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Clin Exp Immunol. Jul 1999; 117(1): 159–165.
PMCID: PMC1905464

Augmented production of chemokines (monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α) and MIP-1β) in patients with systemic sclerosis: MCP-1 and MIP-1α may be involved in the development of pulmonary fibrosis

Abstract

To determine the role of chemokines in the pathogenesis of systemic sclerosis (SSc), we examined serum levels, spontaneous production by peripheral blood mononuclear cells (PBMC), and histological distribution in the affected skin, of MCP-1, MIP-1α and MIP-1β in SSc patients. Serum levels of these chemokines were examined by ELISA in 58 patients with SSc and 20 normal controls. The levels of these chemokines in culture supernatants from PBMC were also measured by ELISA. Serum levels and spontaneous production levels by PBMC of MCP-1, MIP-1α, and MIP-1β were significantly elevated in patients with SSc compared with normal controls. Elevated serum levels of MCP-1 and MIP-1α significantly correlated with the presence of pulmonary fibrosis. MCP-1 expression in the skin of SSc was immunohistochemically examined using anti-MCP-1 MoAb. MCP-1 was strongly expressed in the epidermis, inflammatory mononuclear cells, and vascular endothelial cells in the sclerotic skin of SSc patients, but not expressed in any control skin. Furthermore, the MCP-1 expression in inflammatory mononuclear cells and endothelial cells significantly correlated with earlier onset of SSc. Thus, MCP-1, MIP-1α and MIP-1β may be involved in the disease process, possibly by augmenting leucocyte migration into the affected tissues in SSc. Furthermore, MCP-1 and MIP-1α may play an important role in the development of pulmonary fibrosis in SSc.

Keywords: systemic sclerosis, chemokine, pulmonary fibrosis, skin sclerosis

INTRODUCTION

Systemic sclerosis (SSc) is a connective tissue disorder that is characterized by fibrosis and vascular changes in the skin and other visceral organs. In addition, SSc is generally regarded as an autoimmune disorder because of the presence of antinuclear antibodies. Although the pathogenesis of SSc remains unclear, many previous studies have suggested that some cytokines or growth factors regulate the induction of SSc by stimulating the synthesis of extracellular matrix components, injuring the endothelial cells, and modulating the function of leucocytes [1].

These cytokines or growth factors are produced partly by inflammatory cells, including monocytes/macrophages and T lymphocytes, which infiltrate the affected tissues, such as skin or lungs of patients with SSc. Although both CD4+ T cells and CD8+ T cells are found in the skin of patients with SSc, CD4+ T cells are the major subpopulation [2]. In contrast, analysis of the T cells within bronchoalveolar lavage (BAL) of SSc patients with alveolitis shows increased CD8+ T cells and reduced CD4+ T cells [3]. Furthermore, the infiltration of monocytes/macrophages also increased in BAL fluid of SSc patients [4]. Since the migration of leucocytes into tissue is a highly regulated process during immune responses, these findings indicate some abnormalities in regulating the recruitment of specific leucocytes into the affected tissues of SSc, leading to the abnormal accumulation of specific leucocytes, which may be involved in inducing SSc. However, the mechanisms explaining the abnormal accumulation of monocytes/macrophages and lymphocytes in the affected tissues of SSc have not been clarified yet.

Recent investigations have identified many potential molecules involved in the regulation of recruiting leucocytes to the inflammatory regions. Chemokines are the most potent molecules that regulate the migration and recruitment of specific leucocytes. Chemokines are small proteins secreted primarily by leucocytes and related by a conserved four-cysteine motif. These proteins are involved in a variety of inflammatory and immune responses, acting primarily as chemoattractants and activators of specific leucocytes.

MCP-1 is a member of the C-C chemokines [5, 6]. MCP-1 is produced from a wide variety of stimulated normal cells, such as mononuclear leucocytes, fibroblasts, endothelial cells, smooth muscle cells, and epithelial cells. MCP-1 is a potent chemoattractant mainly acting on monocytes/macrophages by regulating the expression of adhesion molecules and cytokines in these cells [7]. In vivo studies suggest that MCP-1 recruits monocytes/macrophages to sites of inflammation in a wide variety of pathological conditions, including atherosclerosis, rheumatoid arthritis (RA), interstitial lung disease (ILD), and glomerulonephritis [6, 810]. MIP-1, including MIP-1α and MIP-1β, are also members of the C-C subfamily of chemokines [11, 12]. MIP-1α and MIP-1β are secreted by activated T cells, B cells, monocytes, and mast cells. Similar to other C-C chemokines, MIP-1α and MIP-1β are chemoattractants for monocytes and T cells. In addition, MIP-1α, but not MIP-1β, has been shown to chemoattract B cells, eosinophils, and basophils. MIP-1α is suggested to play a role in the selective recruitment of mononuclear cells in some pathological conditions such as RA and ILD [12, 13].

Thus, MCP-1, MIP-1α, and MIP-1β have potent chemotactic activities for specific subpopulations of leucocytes and a variety of proinflammatory activities, suggesting their importance in the induction and development of chronic inflammatory processes in SSc. Therefore, we measured production levels of MCP-1, MIP-1α, and MIP-1β in patients with SSc to clarify the role of these chemokines in the pathogenesis of SSc. Our data suggest that augmented production of these chemokines is involved in the disease process in SSc. Especially, MCP-1 and MIP-1α may contribute to the development of pulmonary fibrosis in SSc.

PATIENTS AND METHODS

Patients and controls

Fifty-eight Japanese patients were diagnosed as having SSc according to the criteria proposed by the American College of Rheumatology (formerly, the American Rheumatism Association) [14]. These patients were grouped according to the classification system proposed by LeRoy et al. [15]: 32 patients had limited cutaneous SSc (lSSc) and 26 patients had diffuse cutaneous SSc (dSSc). In this study, we defined SSc having cutaneous involvement of 3 years or less as SSc with early onset. None had a recent history of infection or other inflammatory diseases. Twenty age- and sex-matched Japanese healthy persons were used as normal controls. The clinical and laboratory data reported here were obtained at the time the serum samples were drawn. Organ system involvement was defined as described previously [16]: lung = bibasilar fibrosis on chest radiography; oesophagus = hypomotility shown by barium radiography; joint = inflammatory polyarthralgias or arthritis; and muscle = proximal muscle weakness and elevated serum creatinine kinase. The protocol was approved by the Kanazawa University School of Medicine and Kanazawa University Hospital, and informed consent was obtained from all patients

Serum and cell culture samples

Serum samples were collected from 58 patients with SSc and 20 normal controls. Fresh venous blood samples were centrifuged shortly after clot formation. All samples were stored at −70°C prior to use. Peripheral blood mononuclear cells (PBMC) were isolated from heparinized blood by standard Ficoll–Hypaque gradient centrifugation in 48 patients with SSc and 20 healthy controls. PBMC (1 × 106 cells/ml in RPMI 1640 containing 10% heat-inactivated fetal calf serum (FCS) and supplemented with 50 U/ml penicillin, 50 μg/ml streptomycin) were cultured at 37°C in a 5% CO2 atmosphere. After 48 h of culture, the supernatants were collected by centrifugation and were frozen at −70°C before use.

ELISA

Serum levels of MCP-1, MIP-1α, and MIP-1β, and production levels of these chemokines from PBMC were measured with specific ELISA kits (R&D systems Inc., Minneapolis, MN) according to the manufacturer's protocol. Each sample was tested in duplicated. The detection limits of each assay were as follows: 10 pg/ml for MCP-1; 7.0 pg/ml for MIP-1α; and 11.0 pg/ml for MIP-1β.

Immunohistochemical staining

MCP-1 expression in the skin tissue was determined using mouse IgG1 anti-human MCP-1 MoAb (Pharmingen, San Diego, CA), as previously described [8]. Frozen dermal tissues were air-dried and subsequently fixed in cold acetone. The tissue sections were incubated overnight with anti-MCP-1 MoAb at 4°C, and then treated with biotinylated rabbit anti-mouse IgG antibody for 45 min at room temperature, followed by the incubation with avidin–biotin–peroxidase complex for 30 min. Sections were incubated with diaminobenzidine tetrahydrochloride substrate solution for 5 min, counterstained with methyl green, and embedded in balsam. Isotype-matched control MoAb was used as a negative control.

Statistical analysis

Statistical analysis was performed using Mann–Whitney U-test for comparison of chemokine levels and Fisher's exact probability test for comparison of frequencies. Spearman's rank correlation coefficient was used to examine the relationship between two continuous variables. P < 0.05 was considered statistically significant.

RESULTS

Serum chemokine levels in patients with SSc

Serum levels of MCP-1, MIP-1α, and MIP-1β in patients with SSc and normal controls are shown in Fig. 1. Serum MCP-1 and MIP-1β levels, which were detected in all the samples, were significantly elevated in patients with SSc when compared with normal controls (P < 0.0005 and P < 0.05, respectively). Concerning subgroups SSc, serum MCP-1 and MIP-1β levels in both lSSc and dSSc patients were significantly higher than in controls. Although MIP-1α was detected only in a limited number of both SSc patients and normal controls, the detection of MIP-1α in sera from patients with SSc (20/58, 34%) was more frequent than in sera from normal controls (3/20, 15%; P < 0.05). Serum MIP-1α was detected more frequently in dSSc (10/26, 38%) than in normal controls (15%, P < 0.05), although the difference in frequency between patients with lSSc (10/32, 31%) and normal controls was not significant. No significant difference between lSSc and dSSc was observed in serum levels of MCP-1, MIP-1α, and MIP-1β. In addition, there were no significant correlations between any pair of these three chemokine levels in patients with SSc.

Fig. 1
Serum levels of MCP-1 (a), MIP-1α (b), and MIP-1β (c) in normal controls, patients with limited cutaneous systemic sclerosis (lSSc), and diffuse cutaneous SSc (dSSc). The short bar indicates the median value in each group. A broken line ...

Values higher than the mean + 2 s.d. of the control serum samples were considered to be elevated in this study. As shown in Table 1, the frequency of pulmonary fibrosis in the SSc patients with elevated MCP-1 levels (46%) was significantly higher than in those with normal MCP-1 levels (19%, P < 0.05). Similarly, patients with elevated MIP-1α levels had pulmonary fibrosis more frequently than those with normal MIP-1α levels (56% versus 21%, P < 0.05; Table 2). The correlation between serum MCP-1 or MIP-1α levels and the presence of pulmonary fibrosis was not due to the presence of anti-topoisomerase I antibody, since the frequency of anti-topoisomerase I antibody positivity in SSc patients with elevated MCP-1 or MIP-1α levels was similar to that in SSc patients with normal MCP-1 or MIP-1α levels (data not shown). Patients with elevated MIP-1β levels had an elevated erythrocyte sedimentation rate (ESR) and IgG levels more frequently than those with normal MIP-1β levels (79% versus 45%, P < 0.05, and 71% versus 34%, P < 0.05, respectively; Table 3). Thus, serum levels of MCP-1, MIP-1α, and MIP-1β increased in patients with SSc, suggesting a possible contribution of these chemokines to the pathogenesis of SSc. Furthermore, MCP-1 and MIP-1α may be involved in the development of pulmonary fibrosis.

Table 1
Clinical and laboratory features of the patients with systemic sclerosis (SSc) classified according to serum MCP-1 levels
Table 2
Clinical and laboratory features of the patients with systemic sclerosis (SSc) classified according to serum MIP-1α levels
Table 3
Clinical and laboratory features of the patients with systemic sclerosis (SSc) classified according to serum MIP-1β levels

Production levels of chemokines from PBMC

The augmented serum levels of MCP-1, MIP-1α, and MIP-1β in patients with SSc prompted examination for the spontaneous production of these chemokines from PBMC of patients with SSc. As shown in Fig. 2, production levels of MCP-1, MIP-1α, and MIP-1β were significantly elevated in patients with SSc when compared with normal controls (P < 0.01, P < 0.05, and P < 0.05, respectively). Concerning subgroups of SSc, production levels of MCP-1, MIP-1α, and MIP-1β from PBMC were significantly elevated in both lSSc and dSSc when compared with normal controls. However, no significant difference between lSSc and dSSc was observed in these chemokine levels. Production levels of MIP-1α significantly correlated with those of MIP-1β in patients with SSc (r = 0.40, P = 0.03; data not shown), while production levels of MCP-1 from PBMC did not correlate with those of either MIP-1α or MIP-1β. Therefore, the increased spontaneous production of these chemokines in PBMC from SSc patients may contribute to the elevated serum levels of these chemokines.

Fig. 2
Production levels of MCP-1 (a), MIP-1α (b), and MIP-1β (c) by cultured peripheral blood mononuclear cells from normal controls and patients with limited cutaneous systemic sclerosis (lSSc) and diffuse cutaneous systemic sclerosis (dSSc). ...

Immunohistochemical expression of MCP-1 in the skin of SSc

It is known that MCP-1 is produced from various normal cells, such as mononuclear leucocytes, fibroblasts, endothelial cells, smooth muscle cells, and epithelial cells, once these cells are stimulated or activated. Therefore, to determine the expression of MCP-1 in the sclerotic skin of SSc patients, we performed immunohistochemical analysis using anti-MCP-1 MoAb (Table 4 and Fig. 3). In the skin from normal persons, MCP-1 expression was not observed in epidermal cells, infiltrating mononuclear cells, and endothelial cells. In contrast, in the sclerotic skin of all SSc patients studied, epidermal cells strongly expressed MCP-1, the detection of which was more frequent than in normal controls (P < 0.05). Similarly, MCP-1 was expressed in mononuclear cells or vascular endothelial cells in 41% (9/22) of SSc patients. Furthermore, the frequency of infiltrating mononuclear cells and endothelial cells that produced MCP-1 was significantly higher in SSc patients with early onset (8/14, 57%) than in SSc patients with late onset (1/8, 13%; P < 0.05). The infiltration of mononuclear cells in the skin tended to be greater when epidermal and endothelial cells expressed MCP-1 than when they were negative for MCP-1 staining (data not shown). Thus, these data suggest that augmented expression of MCP-1 in the sclerotic skin of SSc, especially in the early phase of the disease, is involved in the development of skin sclerosis.

Fig. 3
Immunohistochemical expression of MCP-1 in epidermis of skin tissues from a patient with systemic sclerosis (SSc) (a) and from a normal control (b). Immunohistochemical expression of MCP-1 in vascular endothelial cells (c) of skin tissues from a patient ...
Table 4
Immunohistochemical detection of MCP-1 in the skin tissues of systemic sclerosis (SSc)

DISCUSSION

This study shows that serum MCP-1 and MIP-1β levels were significantly elevated in patients with SSc in comparison with normal controls. In addition, serum MIP-1α was detected more frequently in patients with SSc when compared with normal controls. MCP-1 has been known as an important chemotactic mediator of monocytes/macrophages, although recent studies revealed that MCP-1 chemoattracts T cells and endothelial cells [6]. Both MIP-1α and MIP-1β can chemoattract monocytes/macrophages and T cells. Additionally, MIP-1α has also been shown to have chemoattractant effects on B cells, eosinophils, and basophils. A group has reported that MIP-1α chemoattracts CD8+ T cells while MIP-1β chemoattracts CD4+ T cells [17]. However, the effect of MIP-1β on CD4+ T cells is controversial, since another group has demonstrated that MIP-1β chemoattracts CD8+ T cells [18]. Thus, these findings suggest that differential recruitment of specific subpopulations of leucocytes into the affected tissues of SSc is induced by the differential expression of these chemokines.

In this study, serum levels of MCP-1 significantly correlated with the presence of pulmonary fibrosis. On the lung biopsy from SSc patients with pulmonary fibrosis, there was the accumulation of macrophages in the interstitium, with total increased number of macrophages in BAL fluid [4, 19]. Therefore, the abnormal accumulation of macrophages in the lungs may result from augmented local production of MCP-1 in the affected lungs of SSc, leading to elevated serum MCP-1 levels in patients with SSc. Consistent with this possibility, up-regulation of MCP-1 on lung epithelial cells was observed in idiopathic pulmonary fibrosis with increased interstitial macrophage infiltration [9]. Similarly, the finding that the elevated serum levels of MIP-1α in patients with SSc correlated with pulmonary fibrosis in this study could explain why CD8+ T cells dominantly infiltrate into BAL fluid of patients with SSc, since MIP-1α chemoattracts CD8+ T cells preferentially [17]. A recent study has shown that levels of MIP-1α are significantly elevated in BAL fluid of SSc patients with alveolitis when compared with those of SSc patients without alveolitis or normal controls [20]. In addition, enhanced MIP-1α expression has been reported in alveolar and interstitial macrophages, and interstitial fibroblasts of patients with ILD [13]. Therefore, these findings suggest that MCP-1 and MIP-1α play an important role in induction and/or development of pulmonary fibrosis in SSc via recruiting macrophages and CD8+ T cells to the affected lungs.

In this study, MCP-1 was more frequently expressed in epidermis, inflammatory mononuclear cells, and vascular endothelial cells of the sclerotic skin from patients with SSc compared with normal skin. Furthermore, MCP-1 expression was more frequently detected in SSc patients with short disease duration than in those with long disease duration. Therefore, augmented MCP-1 expression in the skin might contribute to the initiation of skin sclerosis in SSc. Since macrophages are increased in the skin of SSc patients, especially early in the disease [3], it is possible that the augmented expression of MCP-1 abnormally recruits macrophages into the skin of SSc, leading to the initiation of skin sclerosis by some cytokines/growth factors produced by macrophages. Transforming growth factor-beta (TGF-β) is likely to be one of the most significant candidates responsible for fibrosis in SSc [1]. TGF-β is secreted from macrophages and lymphocytes [21, 22]. There have been several reports that TGF-β expression is increased in the skin from patients with SSc, especially in the early stages [2325]. Furthermore, it has been reported that MCP-1 stimulates fibroblast collagen synthesis indirectly via endogenous up-regulation of TGF-β expression [26]. Taken together, these data suggest that MCP-1 is involved in the initiation of skin sclerosis in SSc.

Acknowledgments

We thank Masako Matsubara and Yuko Yamada for valuable technical assistance. This work was supported by a grant for basic dermatologic research from Shiseido Co., Ltd.

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