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Published ahead of print on February 5, 2003, doi:10.1164/rccm.200209-1113OC
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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1355-1359, (2003)
© 2003 American Thoracic Society

High Plasma Osteopontin Level and Its Relationship with Interleukin-12–mediated Type 1 T Helper Cell Response in Tuberculosis

Yoshinobu Koguchi, Kazuyoshi Kawakami, Kaori Uezu, Kiyoyasu Fukushima, Sigeyuki Kon, Masahiro Maeda, Atsushi Nakamoto, Isoko Owan, Mutsuo Kuba, Norifumi Kudeken, Masato Azuma, Satomi Yara, Takashi Shinzato, Futoshi Higa, Masao Tateyama, Jun-Ichi Kadota, Hiroshi Mukae, Shigeru Kohno, Toshimitsu Uede and Atsushi Saito

First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa; Nagasaki Prefecture Tarami Hospital; Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki; Division of Molecular Immunology, Research Section of Molecular Pathogenesis, Institute for Genetic Medicine, Hokkaido University, Sapporo; Immuno-Biological Laboratories Co., Ltd., Gunma; National Okinawa Hospital, Ginowan; and Second Department of Internal Medicine, Oita Medical College, Oita, Japan

Correspondence and requests for reprints should be addressed to Dr. Kazuyoshi Kawakami, M.D., Ph.D., First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903–0215, Japan. E-mail: kawakami{at}med.u-ryukyu.ac.jp


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Osteopontin (OPN, also known as Eta-1), a noncollagenous matrix protein produced by macrophages and T lymphocytes, is expressed in granulomatous lesions caused by Mycobacterium tuberculosis infection. In the present study, we compared plasma concentrations of OPN in patients with active pulmonary tuberculosis with those of healthy control subjects and patients with sarcoidosis, another disease associated with granuloma formation. Plasma OPN levels were significantly higher in patients with tuberculosis (n = 48) than in control subjects (n = 34) and patients with sarcoidosis (n = 20). OPN levels correlated well with severity of pulmonary tuberculosis, as indicated by the size of lung lesions on chest X-ray films. Furthermore, chemotherapy resulted in a significant fall in plasma OPN levels. In patients with tuberculosis, plasma OPN concentrations correlated significantly with those of interleukin (IL)-12. In vitro experiments showed that OPN production by peripheral blood mononuclear cells infected with Mycobacterium bovis bacillus Calmette–Guérin preceded the synthesis of IL-12 and interferon-{gamma} and that the neutralizing anti-OPN monoclonal antibody significantly reduced the production of IL-12 and interferon-{gamma}. Our results suggest that OPN may be involved in the pathologic process associated with active pulmonary tuberculosis by inducing IL-12–mediated type 1 T helper cell responses.

Key Words: osteopontin • interleukin-12 • tuberculosis • sarcoidosis • Mycobacterium bovis bacillus Calmette–Guérin

Osteopontin (OPN, also known as Eta-1) is a phosphorylated acidic glycoprotein, which contains an arginine-glycine-aspartate–binding motif to the integrin family of adhesion molecules (1–3). OPN has been implicated in a number of physiological and pathologic events (1–3). For example, it is abundantly produced by T cells and macrophages during the formation of granulomatous lesions in tuberculosis, Mycobacterium avium-intracellulare infection, silicosis, and sarcoidosis, and after inoculation of Mycobacterium bovis bacillus Calmette–Guérin (BCG) vaccine in humans (4–7). In vitro infection with Mycobacterium tuberculosis results in the expression of OPN messenger RNA in macrophages (5, 8). Many investigators recognize it as a proinflammatory cytokine, which causes cellular adhesion and chemotaxis of inflammatory leukocytes (4, 7, 9–15). Macrophages migrate into the site of subcutaneous injection of OPN (10, 16), and their infiltration under several pathologic conditions is reduced in OPN-knockout mice (13). Furthermore, OPN promotes chemoattraction and adhesion of human peripheral blood T cells (7) and enhances their CD40 ligand expression and interferon (IFN)-{gamma} production on receptor-mediated stimulation (17).

Recently, Ashkar and coworkers (18) identified a new role for OPN, acting as a proinflammatory cytokine for inducing type 1 T helper (Th1) cell–mediated immune responses. Using OPN-knockout mice, they demonstrated that OPN was essential for the development of Th1 responses and granuloma formation through induction of interleukin (IL)-12 production by macrophages. In a recent study, we provided evidences in support of this role in humans (19); OPN regulated IL-12 production by peripheral blood monocytes after infection with Penicillium marneffei, an intracellular fungal pathogen known to cause opportunistic infectious diseases in patients with AIDS. However, the results of two studies contradicted the Th1-polarizing role of this cytokine. Nau and coworkers (20) reported that clearance of M. bovis BCG was profoundly impaired but both IFN-{gamma} and nitric oxide production were normal in OPN-knockout mice. Potter and coworkers (21) demonstrated that no significant differences were seen in nitric oxide and IL-12p40 production between OPN-knockout and normal mouse-derived macrophages on stimulation with Borrelia burgdorferi lipoprotein. Thus, involvement of OPN in the development of the Th1 response remains controversial.

Host defense against M. tuberculosis consists largely of Th1 cell–mediated mechanism (22). IFN-{gamma} is the most critical cytokine for eradicating this infection through the induction of macrophage bactericidal activity (23–25). IL-12 is highly potent in inducing IFN-{gamma} production by natural killer cells and is essential for the development of Th1 cells (26). These cytokines play a critical role in host protection against M. tuberculosis infection (27), as demonstrated by the increased susceptibility of mice with disrupted IFN-{gamma} and IL-12 genes (28–31). Importantly, similar findings were reported in humans bearing abnormal receptors for IFN-{gamma} and IL-12 (32–36).

In the present study, we investigated the pathogenic role of OPN in mycobacterial infection by measuring plasma OPN levels in patients with active pulmonary tuberculosis and by analyzing the relationship between plasma OPN concentrations and plasma IL-12 and IFN-{gamma} concentrations. Furthermore, we used in vitro studies to examine the role of OPN in IL-12 production by peripheral blood mononuclear cells (PBMC) infected with M. bovis BCG. Our results showed that OPN levels were significantly higher in the plasma of patients with tuberculosis than in control subjects. We also found a positive correlation between the synthesis of OPN and IL-12 both in vivo and in vitro. Our results suggest that OPN is involved in the pathologic process associated with pulmonary tuberculosis through the induction of IL-12–mediated Th1 responses.


   METHODS
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 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
We studied 29 male and 19 female patients with active pulmonary tuberculosis, aged 18 to 92 years (59.5 ± 22.1). M. tuberculosis was isolated from sputum of all patients. Patients with collagen vascular diseases, malignant tumors, diabetes mellitus, and other apparent infections with hepatitis viruses or human immunodeficiency virus were excluded from the present study. We excluded patients who had received antituberculosis drugs, corticosteroids, or other immunomodulators in the past. Involvement of disease was classified by chest radiographic findings without knowledge of both the clinical data and OPN results. Peripheral blood was collected at the time of diagnosis and kept in ethylenediaminetetraacetic acid–containing tubes before therapy with antituberculosis drugs. Plasma samples were preserved at -80°C until use. We also studied 9 male and 11 female sarcoidosis patients aged 23 to 70 years (51.0 ± 13.5). The stage of sarcoidosis was stage I in 7 patients, stage II in 10, and stage III in 3. No patients received corticosteroids for at least 2 months before the plasma samples were collected. Plasma samples were also obtained from 20 male and 14 female healthy volunteers (29–82 [56.8 ± 14.1] years) who had no history of pulmonary tuberculosis or other infection, and their chest radiographs showed no evidence of respiratory diseases. In some experiments, PBMC were isolated from heparinized blood of healthy volunteers, as described previously (19). Informed consent was obtained from all participants regarding cytokine measurements.

Culture Condition
PBMC (2 x 106/ml) were cocultured with 1 x 106/ml of live M. bovis BCG (Nihon BCG Co., Tokyo) in RPMI1640 (GIBCO BRL, Grand Island, NY) and 10% fetal calf serum (Cansera, Rexdale, ON, Canada) for 2 days, and the culture supernatants were kept at -80°C until use. In some experiments, neutralizing anti-OPN monoclonal antibody (clone 10A16: mouse IgG1 [19, 37]) or control mouse IgG (Genzyme-Techne, Minneapolis, MN) was added to the cultures.

Measurement of Cytokine Levels
The concentration of OPN was measured by an antigen-capture ELISA, as described previously (37). IL-12p40 and IFN-{gamma} were measured by ELISA (Biosource International, Camarillo, CA and Endogen, Woburn, MA, respectively). The sensitivity of these assays was 5 ng/ml, 8.2 pg/ml, and 2 pg/ml for OPN, IL-12p40, and IFN-{gamma}, respectively.

Statistical Analysis
Statistical analysis was performed using Statview-J5.0 software (Abacus Concept, Inc., Berkeley, CA). Differences between groups were examined using the analysis of variance test with a post hoc analysis (Fisher's protected least significant difference test). The linear least-squares regression analysis was used to estimate the relationship between two defined parameters. A p value less than 0.05 was considered significant.


   RESULTS
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 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
High Plasma OPN Concentrations in Patients with Pulmonary Tuberculosis
To investigate the pathogenic role of OPN in tuberculosis, we compared the plasma concentrations of this cytokine in patients with active pulmonary tuberculosis, patients with sarcoidosis, and healthy control subjects. As shown in Figure 1 , plasma OPN concentrations in patients with active pulmonary tuberculosis (n = 48) were significantly higher than in control subjects (n = 34; p < 0.0001) and patients with sarcoidosis (n = 20; p < 0.05). Plasma OPN concentrations of the latter group were also significantly higher than for the control subjects (p < 0.0001). There was no significant difference in the plasma OPN levels between males and females in both control and patient groups. In addition, OPN levels did not increase with age (data not shown).



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  		Figure 1. Comparison of plasma osteopontin (OPN) concentrations in patients with pulmonary tuberculosis, patients with sarcoidosis, and healthy control subjects. Plasma OPN levels were compared among control subjects (C), patients with tuberculosis (TB), and patients with sarcoidosis (Sa). The 10th, 25th, 50th, 75th, and 90th percentile values are shown.

 
Correlation between Plasma OPN Levels and Clinical Parameters in Patients with Pulmonary Tuberculosis
For further elucidation of the role for OPN in the development of pulmonary tuberculosis, we examined the correlation between plasma OPN concentrations and several clinical parameters, including the results of sputum smear test for acid-fast bacilli and severity of the lung lesions as evaluated by the findings on chest X-ray films (graded into minimal, moderately advanced, and far-advanced lesions). First, plasma OPN levels were significantly higher in sputum acid-fast smear–positive patients (n = 37) than in smear-negative ones (n = 11; p < 0.05). Second, plasma concentrations increased with the size of the pulmonary lesion, being highest in patients with far-advanced tuberculosis (Figure 2) . In addition, we also examined the effect of antituberculous chemotherapy on plasma OPN levels by comparing such values before and after treatment. Plasma OPN concentrations decreased significantly after 6 months of chemotherapy, in parallel with clinical improvement (one-way fractional analysis of variance test, p < 0.05, Figure 3) . Follow-up OPN measurements were done for only seven patients.



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  		Figure 2. High plasma OPN concentrations correlate with severity of pulmonary tuberculosis. Plasma OPN levels were compared for 18 patients with tuberculosis with minimal (M), 18 patients with moderately advanced (MA), and 15 patients with far-advanced (FA) pulmonary lesions. The 10th, 25th, 50th, 75th, and 90th percentile values are shown.

 


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  		Figure 3. Antituberculous chemotherapy reduces plasma OPN concentrations. Plasma OPN concentrations were compared before and after 6 months of chemotherapy. Each symbol indicates one patient. *p Value less than 0.05.

 
Correlation between Plasma OPN and Cytokines in Patients with Pulmonary Tuberculosis
Ashkar and coworkers (18) suggested the involvement of OPN in the production of IL-12 and consequently the initiation of Th1-mediated host responses in a murine system. We recently extended these findings by demonstrating the contribution of OPN to in vitro IL-12 production by human peripheral blood monocytes in patients with P. marneffei infection (19). These findings suggested that OPN might function in pathways upstream to the synthesis of IL-12 during infection with M. tuberculosis. To investigate such a possibility, we measured plasma concentrations of IL-12 and OPN in patients with pulmonary tuberculosis. As shown in Figure 4 , there was a significant relationship between plasma OPN and IL-12 concentrations.



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  		Figure 4. Correlation between plasma OPN and interleukin (IL)-12 in patients with pulmonary tuberculosis. Correlation between OPN and IL-12p40 levels was examined in patients with pulmonary tuberculosis. Each symbol indicates one patient.

 
OPN-mediated Production of IL-12 and IFN-{gamma} by PBMC Infected with M. bovis BCG
The positive relationship between plasma OPN and IL-12 concentrations suggested that OPN may be involved in the synthesis of IL-12 and in the initiation of Th1-mediated immune responses in mycobacterial infection, as reported previously in mice (18) and fungus-infected human peripheral blood monocytes (19). To elucidate this possibility, we examined the production of OPN, IL-12, and IFN-{gamma} by PBMC after in vitro infection with M. bovis BCG. OPN appeared in the culture supernatants at 6 hours, reached a peak concentration at 24 hours, and then decreased at 48 hours (Figure 5A) , whereas IL-12 appeared at 12 hours and increased steeply at 24 and 48 hours (Figure 5B). IFN-{gamma} also showed late appearance at 24 hours but a steep rise at 48 hours (Figure 5C). These results indicated the sequential generation of OPN, IL-12, and IFN-{gamma} in this order and suggested that OPN may regulate the synthesis of IL-12 and IFN-{gamma} at an upstream level. To confirm this possibility, we examined the effects of neutralizing anti-OPN monoclonal antibody on PBMC production of IL-12 and IFN-{gamma} caused by M. bovis BCG infection. As shown in Figure 6 , the production of both IL-12 and IFN-{gamma} was significantly suppressed by anti-OPN monoclonal antibody when compared with the effect of control mouse IgG1.





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  		Figure 5. Kinetics of OPN, IL-12 and interferon (IFN)-{gamma} synthesis by Mycobacterium bovis bacillus Calmette-Guérin (BCG)–infected peripheral blood mononuclear cells (PBMC). PBMC from one healthy donor were cultured with M. bovis BCG for indicated time intervals, and concentrations of OPN (A), IL-12p40 (B), and IFN-{gamma} (C) in the culture supernatants were measured by ELISA. Similar results were obtained with a second donor (not shown). Each symbol represents the mean ± SD values of triplicate cultures.

 



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  		Figure 6. Effects of neutralizing anti-OPN monoclonal antibody (mAb) on IL-12 and IFN-{gamma} production by M. bovis BCG–infected PBMC. PBMC from one healthy donor were cultured with M. bovis BCG in the presence or absence of anti-OPN mAb (closed circles) or control mouse IgG1 (open circles) for 48 hours, and concentrations of IL-12p40 (A) {gamma} (B) in the culture supernatants were measured by ELISA. Similar results were obtained with a second donor (not shown). Each symbol represents the mean ± SD of triplicate cultures. *p Value less than 0.05, compared with the value in the absence of anti-OPN mAb.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, to address human infectious diseases, we measured the levels of circulating OPN and examined the correlation between OPN levels and various clinical parameters in patients with pulmonary tuberculosis. The major findings were (1) elevated plasma levels of OPN in patients with tuberculosis compared with those in healthy control subjects, (2) a positive correlation between OPN concentration and disease severity, represented by the size of lung lesions on chest X-ray films, (3) reduction of OPN concentrations in parallel with clinical improvement by antituberculous chemotherapy, (4) a positive correlation between OPN concentrations and those of IL-12 in plasma, and (5) OPN stimulated the production of IL-12 and IFN-{gamma} by M. bovis BCG–infected PBMC.

Previous studies (5, 8) showed that infection of human alveolar macrophages and a macrophage cell line with M. tuberculosis caused a substantial increase in OPN gene expression. The expression of OPN was elevated in pathologic sections from patients with various granulomatous diseases including pulmonary tuberculosis (4–7). These observations suggested the possible involvement of OPN in the pathogenesis, especially the generation of granulomas, of tuberculosis and sarcoidosis. Our results support this notion by demonstrating the presence of significantly high plasma concentrations of OPN in patients with tuberculosis or sarcoidosis relative to those in control individuals. However, it should be noted that plasma OPN was measured in the present study in an uncleaved form but not in a thrombin-cleaved form (37). The cleaved form of OPN is more potent in causing cell migration and adhesion than the uncleaved form (7, 38, 39). Thus, there may be some limitation in estimating the significance of higher plasma OPN levels in tuberculosis and sarcoidosis.

In other observations, we found significant correlations between high plasma OPN levels and several clinical parameters indicative of disease activity. For example, OPN concentrations were higher in smear-positive patients compared with those in smear-negative patients. The severity of tuberculosis, as evaluated by the size of pulmonary lesions on chest X-ray films, correlated well with plasma OPN concentrations. Furthermore, OPN levels decreased in parallel with clinical improvement after treatment with antituberculous agents. These findings strongly support the role of OPN in the pathologic process associated with pulmonary tuberculosis. However, further investigations are necessary before the mechanisms through which OPN contributes to the pathogenic process associated with pulmonary tuberculosis are fully understood.

OPN polarizes the immune response toward Th1-dominant over Th2-dominant status as demonstrated previously by the induction of IL-12 production and inhibition of IL-10 expression in LPS-stimulated macrophages (18). In OPN-deficient mice, infections characterized by Th1 cytokine response, such as by herpes simplex virus type 1 and Listeria monocytogenes, were associated with abrogation of IL-12 production and enhanced synthesis of IL-10. On the basis of these reciprocal effects on IL-12 and IL-10, it was proposed that OPN might be involved in the progression of the Th1 response in the murine system (18). In support of this conclusion, we found that circulating OPN levels correlated well with the synthesis of IL-12 in the plasma of patients with pulmonary tuberculosis. We also found that PBMC infected with M. bovis BCG produced OPN, IL-12, and IFN-{gamma} sequentially in this order and that neutralizing anti-OPN monoclonal antibody significantly inhibited the production of both IL-12 and IFN-{gamma}, suggesting that OPN initiates the IL-12–induced Th1 immune response during M. tuberculosis infection.

With regard to OPN and mycobacterial infection, previous studies showed that M. bovis BCG grow more rapidly in macrophages derived from OPN-deficient mice than in those from control mice (20). The same study, however, also indicated that the ability of OPN to facilitate the clearance of M. bovis BCG was not mediated by acquired T cell immunity, IFN-{gamma} production, or nitric oxide secretion. In other studies by Nau and coworkers (6), OPN production was reduced in patients who lacked IFN-{gamma}R1 after administration of BCG vaccine, suggesting that the synthesis of OPN was influenced downstream by IFN-{gamma} signaling. These observations are likely inconsistent with the involvement of OPN in the host defense against mycobacterial infection through IL-12–mediated Th1-type immune responses. At present, the mechanisms that account for this apparent discrepancy remain to be elucidated.

In conclusion, the present study suggested the possible contribution of OPN to the pathologic process of pulmonary tuberculosis by triggering the cascade of Th1-mediated inflammatory responses. Because of the limitation in conducting clinical investigation designed to clarify the precise role of OPN in this process, further studies using OPN-deficient mice are important to address this issue. Clinically, our results suggest that OPN may be a useful diagnostic parameter for granulomatous diseases including tuberculosis and sarcoidosis and to predict disease activity as well as evaluate the effectiveness of treatment. However, several recent reports have demonstrated that high OPN levels were detected also in patients with cancer and those undergoing hemodialysis (40–44). Therefore, further careful evaluations will be needed to gain a greater insight into the potential usefulness of OPN in the clinical management of pulmonary tuberculosis.


   FOOTNOTES
 
Supported in part by Grants from the Ministry of Health and Welfare, Japan.

Received in original form September 29, 2002; accepted in final form January 24, 2003


   REFERENCES
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 DISCUSSION
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