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The Journal of Immunology, 2004, 172: 7721-7725.
Copyright © 2004 by The American Association of Immunologists

IL-16 Is Constitutively Present in Peripheral Blood Monocytes and Spontaneously Released During Apoptosis1

Andreas Elssner, Andrea I. Doseff, Michelle Duncan, Mark Kotur and Mark D. Wewers2

The Dorothy M. Davis Heart and Lung Research Institute and Pulmonary and Critical Care Division, The Ohio State University, Columbus, OH 43210


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Constitutive expression of the pro-molecule of IL-16 has been found in T cells, mast cells, eosinophils, epithelial cells, fibroblasts, and dendritic cells. Here we show that IL-16 is also constitutively present in >98% of freshly isolated human CD14-positive peripheral blood monocytes when analyzed by flow cytometry. Because pro-IL-16 is cleaved to its bioactive mature form by caspase-3, and caspase-3 is also the pivotal effector of apoptosis in monocytes, we asked whether IL-16 release occurs in monocytes that undergo spontaneous apoptosis. As expected, freshly isolated, unstimulated monocytes underwent spontaneous caspase-3 activation. This apoptosis was paralleled by the loss of intracellular IL-16, as detected by flow cytometry, and the concurrent release of IL-16, as detected by ELISA. In contrast, stimulation with bacterial LPS inhibited caspase-3 activation and significantly inhibited the release of IL-16. As a specificity control, IL-1{beta} and IL-8 were not released during spontaneous monocyte apoptosis. In summary, our data demonstrate that monocytes contain IL-16 that is released during spontaneous apoptosis.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Peripheral blood monocytes play a central role in immunity. They are able to initiate and amplify an inflammatory response by releasing cell-signaling molecules. In addition, they represent precursors of dendritic cells and tissue macrophages, which are essential to activate the adaptive immune system and to resolve inflammation. In the absence of an inflammatory stimulus, e.g., bacterial LPS or differentiation factors, monocytes spontaneously undergo programmed cell death (1, 2, 3, 10). By this mechanism, blood monocytes are cleared from the circulation with a half-life of 1–2 days (5, 6). Programmed cell death, or apoptosis, is regulated by a machinery of proteolytic enzymes involving a family of enzymes called caspases (4). These enzymes form a cascade that results in cleavage of intracellular proteins, and finally, disintegration of the cell. Among the caspases, a central role in the execution of apoptosis has been shown for caspase-3 (4, 7, 8, 9, 10). Interestingly, besides its role in programmed cell death, caspase-3 also cleaves the pro-IL-16 into the 121-aa, 17-kDa mature IL-16 (11). IL-16 was first described as a T cell chemoattractant factor (12, 13) and it has been linked to diseases that are characterized by accumulation of CD4-positive cells at the site of inflammation, e.g., asthma (14, 15) and Crohn’s disease (16, 17). However, the (patho)physiological role of IL-16 is yet unclear. IL-16 has been described to be constitutively expressed on the mRNA and protein level in T lymphocytes, mast cells, eosinophils, dendritic cells, and cells of the cerebellum (18). So far, expression of IL-16 in peripheral blood monocytes has not been reported.

In the present research, we demonstrate that 1) IL-16 protein is constitutively expressed in human CD14-positive monocytes; 2) the release of IL-16 by monocytes is paralleled by the activation of caspase-3; and 3) the activation of caspase-3 and release of IL-16 can be blocked by proinflammatory stimuli such as bacterial LPS.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Monocyte purification

Fresh human blood was obtained from normal donors and diluted 1/1 with sterile saline solution. The solution was subsequently centrifuged through a Histopaque-1077 gradient column (Sigma-Aldrich, St. Louis, MO) at 600 x g for 20 min at 4°C. The mononuclear layer was removed, washed, spun twice in RPMI 1640 (Life Technologies, Grand Island, NY), and the cells were counted. From this purified population of PBMC, monocytes were positively selected using anti-CD14-coated magnetic beads (Miltenyi Biotec, Auburn, CA) following the instructions of the manufacturer. This procedure consistently leads to a >98% pure population of CD14-positive cells. Where indicated, LPS (LPS Westphal preparation, Escherichia coli 0127:B8; Difco, Detroit, MI) was added to the freshly isolated monocytes at a concentration of 1 ng/ml. All of our media and reagents have been documented to have subpicogram amounts of endotoxin contamination. In all experiments, monocytes were incubated at a concentration of 1 x 106 cells/ml in serum-free RPMI 1640 at 37°C in 5% CO2. Monocytes were cultured in suspension in 5-ml polystyrene tubes (no. 14959-10A; Fisher Scientific, Hampton, NH) to prevent sticking and activation of the cells.

Flow cytometry analysis

Isolated monocytes were cultured at 106 cells/ml in serum-free RPMI 1640 alone or in serum-free RPMI 1640 containing LPS (1 ng/ml) for the indicated time periods. For flow cytometric analysis, cells were stained with an APC-conjugated Ab to CD14 (clone M{phi}P9; BD Biosciences, Mountain View, CA) and then permeabilized to allow intracellular staining with a PE-conjugated Ab to IL-16 (clone 14.1; BD Biosciences) and FITC-conjugated Ab to active caspase-3 (clone C92–605; BD Biosciences). Extra- and intracellular staining was done using Cytofix/Cytoperm (BD Biosciences) as described in the manufacturer’s protocol. Briefly, CD14-positive monocytes were washed with PBS and resuspended at a concentration of 2 x 107/ml in blocking buffer (cold PBS containing 1% FBS and 200 µg/ml human total IgG) and incubated for 15 min on ice. After gentle mixing, the cells were divided into individual tubes containing 1 x 106 cells each and 20 µl of APC-conjugated anti-CD14 or isotype control was added and incubated for 30 min on ice. After 2 washes with blocking buffer, cells were resuspended in 250 µl of Cytofix/Cytoperm and incubated for 20 min on ice. Cells were washed 2 times with Perm/Wash buffer provided by the kit, before resuspending them in Perm/Wash buffer containing 20 µl of PE-conjugated anti-IL-16 and, where indicated, 20 µl of FITC-conjugated anti-caspase-3. Alternatively, the appropriate isotype controls were added. After incubation for 30 min on ice, cells were washed 2 times with Perm/Wash buffer and finally resuspended with 200 µl of blocking buffer. Flow cytometric analysis was performed using FACSCalibur (BD Biosciences).

Western blot analysis of IL-16

CD14-positive monocytes were washed once with PBS, lysed in protein lysis buffer (50 mM Tris-Cl, pH 8.0, 150 mM NaCl, 2 mM EDTA, and 1% Nonidet P-40) and run on a SDS gel. Proteins were electrophoretically transferred to a nitrocellulose membrane. After blocking nonspecific sites with 5% nonfat dry milk in PBS containing 0.05% Tween 20 for 1 h at room temperature, the nitrocellulose membrane was probed with rabbit polyclonal anti-human-rIL-16 Ab (0.2 µg/ml; R&D Systems, Minneapolis, MN) in PBS/Tween for 2 h at room temperature. The secondary reagent, a streptavidin labeled with HRP (Amersham, Arlington Heights, IL), was used at a dilution of 1/10,000 in PBS/Tween for 45 min at room temperature. The signal was visualized by ECL (Amersham Pharmacia Biotech, Piscataway, NJ).

Quantification of IL-16, IL-1{beta}, and IL-8

IL-16 was quantified by immunoassay using a monoclonal (clone 70719.111; R&D Systems) and a biotinylated rabbit polyclonal Ab (R&D Systems), following the instructions of the manufacturer.

Sandwich ELISAs were developed in our laboratory to detect mature IL-1{beta} as described (10, 20). The coating Ab for the IL-1{beta} ELISA has been modified since the previous description. Briefly, anti-human mouse monoclonal IL-1{beta} Ab (clone 8516; R&D Systems) was used as a coating Ab, and a rabbit polyclonal mature IL-1{beta} Ab (raised against entire 17-kDa mature IL-1) as sandwich Ab. HRP-conjugated goat anti-rabbit Ab (Bio-Rad, Hercules, CA) was used as a developing Ab.

Detection of enzymatic caspase-3 activity with amino trifluoromethyl coumarin (AFC)3

For all AFC preparations, monocytes (3 x 106 cells) were collected by centrifugation and washed with KPM buffer (50 mM KCl, 50 mM PIPES, 10 mM EGTA, 1.92 mM MgCl2, pH 7.0, 1 mM DTT, 0.1 mM PMSF, 10 µg/ml cytochalasin B, and 2 µg/ml protease inhibitors: chymostatin, pepstatin, leupeptin, and antipain). Cells were snap frozen in liquid nitrogen and lysed by four cycles of freeze thawing. The presence of active caspases was determined by AFC assay using a specific fluoro-substrate, as described (10, 19). Lysates were incubated with Asp-Glu-Val-Asp (DEVD)-AFC in a cyto-buffer (10% glycerol, 50 mM PIPES, pH 7, and 1 mM EDTA) containing 1 mM DTT and 20 µM DEVD-AFC (Enzyme Systems Products, Livermore, CA). Release of free AFC was determined using a Cytofluor 4000 fluorometer (filters: 400 nm excitation; 505 nm emission; PerSeptive Biosystems, Framingham, MA).

Statistical analysis

All data were expressed as mean ± SEM. Statistics were performed using Microsoft Excel (Microsoft, Redmond, WA) in combination with Winstat statistical software (R. Fitch Software, Staufen, Germany). Comparisons of groups for statistical difference were done using the Student’s t test or the Wilcoxon matched-pairs signed-ranks test in case of the test for a normal distribution failed. Statistical significance was defined as a p value <0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Monocytes constitutively express IL-16

Since we have previously shown the spontaneous activation of caspase-3 in monocytes (10), we were interested to know whether one of the recognized substrates of caspase-3 is present in fresh monocytes. To do this, freshly isolated human blood monocytes were analyzed by flow cytometry using a fluorochrome-conjugated Ab to cell surface CD14 (Fig. 1). After permeabilization of the cells, a fluorochrome-conjugated Ab to IL-16 was added. We found that 97.7 ± 1.0% (n = 3) of the total cells were positive for CD14. From the CD14-positive cells, 98.5 ± 0.6% (n = 3) were positive for IL-16 as well. Fig. 1A shows the result of one representative donor. As controls, either the anti-IL-16 Ab used was preincubated with rIL-16, or the cells were preincubated with unlabeled Ab of the same clone. In both cases, the fluorescence intensity for IL-16 shifted significantly to the background level (Fig. 1B).



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  		FIGURE 1. Monocytes constitutively express IL-16. Human blood monocytes were isolated by CD14 positive selection and analyzed for the expression of IL-16 by flow cytometry using PE conjugated to clone 14.1 against IL-16 and APC conjugated to CD14 Ab (clone M{varphi}P9). A, Dual expression of IL-16 and CD14. Analysis by flow cytometry revealed that 98.4% of the total cells were positive for CD14. From the CD14-positive cells, 98.5% were positive for IL-16 as well (events upper right quadrant divided by events upper left plus upper right quadrant). B, Specificity of IL-16 detection. As controls, the anti-IL-16 Ab was either preincubated with rIL-16, or the cells were preincubated with unlabeled Ab of the same clone. In both cases, the fluorescence intensity for IL-16 shifted significantly to the background level (a, anti-IL-16 PE; b, isotype control; c, anti-IL-16 PE preincubated with rIL-16; d, cells preincubated with unlabeled anti-IL-16).

 
Western blot analysis of whole cell lysates from freshly isolated CD14-positive monocytes revealed a pattern of bands between 75 and 40 kDa (Fig. 2).



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  		FIGURE 2. IL-16 Western blot analysis of lysates from freshly isolated CD14-positive monocytes. Human monocytes purified as in Fig. 1 were lysed and subjected to SDS-PAGE chromatography and immunoblotted using Ab to IL-16. The Western blot shows a pattern of bands between 75 and 40 kDa indicative of pro-IL-16.

 
Activation of caspase-3 by monocytes is paralleled by loss of intracellular IL-16

It has been previously described that pro-IL-16 has to be cleaved by caspase-3 to its active form (11). If not activated, e.g., by bacterial LPS, monocytes undergo spontaneous apoptosis which is orchestrated by the activation of caspases. Within the caspase cascade, caspase-3 plays a central role in executing monocyte apoptosis (10). Significant caspase-3 activity can be detected in CD14-positive monocytes after 4 h in culture (Fig. 3). Using flow cytometry (Fig. 4), we analyzed the coexpression of active caspase-3 with IL-16 in CD14-positive monocytes and found that as early as 4 h after isolation of fresh monocytes, active caspase-3 was found (data not shown). Significant activation of caspase-3 coincided with the loss of IL-16 at 6 and 8 h (Fig. 4, left panels).



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  		FIGURE 3. Effect of LPS on spontaneous activation of caspase-3 in CD14-positive monocytes. Freshly harvested human blood monocytes as described in Fig. 1 were cultured in RPMI 1640 with 5% FBS and analyzed for caspase-3 activity (by DEVD-AFC cleavage in vitro) at multiple time points. Shown are the differences in spontaneous caspase-3 activity detected with (gray bars) or without (dark bars) LPS. The addition of LPS blocked caspase-3 activation significantly (n = 3; p < 0.05 for the comparison of each time point, Student’s t test).

 


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  		FIGURE 4. Caspase-3 activation coincides with loss of intracellular IL-16 and both are inhibited by LPS. Freshly isolated, unstimulated human monocytes were analyzed by ungated flow cytometry for concurrent expression of intracellular IL-16 (PE-conjugated clone 14.1) on the abscissa and active caspase-3 on the ordinate. Cells were analyzed fresh (0 h) and at 6 and 8 h. The percentages of the IL-16-negative/caspase-3-positive cells are given in the right lower corner of the panels. Addition of LPS led to less IL-16-negative/caspase-3-positive cells (right panels) compared with untreated monocytes (left panels).

 
Activation of caspase-3 and loss of intracellular IL-16 is inhibited by stimulation of monocytes with LPS

As previously shown (10), the spontaneous activation of caspase-3 in monocytes can be effectively blocked by LPS. We found that this was also true for monocytes that were selected with anti-CD14-coated magnetic beads (Fig. 3). Moreover, stimulation of the cells with 1 ng/ml LPS resulted in a marked inhibition of caspase-3 activation as well as preservation of intracellular IL-16 (Figs. 3 and 4, right panels).

By Western blot analysis with an anti-IL-16 Ab, we found that untreated monocytes and 6-h LPS-treated monocytes produced unique protein profiles (Fig. 5). In untreated monocytes, we found a more prominent band between 30 and 35 kDa compared with LPS-treated monocytes. In addition, a band was seen above the 15-kDa marker, indicating that in untreated monocytes undergoing spontaneous cell death, active IL-16 (17 kDa) is present within 6 h.



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  		FIGURE 5. Cleavage of IL-16 in monocytes undergoing spontaneous cell death-inhibitory effect of LPS. After 6 h in culture, lysates from untreated monocytes (–LPS) were compared with LPS-treated monocytes (+LPS) for expression of IL-16 by Western blot. In contrast to LPS-treated cells, untreated monocytes showed additional bands below 35 kDa. The band around 17 kDa (arrow) indicates complete processing to active IL-16 in monocytes undergoing spontaneous cell death.

 
Spontaneous release of IL-16 is inhibited by stimulation of monocytes with LPS

Next we analyzed the supernatants of unstimulated CD14-positive monocytes for the release of IL-16 by ELISA. Consistent with the flow cytometry data, we found release of IL-16 after 3 h of culture. Stimulation of the cells with 1 ng/ml LPS significantly reduced the release of IL-16 (Fig. 6). In contrast to the release of IL-16 in unstimulated monocytes, no release of IL-1{beta} or IL-8 could be detected for the corresponding time points (sensitivity IL-1{beta} ELISA, ~30 pg/ml; sensitivity IL-8 ELISA, ~150 pg/ml).



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  		FIGURE 6. Spontaneous release of IL-16 is inhibited by activation of monocytes with LPS. The supernatants of freshly isolated monocytes were analyzed for the effect of LPS on the release of IL-16 by ELISA after 0–8 h in culture. Unstimulated monocytes are shown in dark bars and LPS (1 ng/ml) -stimulated monocytes in gray bars. IL-16 release was observed at 3, 6, and 8 h in culture. IL-16 release was significantly reduced by stimulation of the cells with 1 ng/ml LPS at the 6- and 8-h time points (*; n = 7, p < 0.05, Wilcoxon matched-pairs signed-ranks test).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
When first described, IL-16 was identified as a T cell chemoattractant factor that was generated from PBMC (12, 13). Constitutive expression of the pro-molecule has been found in a variety of cell types, e.g., lymphocytes (18). Expression of IL-16 is also known for dendritic cells and a role for IL-16 in the cross-talk between dendritic cells and T cells has been suggested (18, 21). Yet expression of IL-16 in blood monocytes, which are precursor cells for dendritic cells and tissue macrophages, has not been described. Here we show that IL-16 is constitutively present in freshly isolated human CD14-positive peripheral blood monocytes.

Pro-IL-16 is cleaved by caspase-3 to its bioactive mature form (11). In contrast, caspase-3 plays a central role in cell apoptosis. If not stimulated, blood monocytes undergo spontaneous apoptosis (1, 2, 3, 10). Because caspase-3 is the pivotal effector caspase in monocytes, we asked the question whether there is a relationship between spontaneous activation of the enzyme and the release of IL-16. We found that caspase-3 activation is paralleled by the loss of IL-16 in monocytes. At the same time, release of IL-16 into the supernatant was observed. Because we and others have previously shown that monocytes can evade apoptosis in the presence of LPS, we hypothesized that LPS would not only inhibit caspase-3 activation but also IL-16 release. As expected, stimulation with LPS not only inhibited caspase-3 activation but also blocked the release of IL-16. These findings indicate that the process of spontaneous monocyte apoptosis is closely associated with the release of IL-16. Interestingly, other cytokines like IL-1{beta} and IL-8 are not released during monocyte apoptosis. Thus, it is unlikely that unspecific cell damage or permeabilization during the course of apoptosis leads to the release of IL-16.

Although a caspase-3-specific tetrapeptide inhibitor would be expected to block IL-16 processing and release, we have elected to not include caspase-3 inhibitor experiments. We were unable to culture our monocytes in the specific caspase-3 inhibitor, DEVD-chloromethyl ketone (cmk), without getting monocyte toxicity. The monocytes were not viable after only a few hours of tissue culture in the presence of 100 µM DEVD-cmk. In a prior publication, we demonstrated the ability of DEVD to prevent ladder formation in monocytes undergoing spontaneous apoptosis (10). However, it is conceivable that DEVD-cmk prevents the generation of ladders, which are dependent upon the generation of active caspase-3, but not the ultimate cell death. Indeed, DEVD-cmk did prevent cleavage of intracellular IL-16 (data not included in the manuscript) but it did not prevent release of pro-IL-16. Although we cannot absolutely exclude a reagent problem, it suggests the possibility that spontaneous monocyte apoptosis may convert to necrotic death if caspase-3 is inhibited. This question will need further investigation, but is not directly relevant to the current report.

It is intriguing to speculate about the meaning of apoptosis-induced activation of IL-16 for the in vivo situation. The expression of CD4 on the target cell is required for mature IL-16 bioactivity (18). IL-16 has been shown to chemoattract not only T cells, but also monocytes and dendritic cells, which also express CD4 on their cell surface. The concentrations of IL-16 we found in the supernatants were in the range of the effective dose as a T cell chemoattractant (EC50 ~10–11 M) (22). Although IL-16 may be a proinflammatory cytokine, it is generally held that IL-16 has T cell immunomodulatory rather than proinflammatory functions. Cruikshank et al. (23) have shown that IL-16 stimulation results in inhibition of TCR stimulation and unresponsiveness in lymphocytes (24). In another study, IL-16 has been identified as an anti-inflammatory cytokine in rheumatoid synovitis (25). IL-16 released by dying unstimulated monocytes may hypothetically serve as a modulatory signal for T lymphocytes that inhibits induction of a T cell-mediated immune response. Further studies are needed to define the role of IL-16 release by monocytes.


   Footnotes
 
1 This work was supported in part by Grant HL40871 from the National Heart Lung and Blood Institute of the National Institutes of Health to M.D.W. and Grant DFG EI229/1-1 to A.E. Back

2 Address correspondence and reprint requests to Dr. Mark D. Wewers, The Ohio State University, 201 Davis Heart and Lung Research Institute, 473 West 12th Avenue, Columbus, OH 43210. E-mail address: wewers.2{at}osu.edu Back

3 Abbreviations used in this paper: AFC, amino trifluoromethyl coumarin; DEVD, Asp-Glu-Val-Asp; cmk, chloromethyl ketone. Back

Received for publication July 11, 2003. Accepted for publication April 14, 2004.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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