of sTNF-RI by hydrogen peroxide or phorbol myristate acetate (PMA) was inhibited by pretreatment with the intracellular hydroxyl radical scavengers dimethyl sulfoxide and dimethyl thiourea. A synthetic metalloproteinase inhibitor (KB-R8301) inhibited not only spontaneous release of sTNF-RI but also shedding enhanced by hydrogen peroxide and PMA. Preincubation with a protein kinase C inhibitor, calphostin C, downregulated the hydrogen peroxide- or PMA-induced shedding of sTNF-RI. Neither genistein, a tyrosine kinase inhibitor, nor H-89, a protein kinase A inhibitor, inhibited shedding of sTNF-RI by hydrogen peroxide and PMA. Although the surface expression of TNF-R assessed by 125I-TNF specific binding was decreased in the presence of hydrogen peroxide or PMA, TNF-RI mRNA transcript levels remained unchanged. These results show that hydrogen peroxide is involved in the activation of metalloproteinase and protein kinase C responsible for the shedding of sTNF-RI. Accordingly, ROIs may alter TNF action by enhanced shedding of sTNF-RI and reducing its surface receptor expression.


    Introduction

Abstract
Introduction
Materials and Methods
Results
Discussion
References

Tumor necrosis factor-alpha (TNF-alpha ) is one of the most important cytokines and plays a key role in clinical events during inflammation, septic shock, and cachexia (1, 2). TNF-alpha is also implicated in the pathogenesis of lung inflammatory diseases (3). TNF-alpha mediates its diverse biologic effects by binding to either of two high-affinity receptors, type I (55 kD) or type II (75 kD) (7). Importantly, soluble TNF receptors (sTNF-Rs), which function as natural inhibitors for TNF-alpha , are released by cleavage of the extracellular domain of each type of membrane TNF-R (7, 11).

Recombinant sTNF-Rs are effective not only experimentally for the treatment of airway and lung inflammation (14, 15) and bleomycin-induced pulmonary fibrosis (16), but also clinically for the treatment of rheumatoid arthritis (17). Transgenic mice that continuously expressed sTNF-Rs were reported to be resistant to silica-induced pulmonary fibrosis (18), autoimmune diabetes mellitus (19), and osteoporosis caused by estrogen deficiency (20). All these reports support the important roles that sTNF-Rs play in various pathological conditions. It has also been reported that these physiological inhibitors for TNF are present in various body fluids, including serum (21), urine (22, 24), ascites (25), and the epithelial lining fluids of the respiratory tract (26) under both normal and pathological conditions. The mechanism by which the sTNF-Rs appear in these biological fluids is not fully understood.

Reactive oxygen intermediates (ROIs) are now recognized as important candidates for cellular activation and physiology (29, 30). Extracellular ROIs such as hydrogen peroxide can easily penetrate lipid membranes and potentially affect every molecule in the cell. Hydrogen peroxide is one of the predominant oxidants generated by both neutrophils and macrophages, likely sources of in situ oxidant regulation in the lung (31).

Shedding of sTNF-Rs is mediated by a metalloproteinase that is located near the plasma membrane and is activated by protein kinase C (35). A vascular matrix metalloproteinase is reported to be activated directly by ROIs (39). We investigated the effects of hydrogen peroxide on the shedding of sTNF-Rs in A549 cells to determine whether ROIs are involved in the shedding of sTNF-R. The effects of a metalloproteinase inhibitor, radical scavengers, and protein kinase inhibitors on shedding were also evaluated in this study. Finally, we showed how hydrogen peroxide modulates levels of gene expression by Northern blot analyses and surface expression by 125I-TNF specific binding.

    Materials and Methods

Abstract
Introduction
Materials and Methods
Results
Discussion
References

Cell and Tissue Culture

A549, a human pulmonary epithelial cell line (HSRBB Cell Bank, Osaka, Japan) was cultured in RPMI 1640 medium with 2 mM glutamine, 10 U/ml penicillin, 10 µg/ ml streptomycin, and 10% fetal bovine serum. Unless otherwise indicated, 24 h after incubation with serum-free RPMI 1640 medium, A549 cells were incubated alone or with either hydrogen peroxide (50 to 1,000 µM; Wako Pharmaceutical Co., Tokyo, Japan) or phorbol myristate acetate (PMA; 10 ng/ml; Sigma Chemical Co., St. Louis, MO) for 1, 6, or 24 h. Cell viability after treatment of either hydrogen peroxide or PMA was evaluated by trypan blue dye exclusion test and morphological findings with a microscope. In parallel studies to evaluate apoptosis, cells were labeled with 200 µM Hoechst 33342 (Calbiochem, San Diego, CA) for 2 min at room temperature. Labeled nuclei were evaluated for apoptotic body using a fluorescence microscope (BX-FLA; Olympus Co., Tokyo, Japan).

Shedding of sTNF-Rs

Both type I soluble TNF receptor (sTNF-RI) and type II soluble TNF receptor (sTNF-RII) in the culture supernatants of A549 cells were quantified using enzyme-linked immunoassay (Quantikine; R&D Systems, Minneapolis, MN). Culture supernatants were harvested after the centrifugation (3,000 rpm, 5 min). To investigate the specificity of hydrogen peroxide-induced shedding of sTNF-Rs, a hydrogen peroxide-detoxified enzyme, catalase (200 U/ml; Sigma), and the hydroxyl radical scavengers dimethyl sulfoxide (DMSO; 0.1 to 1%; Sigma) and dimethyl thiourea (DMTU; 50, 75 mM; Sigma) were added before either hydrogen peroxide or PMA treatment. Furthermore, to evaluate the role of protein kinases in the signal transduction by hydrogen peroxide, calphostin C (50 nM; LC Laboratories, Woburn, MA) (40), a protein kinase C inhibitor, genistein (1 µg/ml; LC Labs) (41), a tyrosine kinase inhibitor, or H-89 (50 nM; LC Labs) (42), a protein kinase A inhibitor, was added before either hydrogen peroxide or PMA stimulation, and sTNF-Rs were quantified in culture supernatants of A549 cells. A metalloproteinase inhibitor, KB-R8301 (10 µM; a generous gift from Kanebo, Osaka, Japan) (43), was used to confirm the contribution of metalloproteinase to the shedding of sTNF-Rs.

Quantitation of Receptor Level

To evaluate the binding of 125I-TNF proteins (45.2 µCi/µg; DuPont Company, Wilmington, DE) to A549 cells, the cells were seeded on culture medium into a 15-mm tissue culture plate (Sumilon, Tokyo, Japan) at a density of 2 × 105 cells/plate. After a 1- to 6-h incubation period, at 37°C, in the absence or the presence of hydrogen peroxide (100 to 500 µM) or PMA (10 ng/ml), the plates were transferred to ice. The growth medium was then removed, and 125I-TNF was applied, either alone or in the presence of an excess of the unlabeled TNF (100 ng/ml; Genzyme Corp., Cambridge, MA) in 150 µl phosphate-buffered saline containing 0.5% bovine serum albumin (PBS/BSA) as previously described (13). One hour after incubation at 4°C with constant shaking, the A549 cells were rinsed three times with PBS/BSA, detached in 0.25% trypsin with 1% triton X-100, and transferred to vials to determine the radioactivities. Specific binding of TNF was calculated by subtracting the values of binding observed in the presence of an excess of the unlabeled TNF from the value of binding observed with the labeled TNF alone. The data are presented as means ± SD for quadruplicate samples.

Northern Blot Analysis

Total cellular RNA was isolated by the acid guanidinium thiocyanate-phenol-chloroform method (44). RNA (12 µg) was electrophoresed in 1.2% agarose gel containing 3 M formaldehyde in a 4-morpholinepropanesulfonic acid buffer (45) and transferred to a nylon membrane (Nytran; Schleicher and Schuell, Inc., Keene, NH). Membranes were prehybridized with hybridization buffer containing 0.5 M sodium phosphate buffer, 1 mM ethylenediaminetetraacetic acid, 0.5% BSA, and 7% sodium dodecyl sulfate (SDS) at 65°C for 6 h. Hybridization was performed at 65°C for 36 h with a 32P-labeled TNF-RI probe generated by the random priming method (46). A 304-bp cDNA segment including the sequence from the HindIII site to the EcoRI site of the TNF-RI cDNA was used as a probe as described previously (13). Membranes were washed sequentially at 25°C in 2× standard sodium citrate (SSC)/0.1% SDS, 0.5× SSC/ 0.1% SDS, and finally at 65°C in 0.1× SSC/0.1% SDS. Blots were then exposed to film (XAR-5; Eastman Kodak Co., Rochester, NY) with an intensifying screen (Eastman Kodak Co.).

Statistical Significance

Data on concentrations of sTNF-RI in culture media and specific 125I-TNF binding were analyzed by analysis of variance. A P < 0.05 value was considered to have statistical significance.

    Results

Abstract
Introduction
Materials and Methods
Results
Discussion
References

Hydrogen Peroxide Induces Shedding of sTNF-RI from A549 Cells

Resting A549 cells spontaneously shed sTNF-RI. Hydrogen peroxide accelerated the shedding of sTNF-RI into the culture medium (Figure 1a), although PMA enhanced the shedding of sTNF-RI more intensely (Figure 1b). Each shedding level was completely blocked by pretreatment with a metalloproteinase inhibitor, KB-R8301. Inhibition by KB-R8301 of hydrogen peroxide-induced shedding of sTNF-RI was dose-dependent (data not shown). The addition of catalase to the culture inhibited shedding mediated by hydrogen peroxide but not shedding mediated by PMA.


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  		Figure 1.   Hydrogen peroxide enhances shedding of sTNF-RI. (a) A549 cells were pretreated in the presence or absence of either KB-R8301 (10 µM) or catalase (200 U/ml) for 1 h, and stimulated with hydrogen peroxide (100 µM) for 24 h. (b) Similarly, A549 cells were pretreated for 1 h and stimulated with PMA (10 ng/ml) for 24 h. Culture supernatants were evaluated for sTNF-RI. Data shown are means ± SD of duplicate assays.

Hydrogen peroxide induced the shedding of sTNF-RI in dose-dependent fashions (Figure 2a). Maximal shedding of sTNF-RI was observed at the concentration of 500 µM hydrogen peroxide and declined with higher concentrations. Following a fixed dose of hydrogen peroxide (100 µM), shedding of sTNF-RI was accelerated up to 6 h compared with the unstimulated condition in A549 cells (Figure 2b). We could not detect any sTNF-RII in culture supernatants from both resting and stimulated A549 cells (data not shown). Cell viability assessed by trypan blue dye kept > 95%, and morphologically no cellular detachment occurred through the experiments except at a concentration of 1,000 µM hydrogen peroxide. Consistent with previous studies (47), few apoptotic bodies were observed in A549 cells treated with 100 to 1,000 µM hydrogen peroxide (less than 1%).


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  		Figure 2.   (a) Dose-dependent effects of hydrogen peroxide on sTNF-RI shedding from A549 cells. Hydrogen peroxide (50, 100, 500, and 1,000 µM) was applied for 6 h, and the level of sTNF-RI in culture supernatant was determined. Data shown are means ± SD of quadruplicate assays. (b) Time-dependent shedding of sTNF-RI from A549 cells by hydrogen peroxide. A549 cells were cultured in the absence or presence of hydrogen peroxide (100 µM) for 1, 6, 12, and 24 h. Triplicate culture supernatants were evaluated for sTNF-RI. Data shown are means ± SD.

Effects of Hydroxyl Radical Scavengers on Hydrogen Peroxide-Induced Shedding of sTNF-RI

The addition of such hydroxyl radical scavengers as DMSO and DMTU to the culture hindered hydrogen peroxide- induced shedding of sTNF-RI (Figure 3a). Dose-dependent inhibition was demonstrated in the case of DMSO. Interestingly, DMSO and DMTU pretreatment also inhibited PMA-induced sTNF-RI shedding in A549 cells (Figure 3b).


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  		Figure 3.   Effects of pretreatment with radical scavengers on levels of sTNF-RI shed by hydrogen peroxide and PMA stimulation in A549 cells. (a) A549 cells were pretreated with DMSO (0.1, 0.2, and 1%) or DMTU (50 mM) for 1 h and stimulated with hydrogen peroxide (100 µM) for 6 h. Quadruplicate culture supernatants were evaluated for sTNF-RI. (b) A549 cells were pretreated with DMSO (0.1 and 1%) and DMTU (75 mM) for 1 h and stimulated with PMA (10 ng/ml) for 6 h. Triplicate culture supernatants were evaluated for sTNF-RI. Data shown are means ± SD. *P < 0.01, **P < 0.001 versus hydrogen peroxide or PMA.

Protein Kinases Involved in the Signal Transduction Pathways of Hydrogen Peroxide-Induced Shedding of sTNF-RI

Calphostin C but not genistein and H-89 inhibited the shedding of sTNF-RI induced by hydrogen peroxide (Figure 4a). The inhibition of shedding TNF-RI by calphostin C was dose-dependent (data not shown). This result was the same in the case of PMA in which inhibition of protein kinase C decreased the shedding of sTNF-RI after PMA stimulation, but inhibition of tyrosine kinase and protein kinase A did not (Figure 4b).


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  		Figure 4.   Effects of pretreatment with protein kinase inhibitors on levels of sTNF-RI shed by hydrogen peroxide and PMA stimulation in A549 cells. A549 cells were pretreated with calphostin C (50 nM; cal C), genistein (1 µg/ml; gen), and H89 (50 nM) for 1 h. Because these protein kinase inhibitors contain DMSO (< 0.1%) as a solvent, control A549 cells were pretreated with 0.1% DMSO. After preincubation, A549 cells were stimulated with 100 µM hydrogen peroxide (a) and 10 ng/ml PMA (b) for 6 h. Quadruplicate culture supernatants were evaluated for sTNF-RI. Data shown are means ± SD. **P < 0.001 versus 0.1% DMSO and each stimulant.

TNF Binding to Unstimulated and Hydrogen Peroxide-Stimulated A549 Cells

At 1 and 6 h after incubation with hydrogen peroxide, specific TNF binding to A549 cells was decreased in a dose-dependent fashion (Table 1). In contrast, TNF binding to A549 cells was markedly decreased to one-quarter the level of resting cells after 1 h and remained decreased after 6 h stimulation with PMA.

                              
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TABLE 1
Effect of hydrogen peroxide and PMA on 125I-TNF binding in A549 cells

TNF-RI Gene Expression in A549 Cells

Effects of hydrogen peroxide (100 µM) on TNF-RI gene expression in A549 cells are shown in Figure 5. Northern blot analyses demonstrated that A549 cells express 3.0-kb type I TNF-R mRNA transcript and that hydrogen peroxide did not modulate TNF-RI gene expression during the 24-h period. Ethidium bromide-stained agarose gel showed equal levels of total cellular RNA applied in each lane.


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  		Figure 5.   Hydrogen peroxide did not modulate TNF-RI gene expression in A549 cells. A549 cells were treated both with and without hydrogen peroxide (1, 10, 100, and 500 µM) for 24 h, and total RNA (12 µg) was extracted and subjected to Northern blot analyses. Nylon membranes were hybridized with a 32P-labeled type I TNF-R cDNA probe (upper panel ). The sizes of mRNA transcripts are indicated by arrows. Ethidium bromide-stained agarose gel (lower panel ). The data shown are representative of two independent experiments.

    Discussion

Abstract
Introduction
Materials and Methods
Results
Discussion
References

In this study, we demonstrated that hydrogen peroxide enhanced the shedding of sTNF-RI on A549 pulmonary epithelial cells. Hydrogen peroxide-mediated shedding of sTNF-RI was fully inhibited by a synthetic metalloproteinase inhibitor, KB-R8301, and was partially hindered by extracellular catalase, intracellular hydroxyl radical scavengers, and protein kinase C inhibitor. In addition, TNF-alpha - specific binding was markedly reduced after stimulation by hydrogen peroxide, which, however, did not accompany modulation of its gene expression.

Hydrogen Peroxide-mediated Shedding of sTNF-RI

A variety of stimuli are known to regulate the shedding of sTNF-RI in multiple cell types. TNF-alpha , interleukin (IL)-1, PMA, and prostaglandin E2 have been reported to shed sTNF-RI in vitro (13, 35, 36, 48). In neutrophils, adherence per se to a biological surface can induce the release of sTNF-RI (49). Lipopolysaccharide, IL-1alpha , and TNF induce the shedding of sTNF-RI in vivo (50, 51). A continuous intravenous infusion of IL-6 into cancer patients results in an increase in sTNF-RI (52). The present finding on hydrogen peroxide added a new stimulus for the shedding of sTNF-RI in A549 cells in vitro.

Both hydrogen peroxide- and PMA-mediated shedding of sTNF-RI were completely inhibited by a pretreatment with the metalloproteinase inhibitor KB-R8301, which inhibits the release of soluble Fas ligand (FasL) from human FasL cDNA transfectants and activated human T cells (43). These results are consistent with the finding that a cell surface metalloproteinase is involved in the shedding process for sTNF-Rs (34, 37, 38). Because shedding of the sTNF-Rs as well as the IL-6 receptor can be inhibited by a TNF-alpha proteinase inhibitor, which is a metalloproteinase inhibitor and has been originally identified as an inhibitor of the release of TNF-alpha from its membrane-bound precursor (37), it may be possible that the shedding of other soluble cytokine receptors can be regulated by ROIs. The amount of sTNF-RI shedding caused by hydrogen peroxide was less than that of PMA, and the time course of shedding looks transient. These findings may be explained by the short life of ROIs in the in vitro system.

Intracellular Mechanism of Shedding of sTNF-RI by Hydrogen Peroxide

The finding that extracellular catalase can inhibit the shedding of sTNF-RI by hydrogen peroxide but not by PMA supports evidence that hydrogen peroxide per se is an enhancer for shedding sTNF-RI. It has been reported that ROIs, including hydrogen peroxide, directly regulate the activity of a matrix metalloproteinase (39). Whether metalloproteinases' involvement in the shedding of soluble cytokine receptors is identical to already-known matrix metalloproteinases still remains to be elucidated; however, ROIs may directly activate an unknown metalloproteinase responsible for shedding of sTNF-RI. Hydroxyl radical, which formed via the hydrogen peroxide-dependent Fenton reaction, may be an important messenger in the signal transduction pathway for shedding induced by hydrogen peroxide, as DMSO and DMTU inhibited the hydrogen peroxide-induced shedding of sTNF-RI.

Protein kinases C and A have both been reported to be involved in the generation of sTNF-RI (53). However, this study, using the A549 cell line, demonstrated that hydrogen peroxide modulated shedding of sTNF-RI mainly by the activation of protein kinase C, not protein kinase A. This result accords well with the finding that ROIs activate protein kinase C (54).

It is interesting that PMA-induced shedding of sTNF-RI was blocked by DMSO and DMTU. These results suggest that PMA-induced shedding of sTNF-RI may be partially mediated by ROIs. Because PMA is known to activate protein kinase C, the hydroxyl radical may be a signal transducer that exists in the downstream of protein kinase C.

Modulation of Surface Expression of TNF-RI by Hydrogen Peroxide

Downregulation of TNF-alpha binding by hydrogen peroxide was augmented in proportion to the concentration of hydrogen peroxide in the culture medium. Decreased surface expression of TNF-R by hydrogen peroxide can be explained in several ways. It is conceivable that enhanced shedding of sTNF-RI as demonstrated in our study can cause a decrease in TNF-alpha binding. Levels of decreased 125I-TNF binding seem to be well correlated to the degree of shedding of sTNF-RI as demonstrated in Figure 2a and Table 1. Shedding of sTNF-RI is also reported to downregulate the surface expression of TNF-R in other cell lines (55). The internalization of TNF-RI may occur after stimulation with hydrogen peroxide. However, there is no report that activation of protein kinase C could internalize TNF-Rs. It is also possible that hydrogen peroxide downregulates TNF-alpha -binding affinity. This point is controversial because the relationship between the activation of protein kinase C and TNF-binding affinity remains unknown (56, 57). Further studies will be needed to clarify these points. Nevertheless, the enhanced shedding of sTNF-RI and reduced TNF-alpha binding after stimulation with hydrogen peroxide would have biological and clinical implications.

We showed that the shedding of sTNF-RI was not parallel to TNF-R gene expression in which hydrogen peroxide did not change TNF-RI mRNA transcript levels in A549 cells. On the other hand, we have previously demonstrated that PMA upregulates TNF-RI mRNA levels in A549 cells (13). Because the half-life of hydrogen peroxide is very short in the in vitro condition, it might be valuable to study the effects of continuous exposure to low doses of ROIs, as noted in vivo at the inflammatory site, on TNF-RI gene expression.

We conclude that hydrogen peroxide enhanced the shedding of sTNF-RI from A549 cells, which resulted in decreased surface expression, and activation of protein kinase C and matrix metalloproteinase were involved in these processes. The modulation of TNF-R levels on lung epithelial cells by ROIs would imply that the response to TNF mediated by target cell receptors can be modulated by ROIs such as hydrogen peroxide. This study suggests one of the important interactions between ROIs and cytokine receptors in various pathological conditions, including inflammatory lung diseases.

    Footnotes

Address correspondence to: Hidenori Nakamura, M.D., The First Department of Internal Medicine, Yamagata University School of Medicine, Iida-Nisi 2-2-2 Yamagata 990-23, Japan. E-mail: hnakamur{at}med.id.yamagata-u.ac.jp

(Received in original form October 20, 1997 and in revised form April 28, 1998).

Abbreviations: dimethyl sulfoxide, DMSO; dimethyl thiourea, DMTU; phorbol myristate acetate, PMA; reactive oxygen intermediates, ROIs; sodium dodecyl sulfate, SDS; standard sodium citrate, SSC; soluble tumor necrosis factor receptor, sTNF-R; tumor necrosis factor-alpha , TNF-alpha .

Acknowledgments: This study was supported in part by grants-in-aid for Scientific Research (No. 09670597) from the Ministry of Education, Science and Culture, Japan. The authors gratefully acknowledge Toshiki Miyazaki and Eiji Tsuchida for their technical assistance in this study.
    References

Abstract
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Materials and Methods
Results
Discussion
References

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