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(Chest. 2002;121:1493-1497.)
© 2002 American College of Chest Physicians

Role of Interleukin-18 and T-helper Type 1 Cytokines in the Development of Mycoplasma pneumoniae Pneumonia in Adults*

Hiroshi Tanaka, MD; Mitsuo Narita, MD; Shin Teramoto, MD; Toyohiro Saikai, MD; Kensuke Oashi, MD; Tomofumi Igarashi, MD and Shosaku Abe, MD

* From the Third Department of Internal Medicine (Drs. Tanaka, Teramoto, Saikai, Oashi, and Abe), Sapporo Medical University School of Medicine, Sapporo; Department of Pediatrics (Dr. Narita), Sapporo Tetsudo (JR) Hospital; and Respiratory Medicine (Dr. Igarashi), Kushiro City General Hospital, Kushiro, Japan.

Correspondence to: Hiroshi Tanaka, MD, Third Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan; e-mail: tanakah{at}sapmed.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: Interleukin (IL)-18 is a proinflammatory cytokine, originally termed interferon (IFN)-{gamma}-inducing factor, which promotes T-helper type 1 (Th1) cytokine responses. We recently reported that serum IL-18 levels were elevated in children with Mycoplasma pneumoniae pneumonia (MP). In this study, we investigated the contribution of IL-18 to the infection and assessed the Th1 cytokine response to pulmonary involvement in adults.

Methods: We investigated the clinical course, pulmonary involvement, and serum levels of IL-18, IFN-{gamma}, IL-12p40, and soluble IL-2 receptor (sIL-2R) in 21 patients with acute-stage MP and in 21 age- and sex-matched control subjects.

Results: Significantly (p < 0.001) increased serum IL-18 (median, 248 pg/mL [range, 89 to 441 pg/mL] vs median, 126 pg/mL [range, 47 to 217 pg/mL]) and sIL-2R (median, 617 U/mL [range, 410 to 1,032 U/mL] vs median, 425 U/mL [range, 268 to 601 U/mL]) were found in patients with MP as compared with healthy control subjects, and there was a tendency toward increased serum IFN-{gamma} and IL-12p40. Circulating IL-18 values had a positive correlation with serum sIL-2R levels (r = 0.62, p = 0.028) and the number of affected pulmonary lobes ({varsigma} = 0.61, p = 0.024), but not with the serum levels of antibodies to M pneumoniae, IFN-{gamma}, or IL-12p40. Serum IL-18 and sIL-2R values in severe cases were significantly higher (p < 0.03) than those in mild cases. IFN-{gamma} and sIL-2R levels in four patients with pleural effusion were significantly (p < 0.05) higher than those in the other 17 subjects.

Conclusions: Serum levels of IL-18 were raised during the acute phase of MP. We suggest IL-18 and Th1 cytokines may play a significant role in the immunopathologic responses in MP.

Key Words: interferon-{gamma} • interleulin-2 • interleukin-12 • interleukin-18 • Mycoplasma pneumonia • pleuritis


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Cell-mediated immunity of the host plays an important role in the development of Mycoplasma pneumoniae pneumonia (MP),1 2 and delayed-type hypersensitivity (DTH) skin reactions to M pneumoniae antigens appear to correlate with the severity of pneumonia.3 The radiologic pattern of MP is altered by the host’s immunologic state, ie, a bilateral reticulonodular pattern appeared in a patient with sarcoidosis (T-helper type 1 [Th1] disease), but there was a lack of radiologic findings in subjects with immunodeficiency syndrome.4 5 We previously reported that the T-lymphocyte response might exacerbate pneumonia lesions in Mycoplasma pulmonis-infected mice and that interleukin (IL)-2 administration increased perivascular and peribronchial lymphocyte cuffing and accumulation of macrophages around bronchioles. However, cyclosporin A treatment decreased these pathologic findings.6 7 Serum soluble IL-2 receptor (sIL-2R) is thought to be a marker of T-lymphocyte activation, and serum sIL-2R levels were reported to be elevated in patients with MP.8 From this evidence, it is hypothesized that Th1 cytokines have a critical role in the development of pulmonary manifestations.

IL-18, structurally homologous to IL-1 and its receptor, which belongs to the IL-1R/Toll-like receptor, has been identified as a proinflammatory cytokine. IL-18 messenger RNA is expressed in a wide range of cells including macrophages, T cells, B cells, dendric cells, Kupffer cells, osteoblasts, and keratinocytes. IL-18, originally called interferon (IFN)-{gamma}-inducing chemokine, is not only produced in immune cells but also in nonimmune cells as mentioned above.9 10 11 12 In collaboration with IL-12, IL-18 stimulates Th1-mediated immune responses, which play an important role in the host defense against infection. Host resistance and Th1 response to infection with Cryptococcus neoformans was reduced in IL-18-deficient mice.13 In mice inoculated with Legionella pneumophila, IL-18 together with IL-12 regulated intrapulmonary growth of the bacteria.14 However, IL-18 was reported to induce granulocyte/macrophage colony-stimulating factor and upregulate the intercellular adhesion molecule; thus, the effects of IL-18 on disease conditions are not restricted to those by IFN-{gamma} induction and must vary in terms of being beneficial or detrimental depending on the organs and mediators involved.15 IL-18 has been noted to play a key role in innate immunity to the intracellular pathogens, Mycobacterium tuberculosis, C neoformans, and L pneumophila.14 16 17 However, little is known about the potential role of IL-18 in human MP. We recently reported that serum IL-18 levels were raised in children with mycoplasma infection and also suggested local production of IL-18 in the lung.18 The aims of this study were to investigate the contribution of IL-18 and Th1 cytokines to host defense and pulmonary involvement in MP in adults. We assessed the disease severity, serum levels of antibodies to M pneumoniae, findings of chest radiography and CT scans, and serum levels of IL-18, IFN-{gamma}, IL-12p40, and sIL-2R during acute MP.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
Twenty-one patients with MP (median, 34 years; range, 20 to 64 years; 17 women and 4 men) and 21 sex- and age-matched healthy subjects (median, 33 years; range, 20 to 61 years; 17 women and 4 men) were recruited from Sapporo Medical University Hospital and Kushiro City General Hospital after giving informed consent. All patients were febrile with a persistent cough and were admitted to the hospital because of acute pneumonia. We excluded patients with the following conditions: (1) purulent sputum, (2) other underlying pulmonary diseases or hepatitis, (3) prior treatment with antibiotics, and (4) treatment with corticosteroids or immunosuppressive drugs.

Study Design
Blood samples and CT scans were obtained simultaneously on the hospital admission day, which was within 5 days from the onset of the symptoms. Serum samples were stored at - 80°C until assayed for IL-18, IFN-{gamma}, IL-12p40, and sIL-2R. The diagnosis of MP was confirmed by a fourfold or greater rise in the indirect hemagglutination titer between the acute and convalescent stage.19 This titer was measured using a commercial test kit (Serodea-Myco II; Fujirebio; Tokyo, Japan). CT scans were obtained from CT scanners (model GE-9800; GE Medical Systems; Waukesha, WI; or model SCT5000TH; Shimazu; Kyoto, Japan) using 5- or 10-mm collimation at 10-mm intervals, at full inspiration in the supine position. CT scans were interpreted by a chest radiologist.

The disease severity was determined according to previous studies.20 21 Patients with hypoxemia (PaO2 < 70 mm Hg) or who needed > 14 days of hospitalization were considered to have a severe clinical course, while the remaining cases were classified as mild.

Cytokine and Mediator Determinations
Determination of the IL-18, IFN-{gamma}, and IL-12p40 in sera was carried out using commercial kits; IL-18 (Human IL-18 ELISA Kit; Medical and Biological Laboratories; Nagoya, Japan), IFN-{gamma} was measured with enzyme-linked immunosorbent assay (High-Sensitivity Interferon-{gamma} Human ELISA system; Amersham Life Science; Buckinghamshire, England), IL-12p40 (Quantikine Human IL-12p40; R&D Systems; Minneapolis, MN), and sIL-2R (Endogen; Woburn, MA). These kits can detect concentrations of IL-18, IFN-{gamma}, IL-12p40, and sIL-2R as low as 12.5 pg/mL, 0.1 pg/mL, 11 pg/mL, and 85 U/mL, respectively. Reproducibility of the assays was good; the coefficient of variation of intra-assays and interassays was < 10% in all assays by our measurements. All assays were performed in duplicate. When cytokines and mediators were undetectable, a value of one half of the lowest detectable concentration was assigned for statistical analysis.

Statistical Analysis
Data on circulating IL-18, IFN-{gamma}, IL-12p40, and sIL-2R levels are presented as medians and ranges. Comparisons of these parameters among groups were made by the Mann-Whitney U test. {chi}2 test was used in gender comparisons. Pearson correlation was calculated to evaluate the relationship between cytokines and Fisher Exact Test was used to calculate p values for the correlation. Spearman’s {varsigma} was used to determine the correlation between serum cytokine levels and the number of affected pulmonary lobes. Statistical significance was assumed for p < 0.05.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Significantly higher levels of serum IL-18 (median, 248 pg/mL [range, 89 to 441 pg/mL] vs median, 126 pg/mL [range, 47 to 217 pg/mL]; p < 0.0001) and sIL-2R (median, 617 U/mL [range, 410 to 1,032 U/mL] vs median, 425 U/mL [range, 268 to 601 U/mL]; p < 0.0001) were found in patients with MP as compared with healthy control subjects (Fig 1 ). There was a nonsignificant trend to an increase in serum IFN-{gamma} (median, 0.61 pg/mL [range, < 0.1 to 12.7 pg/mL] vs median, < 0.1 pg/mL [range, < 0.1 to 0.71 pg/mL]; p = 0.078) and in IL-12p40 (median, 135 pg/mL [range, 76 to 249 pg/mL] vs median, 102 pg/mL [range, 39 to 153 pg/mL]; p = 0.072) in MP patients as compared with control subjects. There was a significant relationship between serum IL-18 and sIL-2R levels (r = 0.62, p = 0.28; Fig 2 ). However, there were no significant relationships between other combinations of cytokines and antimycoplasma antibodies.



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  		Figure 1.. Serum IL-18 and sIL-2R levels in patients with MP and healthy control subjects. Significantly higher values of serum IL-18 and sIL-2R are revealed in patients with MP.

 


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  		Figure 2.. Correlation between serum IL-18 levels and sIL-2R in patients with MP. There is a significant correlation (n = 21, r = 0.62, p = 0.028).

 
There were significant differences between patients experiencing a severe clinical course and those with a mild illness in serum IL-18 (p = 0.013) and sIL-2R levels (p = 0.021; Fig 1 ), but not in IFN-{gamma} and IL-12p40 levels. A significant positive correlation was observed between circulating IL-18 and the number of affected lobes assessed by CT scans ({varsigma} = 0.61, p = 0.024; Fig 3 ), but not with IFN-{gamma}, IL-12p40, and sIL-2R levels. The serum IFN-{gamma} levels (p = 0.047) and sIL-2R (p = 0.049) in four patients with pleural effusion were significantly higher than those in 17 subjects without effusion (Table 1 ).



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  		Figure 3.. Relationship between circulating IL-18 levels and the number of affected pulmonary lobes detected by CT scans. There is a significant positive correlation between circulating IL-18 and the number of affected lobes (n = 21, {varsigma} = 0.61, p = 0.024). Open squares represent patients with moderate pleural effusion; closed squares represent those with a small effusion.

 

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  		Table 1.. Comparison of Patients With MP With and Without Pleural Effusion*

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, serum IL-18 levels in patients with severe MP were higher than those in mild cases, and the IL-18 levels, but not serum IFN-{gamma} levels, correlated with the number of affected lobes detected by CT scans. We have previously shown that IL-18 levels are high when pleural effusion is associated with MP.18 IL-18 can induce granulocyte/macrophage colony-stimulating factor and upregulate the intercellular adhesion molecule 1 expression in a monocyte cell line; thus, the effects of IL-18 on disease conditions are not restricted to those mediated by IFN-{gamma} induction.15 Kitching et al22 reported that, even in the absence of IL-12, IL-18 could induce an in vivo DTH response. The DTH response to the mycoplasma organism appears to be correlated with the severity of pneumonia,3 suggesting that IL-18 might directly affect the respiratory infectious condition due to M pneumoniae.

IL-18 is known to induce proliferation of activated T cells and activation of natural killer (NK) cells, and participates in both innate and acquired immunity.23 We found an increase in serum sIL-2R levels, a serum marker of T-lymphocyte activation in patients with acute MP. This finding agrees with a previous report.8 Hayashi and colleagues24 reported an increase in activated T cells and an elevated CD4/CD8 ratio in the lymphocyte subpopulation in BAL. Koh et al25 reported a significant increase of IL-2 levels in BAL fluid in patients with MP. LEW rats develop more severe mycoplasma infection with a dramatic increase in mononuclear cells along the respiratory tract as compared with F344 rats, and this difference may reflect the fact that the number of CD4-positive T cells in LEW rats is greater than in F344 rats.26 We previously reported that IL-2 administration exacerbated peribronchial and perivascular cuffing of lymphocytes and plasma cells and emphasized nodular lesions consisting of macrophage accumulation within the bronchiole in an animal model. Cyclosporin A administration, which inhibits the transcription of IL-2 and IFN-{gamma}, reduced these pulmonary lesions, suggesting that Th1 immunoreaction might occur in the lung in patients with MP.6 We measured serum sIL-2R as a marker of T-lymphocyte proliferation and IL-12p40 as an essential factor for active IL-12.27 In this study, serum IL-18 values also correlated with the sIL-2R levels, but not with IFN-{gamma} or IL-12p40. It was suggested that IL-18 might play a significant role in the development of pulmonary manifestations through T-lymphocyte activation, but probably not through Th1 cytokines in MP.

Serum IFN-{gamma} levels in patients with MP and pleural effusion were higher than in those without an effusion in this study. We recently observed that IL-18 and IFN-{gamma} levels were higher in pleural fluid used to detect mycoplasma organisms by polymerase chain reaction, although the IFN-{gamma} levels did not correlate with IL-18 levels.18 Son et al28 recently reported that IL-18 combined with IL-2 enhanced IFN-{gamma} production and the expansion of NK cells. INF-{gamma} activates macrophages and inhibits the growth of mycoplasma organisms, and clearance of mycoplasma organisms from lungs was impaired in mice treated with anti-IFN-{gamma} antibody.29 Lai et al30 indicated that NK cell function is enhanced within 24 h after mycoplasma infection in mice, and NK cells directly inhibit mycoplasma organisms by secretion of IFN-{gamma}. They suggested that IFN-{gamma} might have protective effects in mycoplasma infection of the lung, while IFN-{gamma} production might be independent of IL-18 production.

IL-12 enhances Th1 cytokine production when combined with IL-18 and cytotoxicity of T and NK cells and promotes the differentiation of naive T cell into Th1. IL-12 consists of a p35 and a p40 subunit, and the production of both is required to form biologically active p70 heterodimer (p35 and p40). In our preliminary study, serum levels of active IL-12p70 were not detected in control subjects, and detectable levels were found only in the minority with adult mycoplasma infection. The overproduction of IL-12p40 has been generally described in vivo, and it was reported that IL-12p40 levels were much higher than those of IL-12p70 in the infectious disease melioidosis.31 Free circulating IL-12p40 can easily form homodimers and can exert anti-inflammatory effects and inhibit the binding of the biologically active IL-12p70 to IL-12 receptor.32 However, IL-12p40 homodimer may have immunostimulatory effects on CD8+ cells, leading to the production of IFN-{gamma}.33 Therefore, we measured serum IL-12p40 because its role during acute MP remains to be established.

MP was assessed by chest CT scans rather than chest radiographs in this study because subtle pulmonary findings (bronchovascular thickening, centrilobular nodules, linear opacities, and airspace consolidation) and pleural effusion were often difficult to recognize on conventional radiography.34 35 Actually, the presence of a pleural effusion in one of our four patients with pleural effusion could not be detected by chest radiography.

In conclusion, it is suggested that IL-18 might modulate the pulmonary lesions in acute MP through T-lymphocyte activation and not through the Th1 cytokine pathway. IL-18 and Th1 cytokines may be induced by M pneumoniae infection and play a significant role in immunopathologic responses.


   Footnotes
 
Abbreviations: DTH = delayed-type hypersensitivity; IFN = interferon; IL = interleukin; MP = Mycoplasma pneumoniae pneumonia; NK = natural killer; sIL-2R = soluble IL-2 receptor; Th1 = T helper type 1

Received for publication May 14, 2001. Accepted for publication October 30, 2001.


   References
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 Abstract
 Introduction
 Materials and Methods
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 References
 

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