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Annals of Clinical & Laboratory Science 33:149-155 (2003)
© 2003 Association of Clinical Scientists

Monokine Levels in Cancer and Infection

Gi-Soo Shin1, Bong-Hee Lee2, Seong Lee3, Seung-Yun Chung4, Myungshin Kim5, Jihyang Lim5, Yonggoo Kim5, Hi Jeong Kwon5, Chang Suk Kang5 and Kyungja Han5
1 Red Cross College of Nursing, 2 Department of Bioscience, Korea University, and 3 Departments of Surgery, 4 Pediatrics, and 5 Clinical Pathology, College of Medicine, Catholic University of Korea, Seoul, Korea

Address correspondence to Kyungja Han, M.D., Department of Clinical Pathology, Catholic University Medical College, St. Mary’s Hospital, Youngdeungpo-gu, Youido-dong 62, Seoul, Korea (south) 150-713; tel 82 2 3779 1297; fax 82 2 783 6648; e-mail: hankja{at}catholic.ac.kr.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgement
 References
 
The levels of monocyte intracellular monokines (TNF{alpha}, MIP, and MIG) in patients with cancer or bacterial infection were studied by multiparameter flow cytometry and comparative fluorescence analysis. TNF{alpha}, MIP, and MIG levels in peripheral blood of patients with cancer or bacterial infection were higher than in normal controls (p <0.005). In normal controls, no significant relationships were found among TNF{alpha}, MIG, MIP levels, monocyte count, and lymphocyte count in peripheral blood. In cancer patients, TNF{alpha} was strongly related to MIP (r = 0.809,p <0.001) and MIG (r = 0.773, p <0.001). Of the 3 monokines, TNF{alpha} and MIG levels were related to monocyte count, but none showed correlation with lymphocyte count in cancer patients. In patients with bacterial infection,TNF{alpha} was not significantly related to MIP (r = 0.423, p = 0.051), but it was related to MIG (r = 0.457; p = 0.033). None of the monokines (TNF{alpha}, MIP, MIG) was related to the monocyte count, but the MIP level was related to the peripheral blood lymphocyte count in patients with bacterial infection (r = 0.559, p = 0.008). These results suggest that circulating monocytes may play an important role in both cancer and bacterial infection through increased production of monokines. Moreover, correlations of the monokine levels with each other and their relationships to the monocyte count differ in patients with cancer and bacterial infection.

(received 19 September 2002; accepted 30 November 2002)

Keywords: TNF{alpha}, MIP, MIG, cancer, bacterial infection


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Acknowledgement
 References
 
The cytokines are a diverse group of inter-cellular signaling proteins that regulate immune responses and many other biologic processes. The cytokines are secreted by particular cell types in response to a variety of stimuli and they affect target cells in highly specific manners. Tumor necrosis factor-alpha (TNF{alpha}) was originally characterized as a protein that induces the necrosis of methylcholanthrene-induced sarcomas in vivo [1]. It is a representative monokine, and plays an important role in solid tumors [2–6]. Recently identified cytokines, including, macrophage inflammatory protein-1-alpha (MIP1{alpha}), and monokine induced by gamma interferon (MIG) have also been found to have antitumor activity in vivo [3,4,7]. These monokines also have significant activities in infection, autoimmune diseases, skin diseases, and organ transplantation [8–14]. Monocytosis is found in patients with cancers and other benign diseases, including bacterial infections, and monocytosis is usually a favorable sign, except in tuberculosis [5]. It is unclear whether the monocytes found in different diseases are same or different in nature. Although communications between monocytes and other cells of the immune system play a key role in regulating host immunity against cancer and infection [15,16], cancer and infection are very different in terms of pathogenesis. If monocytes have different roles in these diseases, the monokine levels in the monocytes could well be different.

Monocytes in the peripheral blood can reach any target site within a short time, and the monocyte system is able to seek out and destroy infectious and malignant intruders with efficiency and deadly intent, partly through the synthesis and release of cytokines [17–19].

The multiparameter capability of flow cytometry has been adapted to measure cytokine levels in specific cell populations using single cells [20–22]. In the present study, the use of anti-cytokine antibodies directly conjugated to phycoerythrin (PE) and FITC conjugated anti-CD14 antibodies enabled us to estimate the intracellular cytokine levels of monocytes. We quantified monocytic intracellular monokine levels in patients with cancer or with bacterial infection, to gain insights into the possible roles of monocytic monokines in these diseases.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Acknowledgement
 References
 
Patients.  We studied 29 adult patients (age 33 to 76 yr) with solid cancers (12 stomach cancer, 10 breast cancer, 5 lung cancer, 2 ovarian cancer), and 22 adult patients (age 21 to 54 yr) with bacterial infections. The diagnoses of cancer were made by pathological examination of biopsies, and blood samples were collected before operation and chemotherapy. The diagnosis of bacterial infection was made by culture and identification of the bacteria in blood (3 patients), sputum (4 patients), and wounds (4 patients) or by clinical symptoms (fever) and signs (11 culture-negative patients with neutrophilia >7.0 x 103/µl with toxic granules). Cultured organisms were identified using an automated identification system (Microscan, Dade, Germany). The isolated organisms are listed in Table 1Go.


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  		Table 1. Organisms isolated and identified in 11 patients with bacterial infections.
 
The patients all gave informed consent to use any blood specimens that remained after complete blood cell counting; the IRB committee approved this study. EDTA-anticoagulated peripheral blood samples were used within 2 hr of collection. Samples were kept at room temperature (18 to 20°C) until analyzed. Adult healthy donors (n = 16, age 27 to 50 yr) were tested as normal controls.

Lymphocyte and monocyte counts were performed using an automatic blood cell counter (Coulter GenS, Hialeah, FL).

Flow cytometric assay of intracellular monokines.  Peripheral blood mononuclear cells (PBMCs) were isolated by centrifugation on Ficoll-Hypaque (Sigma-Aldrich, St. Louis, MO) of blood specimens from patients and normal controls. Standardization of the flow cytometer was carried out twice a week using CaliBRITETM beads (Becton Dickinson, San Diego, CA). PBMCs were initially diluted to 1 x106/ml with PBS, and 20 µl of FITC conjugated anti-CD14 was added to 50 µl of the diluted PBMCs. The mixture was then incubated in the dark at room temperature for 15 min, and erythrocytes were lysed with lysing solution (Becton Dickinson).

PBMCs were fixed and permeabilized using a Cytofix/Cytoperm kit (BD Pharmingen, San Diego, CA), following the manufacturer’s instructions. PE-conjugated antibodies to human TNF{alpha}, MIP, and MIG were purchased from Serotec Ltd. (Oxford, UK). Ten µl of antibodies to human TNF{alpha}, MIP, and MIG were added to each tube and incubated for 30 min at 4°C. After washing with Perm/Wash solution supplied with the kit, 20,000 cells were analyzed by flow cytometery (FACS-Calibur, Becton Dickinson) using the CellQuest program (FACS-Calibur, Becton Dickinson).

Peripheral blood mononuclear cells showing CD14 positive signals were gated and analyzed (Fig. 1Go). Results are presented as the geometric mean fluorescence intensities; the mean number of bound PE molecules per cell was calculated using the QuantiBRITE and QuantiQuest programs (Becton Dickinson) [23–26]. The monocytes of all patients did not show high expression of monokines after in vitro stimulation. Mean levels of intracellular monokines of all monocytes were estimated instead of discriminating the monocytes into 2 groups (CD14-positive and CD14-negative). Results are reported as bound PE molecules per cell (mean ± SE).



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  		Fig. 1. Dot scattergrams of peripheral blood mononuclear cells isolated by centrifugation on Ficoll-Hypaque. Panel A shows the scattergram of isolated mononuclear cells. Monocytes (CD14 positive) in the mononuclear cells from a patient with breast cancer show a higher level of intracellular TNF{alpha} (panel C), compared to a normal control (panel B).

 
Statistical analysis.  Comparisons between the cancer and infected patients and the normal controls were made by ANOVA and Mann-Whitney U test, using the SPSS programs. Correlations between the amounts of cytokines in each group and the numbers of monocytes, lymphocytes, and neutrophils were tested by the Pearson correlation coefficient; p values <0.05 were considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Acknowledgement
 References
 
The monocytic intracellular monokine levels in each group of patients are summarized in Fig. 2Go. The monocytic intracellular TNF{alpha} and MIP levels were significantly different between the 2 groups of patients (p = 0.023 for TNF{alpha}; p = 0.009 for MIP). However, the monocytic intracellular MIG levels between the groups of patients were not significantly different (p = 0.139). In cancer patients, the monocytic intracellular TNF{alpha} level was 314 ± 59 bound PE molecules/cell, and this was significantly higher than that in the normal controls (107 ± 7, p = 0.013) (Fig. 2Go).



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  		Fig. 2. Monocytic intracellular cytokine levels in both groups of patients and in normal controls. The ordinate is bound PE molecules per cell (mean ± SE).

 
The MIP levels (391 ± 56 bound PE molecules/cell) were also higher in the cancer patients than in the normal controls (150 ± 10, p = 0.003). In patients with bacterial infection, the monocytic intracellular TNF{alpha} level averaged 241 ± 38, which was significantly higher than in normal controls (107 ± 7, p = 0.005). The MIP level (315 ± 46) was also higher in patients with bacterial infection than in the normal controls (150 ± 10, p = 0.005). TNF{alpha}and MIP levels were higher in cancer patients than in patients with bacterial infection, but this was statistically insignificant (p >0.05).

The MIG levels averaged 331 ± 37 bound PE molecules/cell in cancer patients, 169 ± 18 in infected patients and 75 ± 2 in normal controls, but the differences among groups was insignificant. Lymphocyte counts were lower in cancer patients (2480 ± 260 cells/µl) than in normal controls (3530 ± 170 cells/µl, p = 0.006) and monocyte counts were higher in cancer patients (1660 ± 170 cell/µl) than in normal controls (630 ± 50 cells/µl, p <0.001). Lymphocyte counts were also lower in patients with bacterial infection (2220 ± 190 cells/µl) than in normal controls (3530 ± 170 cells/µl, p <0.001), and monocyte counts were higher in patients with bacterial infection (1550 ± 170 cells/µl) than in the normal controls (630 ± 50 cells/µl, p <0.001). No significant differences were observed between the lymphocyte or monocyte counts of cancer patients and those with bacterial infections.

In normal controls, no significant correlations were found among monocytic intracellular TNF{alpha}, MIG, MIP levels, amonocyte counts, and lymphocyte counts in the peripheral blood (Table 2Go).


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  		Table 2. Correlations among monocytic intracellular TNF{alpha}, MIG, MIP levels, monocyte count, and lymphocyte count in the peripheral blood of 22 normal adult control subjects (p = significance of correlation).
 
In cancer patients, the monocytic intracellular TNF{alpha} level was strongly correlated with the MIP level (r = 0.809,p <0.001), the MIG level (r = 0.773, p <0.001), and the monocyte count in peripheral blood (r = 0.551, p = 0.003) (Table 3Go). The monocytic intracellular MIG level was correlated with the MIP level (r = 0.657, p <0.001), and the monocyte count in peripheral blood (r = 0.475, p = 0.012). However, the monocytic intracellular MIP level was not correlated with the monocyte count. The 3 monocytic intracellular monokine levels were unrelated to the lymphocyte count in peripheral blood.


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  		Table 3. Correlations among monocytic intracellular TNF{alpha}, MIG, MIP levels, monocyte count, and lymphocyte count in the peripheral blood of 29 adult patients with cancer (stomach,12; breast, 10; lung, 5; ovary, 2) (p = significance of correlation).
 
In patients with bacterial infection, monocytic intracellular TNF{alpha} level was not correlated with MIP level or with the monocyte count in peripheral blood , but it was correlated with the MIG level (r = 0.457, p = 0.033) (Table 4Go). The monocytic intracellular MIP level was correlated with the MIG level (r = 0.511, p = 0.015) and with the lymphocyte count in peripheral blood (r = 0.559, p = 0.008). Monocytic intracellular MIP level was not correlated with the monocyte count.


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  		Table 4. Correlations among monocytic intracellular TNF{alpha}, MIG, MIP levels, monocyte count, and lymphocyte count in the peripheral blood of 22 adult patients with bacterial infections (p = significance of correlation).
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Acknowledgement
 References
 
Monokines, especially TNF{alpha}, have antitumor effects [1,5,6]. Most cytokines act locally over extremely short distances, and the systemic use of TNF in cancer therapy has produced disappointing results because of toxic side effects [27,28]. Attempts have been made to attain high levels of TNF locally, but the results of TNF perfusion remain disappointing [29–31]. Peripheral blood monocytes can move rapidly to a distant site. Therefore, peripheral blood monocytes may play an important role in tumor immunology in addition to lymphocytes by increasing the availability of monokines at the target site [32]. Recently, adaptive immunology in cancer using monocyte-derived macrophages has been reported [20]. Furthermore, the circulating monocyte count is significantly increased in cancer patients [15]. Therefore, peripheral blood monocytes could play an important role in tumor immunology by increasing the production of monokines and by delivering these monokines to the target site.

The quantity of intracellular monokines in circulating monocytes has not been well studied in cancer patients. In the present study, monocytic intracellular TNF{alpha}, MIP, and MIG levels were found to be significantly higher in cancer patients than in normal controls. The monocyte count was also higher in cancer patients. This means that the number of monocytes that have more cytokines than normal are increased in cancer patients.

Interestingly, all of these monocytic intracellular monokines are also increased in patients with bacterial infection, although not to the same extent as in cancer patients. The monokine, MIG, has an important role in antibody production and in providing optimal humoral responses to various pathogens [12]. In the present study, the numbers of the various isolated organisms were too small for statistical analysis. However, it seems possible that monokines in the circulating monocytes are produced to antigens presented by both cancer and bacterial infections.

Different cell types respond differently to monokines (especially to TNF) [33]. In this study, no significant difference was found between the lymphocyte counts or the monocyte counts of cancer patients and patients with bacterial infection, which implies that cancer and bacterial infection both cause similar changes in the numbers of circulating lymphocytes and monocytes. However, the correlations among the monokine levels differed in cancer patients and in patients with bacterial infections. In normal controls, no significant correlations were found between monocytic intracellular TNF{alpha}, MIG, MIP levels, monocyte count, or lymphocyte count in the peripheral blood. In cancer patients, the monocytic intracellular TNF{alpha}level was strongly related to the MIP and MIG levels. In patients with bacterial infection, the monocytic intracellular TNF{alpha} level was unrelated to the MIP level, and only weakly correlated with the MIG level.

These results suggest that the induction mechanism of monocytic intracellular monokine production is antigen-dependent. Tumor antigen evidently strongly stimulates the production of all of the monocytic monokines. Bacterial antigens appear to induce monocytic monokines to a lesser extent than cancer antigens and in different manner. Among the three monokines, TNF{alpha} and MIG levels were related to the monocyte count; neither showed correlation with the lymphocyte count in the peripheral blood of cancer patients. This implies that some antigens of cancer cells induce TNF{alpha} and MIG in monocytes in addition to stimulating the proliferation of monocytes in the bone marrow. However, in patients with bacterial infection, none of the 3 monokines was related to the monocyte count in the peripheral blood. These differences suggest that the antigenic stimuli that cause monokine production and monocytosis have different mechanisms in patients with cancer and bacterial infection.

In conclusion, the results of this study suggest that circulating monocytes may play an important role in both cancer and bacterial infection through increased production of monokines. Moreover, correlations of the monokine levels with each other and their relationships to the monocyte count differ in patients with cancer and bacterial infection.


   Acknowledgement
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgement
References
 
This study was supported in part by a grant from Sam Kwang.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgement
 References
 

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