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The Journal of Immunology, 1998, 160: 555-558.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Detection of MCP-4 in Dermal Fibroblasts and Its Activation of the Respiratory Burst in Human Eosinophils1

Holger Petering, Renate Höchstetter, Daniela Kimmig, Regina Smolarski, Alexander Kapp and Jörn Elsner2

Department of Dermatology, Hannover Medical School, Hannover, Germany


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
CC-chemokines are an important family of proinflammatory mediators that promote the recruitment and activation of human eosinophils in chronic inflammatory diseases. Recently, a novel human CC-chemokine, monocyte chemotactic protein 4 (MCP-4), has been reported that shows amino acid sequence similarities with eotaxin and RANTES, induces chemotaxis of eosinophils, and signals through specific chemokine receptors. In this study, we investigated the effect of MCP-4 on different eosinophil effector functions leading to the activation of the respiratory burst. In human eosinophils, MCP-4 dose dependently induced the production of reactive oxygen species and actin polymerization as a related event. Pretreatment of eosinophils with different enzyme inhibitors interacting with the signal transduction cascade revealed that Gi protein, protein kinase C, tyrosine kinase, and phosphatidylinositol-3-kinase are involved in the signaling following stimulation with MCP-4. In addition, cytokine-stimulated human dermal fibroblasts expressed high levels of MCP-4 mRNA, suggesting that fibroblasts are a physiologic source of MCP-4. Therefore, this study demonstrates that there is an important role of MCP-4 in the activation of eosinophils and that the interaction between dermal fibroblasts and human eosinophils may play an important role within the cytokine network.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Inflammation is normally a protective response to a range of exogenous and endogenous disorders, but in certain chronic inflammatory diseases such as bronchial asthma and atopic dermatitis, the human eosinophil seems to be excessively activated (1, 2). The mechanisms that control the tissue recruitment of eosinophils are of fundamental importance. A number of factors have been described as activators of eosinophils; these include C5a, C3a, PAF, and 5-oxo-eicosanoids and chemokines such as eotaxin (3, 4, 5, 6, 7). Chemokines are classified into four subfamilies, C-X-C, C-C, C, and CX3C, according to conserved cysteines at the amino-terminal domain (8). Belonging to the CC-chemokine subfamily are RANTES (9), MCP-3 (10), and eotaxin (11, 12), which are characterized as potent chemokines with a discrete or, in the case of eotaxin, absolute target-cell selectivity for human eosinophils.

Uguccioni et al. (13) have recently reported a new CC-chemokine that induced chemotaxis of human eosinophils and led to a release of cytosolic free calcium ([Ca2+]i).3 Desensitization experiments revealed that the chemokine was signaling through distinct receptors (14). The new chemokine was termed monocyte chemotactic protein 4 (MCP-4). In addition, Godiska et al. screened the GenBank Expressed Sequence Tags database and uncovered a cDNA sequence identified later on as the CC-chemokine MCP-4 (15).

In this study, we have characterized the effects of MCP-4 on the respiratory burst and related events such as actin polymerization in human eosinophils in comparison with RANTES, MCP-3, and eotaxin. In addition, we studied the effects of different enzyme inhibitors on the signal transduction cascade after stimulation of eosinophils with MCP-4. Furthermore, RT-PCR analysis of cytokine-stimulated fibroblasts was conducted for the detection of mRNA specific for MCP-4.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Chemokines, enzyme inhibitors, and Abs

Recombinant human chemokines were obtained from Peprotech Inc. (London, U.K.). C5a was from Sigma (Deisenhofen, Germany). Pertussis toxin, staurosporin, wortmannin, and genistein were obtained from Calbiochem/Novabiochem (San Diego, CA). Anti-CD16 Abs were obtained from Immunotech (Hamburg, Germany) and coated Dynabeads M-450 from Dynal (Hamburg, Germany).

Purification of human eosinophil granulocytes

Human eosinophils were recovered using a combination of discontinuous Ficoll density gradient centrifugation and negative selection with anti-CD16 Ab-coated Dynabeads M-450 as described previously (6, 16). The final preparation consisted of up to 99.5% eosinophils.

Assessment of actin polymerization in human eosinophils

The relative F-actin content of purified human eosinophils was determined by nitrobenzoxadiazole (NBD)-phallacidin staining as described by Howard and Meyer (17). Stained cells were analyzed on a Becton Dickinson (San Jose, CA) FACScan with a linear fluorescence channel (FL1), where the detected fluorescence signal was proportional to F-actin content (17). The ratio of the mean channel fluorescence (or integrated fluorescence) between chemotaxin-stimulated and nonstimulated cells was a measure for the relative F-actin content (18).

Lucigenin-dependent chemiluminescence

The measurement of intracellular and extracellular reactive oxygen species was performed using a single-photon imaging system (MTP reader, Hamamatsu Photonics, Herrsching, Germany) for continuous monitoring of the lucigenin-dependent chemiluminescence as described previously (5, 6, 16). Triplicates were measured and indicated as intensity integral counts.

Statistical analysis

Unless otherwise stated, data are expressed as the mean ± SEM. Analysis of variance (ANOVA) was used to compare experimental group to control value. When the global test of differences was significant at the 5% level, pairwise tests of differences between groups were applied (Student’s t test for paired data using 5% significance level, closed test procedure).

mRNA analysis of human dermal fibroblasts

Human dermal fibroblasts were cultured for 36 h in RPMI medium alone or in RPMI with 100 ng/ml IFN-{gamma}, 50 ng/ml IL-4, or 30 ng/ml TNF-{alpha} (Genzyme, Cambridge, MA), respectively. Total RNA was extracted using TRIzol (Life Technologies, Eggenstein, Germany) based on the guanidine isothiocyanate method. RT-PCR was performed using the first-strand cDNA synthesis kit (Boehringer Mannheim, Mannheim, Germany) following the instruction manual as described previously (19, 20). Specific PCR primers were designed according to the human mRNA sequence (GenBank accession No. U46797): MCP-4, antisense 5'-TGAAGCTTCAGCCAGATGCACTC-AACCGT-3' and sense 5'-TGGTCGACTCAAGTCTTCAGGGTGTGAGC-3'; ß-actin, antisense 5'-GAAGGTAGTTTCGTGGATGCC-3' and sense 5'-GAGCGGGAAATCGTG-CGTGACATT-3'.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
Belonging to the CC-chemokine subfamily MCP-3, RANTES and eotaxin have been identified as potent chemokines leading to the production of ROS in human eosinophils (8, 12). Recently, a novel human CC-chemokine, MCP-4, has been reported that shows amino acid sequence similarities and functional parallelism to other chemokines (13, 14, 15). Since MCP-4 is a well-known chemotaxin for eosinophils, in this study we investigated chemotaxis-related events, especially the ROS production in human eosinophils after stimulation with MCP-4.

Effect of MCP-4 on actin polymerization in human eosinophils

Changes in the average length of actin filaments and, therefore, alterations in the viscoelastic properties of the cytoplasm of eosinophils are necessary not only for chemotactic migration but also for production of ROS where a dynamic self-assembly and disassembly of actin filaments seems to be of biologic importance (21, 22, 23). Flow cytometric measurement with NBD-phallacidin-stained human eosinophils demonstrated that MCP-4 induced a rapid actin polymerization. The highest relative F-actin content was detected 30 s after stimulation. Maximal activation was followed by gradual depolymerization down to basal F-actin levels after 300 s (Fig. 1Go). Compared with eotaxin and RANTES, the effect of MCP-4 on eosinophil actin polymerization was slightly decreased (p < 0.05). MCP-4 was as efficient as MCP-3 in inducing actin polymerization (Fig. 1Go).



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  		FIGURE 1. MCP-4 induces actin polymerization in human eosinophils. Eosinophils were stimulated with 100 ng/ml of MCP-4, MCP-3, eotaxin, and RANTES or 10-8 M of C5a. F-actin content in eosinophils was measured using NBD-phallacidin staining and flow cytometry. The diagram shows relative F-actin content after stimulation at different time points. The ratio of the mean channel fluorescence between chemotaxin-stimulated and nonstimulated cells was a measure for the relative F-actin content. SEM has been omitted for clarity.

 
Effect of MCP-4 as a potent activator of the respiratory burst of human eosinophils

In addition to the effect of MCP-4 on actin polymerization as an important modulatory event in the activation of the respiratory burst, the release of ROS after stimulation with MCP-4 was measured. The production of ROS by excessively activated human eosinophils leads to an extensive destruction of the surrounding tissue at the side of inflammation and provokes the severity of chronic inflammatory diseases (24, 25). Lucigenin-depended chemiluminescence revealed that MCP-4 dose dependently induced the production of ROS in human eosinophils. A significant ROS release was observed in concentrations of 10 ng/ml to 200 ng/ml showing a typical time course (Fig. 2GoA). Half-maximal and maximal production of reactive oxygen species were detected between 30 and 200 ng/ml, respectively (Fig. 2GoA). Higher concentrations of MCP-4 resulted in a diminished ROS production. In activating the respiratory burst, MCP-4 was less effective than eotaxin, which represents the most potent chemokine tested (Fig. 2GoB).



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  		FIGURE 2. MCP-4 induces the production of ROS in human eosinophils measured by lucigenin-dependent chemiluminescence. A, Time course of ROS release following stimulation with MCP-4 in different concentrations (10–500 ng/ml). Maximum efficacy of MCP-4 at a concentration of 200 ng/ml. One representative experiment of eight is shown. B, Effect of MCP-4 on the activation of the respiratory burst of human eosinophils. ROS production of eosinophils following stimulation with MCP-4, MCP-3, eotaxin, RANTES, and C5a are shown. Results are expressed as the mean ± SEM of integral intensity counts out of six experiments. Global differences between groups: p < 0.001 (ANOVA); ***, p < 0.0001 compared with medium-stimulated cells (Student’s t test); **, p < 0.001 compared with medium-stimulated cells (Student’s t test); *, p < 0.01 compared with medium-stimulated cells (Student’s t test). One representative experiment of eight is shown.

 
MCP-4-induced respiratory burst is inhibited by enzyme inhibitors acting on the receptor-mediated signal transduction

In addition to [Ca2+]i, protein kinase C has been implicated in many biologic regulatory mechanisms, including the activation of the NADPH oxidase in eosinophils following stimulation with chemokines (26). Two other classes of kinases, tyrosine kinase and phosphatidylinositol-3-kinase, were identified as playing an important role in the activation of the respiratory burst in human granulocytes (27, 28).The signaling of MCP-4 leading to the activation of the respiratory burst in eosinophils was investigated. For this purpose, eosinophils were preincubated with selective enzyme inhibitors, interfering with the signal transduction cascade. Pretreatment of human eosinophils with 100 nM staurosporin, a protein kinase C inhibitor (29), 1 µM genistein, a tyrosine kinase inhibitor (27), and 10 nM wortmannin, a phosphatidylinositol 3-kinase inhibitor (28), abolished the response to MCP-4. The inhibitory effects of these agents following stimulation with MCP-4 were similar to the other CC-chemokines eotaxin, RANTES, MCP-3, and C5a (Table IGo). In addition, pretreatment of human eosinophils with 2 µg/ml pertussis toxin, which leads to ADP-ribosylation of Gi proteins (30), also inhibited MCP-4-induced ROS production (Table IGo).


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  		Table I. MCP-4-induced ROS production of human eosinophils is inhibited by staurosporin, genistein, wortmannin, and pertussis toxin1

 
To rule out whether ROS production was diminished due to toxic effects of these enzyme inhibitors, we determined the cell viability, which was more than 95% by staining with propidium iodide in flow cytometry.

Human dermal fibroblasts expressed high levels of MCP-4 mRNA following stimulation with IFN-{gamma}, IL-4, and TNF-{alpha}

In previous studies, it was demonstrated that MCP-4 mRNA is expressed at high levels in the small intestine, colon, and lung (15). In addition, in situ hybridization techniques revealed that MCP-4 mRNA is expressed in nasal tissue of allergic and nonallergic sinusitis (13). We investigated whether dermal fibroblasts, which are well-known sources of other CC-chemokines such as eotaxin and RANTES (31, 32), are also able to express mRNA specific for MCP-4.

Human dermal fibroblasts between the fifth and seventh passage were cultured and stimulated for 36 h with 100 ng/ml IFN-{gamma}, 50 ng/ml IL-4, 30 ng/ml TNF-{alpha}, or RPMI alone; these stimuli are thought to induce MCP-4 mRNA (14). RT-PCR was then performed. Using the indicated primer pairs, DNA fragments with an expected size of 234 bp specific for human MCP-4 could be detected in stimulated fibroblasts (Fig. 3Go). No MCP-4 mRNA was discovered in medium-incubated fibroblasts. The same samples were used for RT-PCR with the indicated ß-actin primer pairs as an internal standard amplifying a fragment, with an expected size of 221 bp in all four lanes (Fig. 3Go). The signal quantities of the different MCP-4 amplicons showed higher signal intensities after stimulation of the fibroblasts with IL-4 and TNF-{alpha} than after stimulation with IFN-{gamma}. Therefore, dermal fibroblasts seem to be a physiologic source of MCP-4 following cytokine activation.



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  		FIGURE 3. MCP-4 mRNA is expressed by IFN-{gamma}-, IL-4-, and TNF-{alpha}-stimulated human fibroblasts but not by medium-incubated cells. After stimulation of fibroblasts with 100 ng/ml IFN-{gamma}, 50 ng/ml IL-4, 30 ng/ml TNF-{alpha}, or medium alone, mRNA was isolated, and a first-strand cDNA synthesis was performed. The PCR was conducted with specific primer pairs; the graph shows amplicons for MCP-4 (234 bp) on the left side and ß-actin (221 bp) on the right side. The amplicons were separated electrophoretically in 2.0% agarose gel and stained by ethidium bromide. Lane M, 100 bp DNA size marker; lane 1, IFN-{gamma}-stimulated; lane 2, IL-4-stimulated; lane 3, TNF-{alpha}-stimulated fibroblasts. Lane 4, medium-incubated cells.

 
In summary, this study demonstrates that MCP-4 represents more than a potent activator of human eosinophil chemotaxis. Herein, we find that MCP-4 induces actin polymerization and activates the respiratory burst in human eosinophils. Therefore, it is likely that MCP-4 represents an important CC-chemokine responsible for the selective activation of human eosinophils. The detection of mRNA in human fibroblasts specific for MCP-4 suggests that the interaction between dermal fibroblasts and human eosinophils may play an important role within the cytokine network, which may be of clinical relevance in allergic and autoimmune diseases.


   Footnotes
 
1 This work was supported by Grant EL 16013-2 from the Deutsche Forschungsgemeinschaft. Back

2 Address correspondence and reprint requests to Dr. Jörn Elsner, Hannover Medical School, Department of Dermatology,Ricklinger Str. 5, D-30449 Hannover, Germany. E-mail address: Back

3 Abbreviations used in this paper: [Ca2+]i, cytosolic free calcium; MCP, monocyte chemotactic protein; RT-PCR, reverse transcriptase-PCR; NBD, nitrobenzoxadiazole; ROS, reactive oxygen species. Back

Received for publication September 17, 1997. Accepted for publication November 14, 1997.


   References
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 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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