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Psychosomatic Medicine 65:362-368 (2003)
© 2003 American Psychosomatic Society

ORIGINAL ARTICLES

The Relation of Severity of Depressive Symptoms to Monocyte-Associated Proinflammatory Cytokines and Chemokines in Apparently Healthy Men

Edward C. Suarez, PhD, Ranga R. Krishnan, MB, ChB and James G. Lewis, PhD

From the Department of Psychiatry and Behavioral Science (E.C.S., R.R.K.) and Department of Pathology (J.G.L.), Duke University Medical Center, Durham, North Carolina.

Address reprint requests to: Dr. Edward C. Suarez, Box 3328, Duke University Medical Center, Durham, NC 27710. Email ecs.jr{at}duke.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: We examined the relation of severity of depressive symptoms to lipopolysaccharide-stimulated expression of monocyte-associated proinflammatory cytokines and chemokines in 53 nonsmoking, healthy men.

METHODS: Assessments of cytokine and chemokine expression and severity of depressive symptoms were conducted on the same day. The 21-item Beck Depression Inventory (BDI) was used to assess severity of depressive symptoms experienced during the week before study participation. Dual-color flow cytometry was used to determine monocyte-associated (CD14+) expression of interleukin-1{alpha} (IL-1{alpha}), IL-1ß, tumor necrosis factor-{alpha} (TNF-{alpha}), IL-8, and monocyte chemotactic protein-1 (MCP-1) after in vitro lipopolysaccharide stimulation of undiluted whole blood.

RESULTS: Calculations of partial correlation coefficients controlling for age, race, body mass index, and alcohol use indicated that BDI score was significantly associated with IL-1{alpha} (r = 0.27), IL-1ß (r = 0.44), TNF-{alpha} (r = 0.57), MCP-1 (r = 0.52), and IL-8 (r = 0.33). In addition, relative to men with BDI scores below 10, men with BDI scores of 10 or above exhibited an overexpression of IL-1ß (p = .004), TNF-{alpha} (p = .005), IL-8 (p = .002), and MCP-1 (p = .025).

CONCLUSIONS: Relative to men with no or minimal symptoms of depression, men with mild to moderate levels of depressive symptoms showed overexpression of monocyte-associated proinflammatory cytokines and chemokines.

Key Words: severity of depressive symptoms • interleukin-1 • interleukin-8 • tumor necrosis factor-{alpha} • monocyte chemoattractant protein-1 • men

Abbreviations: ASCVD = atherosclerotic cardiovascular disease;; BDI = Beck Depression Inventory;; BMI = body mass index;; CHD = coronary heart disease;; IL = interleukin;; LPS = lipopolysaccharide;; MCP-1 = monocyte chemoattractant protein 1;; MFI = mean fluorescence intensity;; MI = myocardial infarction;; TNF-{alpha} = tumor necrosis factor {alpha}.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Among initially healthy individuals, severity of depressive symptoms significantly predicts both nonfatal myocardial infarction (MI) and fatal coronary heart disease (CHD) even after adjusting for possible confounding variables (for review see Ref. 1). Similarly, severity of depressive symptoms predicts recurrent nonfatal and fatal MI as well as all-cause mortality in CHD patients (1). Recently a 4-year longitudinal study of older men and women with and without cardiac disease reported that cardiac and CHD death rates were higher among persons with minor and major depression relative to participants with minimal depressive symptoms (2). In the same study, the relation of cardiac mortality to level of depressive symptoms, assessed using the Center for Epidemiologic Studies–Depression Scale (CES-D), was such that higher CES-D scores were associated with increased risk of cardiac death among healthy participants and cardiac patients. Overall the preponderance of evidence has led to the conclusion that depression and severity of depressive symptoms are both important and independent risk factors for the development and progression of cardiovascular disease in the general population as well as in cardiac patients (3).

At this time it is not well understood how severity of depressive symptoms contributes to the initiation and progression of cardiovascular disease in initially healthy persons. It is acknowledged, however, that atherosclerosis is one of the primary causes underlying atherosclerotic cardiovascular disease (ASCVD) and its complications (4–6). It is been suggested that inflammation and its cellular and molecular constituents not only characterize ASCVD but also promote the risk of the disease (4). For example, on the cellular level, blood monocytes are recognized as a key cellular component in the pathogenesis of ASCVD (6). On the molecular level, proinflammatory cytokines seem to orchestrate the cascade of inflammatory events leading to ASCVD (4–6). Recent studies have shown that concentrations of proinflammatory cytokines predict coronary mortality in cardiac patients (7) and increased cardiovascular risk in healthy subjects (8). Thus, an association between severity of depressive symptoms and monocyte-associated proinflammatory cytokines would promote the general hypothesis that inflammation is a potential pathophysiological mechanism linking severity of depressive symptoms to ASCVD (9).

There is evidence to suggest an association between major depressive disorder (MDD) and proinflammatory cytokines implicated in ASCVD (for review see Ref. 10). For example, some studies have shown that relative to healthy control subjects, patients with major depressive disorder (MDD) and dysthymia exhibit higher interleukin-1ß (IL-1ß) production by mitogen-stimulated peripheral blood mononuclear cells (PBMCs) (11–13). Other studies, however, have not confirmed a relationship between IL-1ß and MDD (14, 15). Similarly, MDD has been associated with tumor necrosis factor-{alpha} (TNF-{alpha}) produced by stimulated PBMCs and serum TNF-{alpha} (16, 17) in some, but not all, studies (15, 18, 19). Among the chemokines, MDD has been associated with elevations in serum IL-8 (20). To date no studies have examined the relation of MDD to monocyte chemotactic protein-1 (MCP-1) expression or production.

In contrast to the number of studies examining the relation of MDD to proinflammatory cytokines, there is a paucity of evidence for an association between severity of depressive symptoms and proinflammatory cytokines in nonpatient samples. Two recent studies of older, healthy adults reported that self-report measures of severity of depressive symptoms and depressive mood were positively associated with IL-6 (21, 22). At this time, however, no studies have examined the relation of severity of depressive symptoms to other proatherogenic cytokines, such as IL-1, TNF-{alpha}, MCP-1, and IL-8, in healthy, nonpatient samples. Given that TNF-{alpha} and IL-1 stimulate the production of IL-6 (8), it is likely that these, as well as other cytokines and chemokines involved in ASCVD, could be associated with severity of depressive symptoms.

The aim of the current study was to examine the relation of severity of depressive symptoms to the stimulated expression of monocyte-associated proinflammatory cytokines and chemokines in a group of healthy, nonsmoking men. We examined severity of depressive symptoms because 1) it prospectively predicts cardiovascular disease risk among initially healthy persons (2, 3), 2) it predicts increased risk of cardiac events in the absence of diagnosed major depressive episodes (23), and 3) it is related to future cardiac events along a continuum (3). Given these previous observations, we hypothesized that severity of depressive symptoms would be positively associated with greater expression of monocyte-associated proinflammatory cytokines and chemotactic proteins. To test this hypothesis, we examined the relation of total score on the Beck Depression Inventory (BDI, Ref. 38) to monocyte-associated IL-1{alpha}, IL-1ß, TNF -{alpha}, IL-8, and MCP-1. Although numerous cytokines have been implicated in ASCVD, we examined IL-1 (both {alpha} and ß), TNF-{alpha}, IL-8, and MCP-1 in light of the evidence indicating their roles in atherogenesis and their associations with various risk factors and disease end points. For example, TNF-{alpha} and IL-1 have been associated with 1) disease severity (24, 25) and recurrent coronary events in coronary patients (26); 2) higher systolic blood pressure, smoking, and hypertension in persons with asymptomatic carotid artery disease (27); and 3) traditional cardiovascular risk factors in at-risk individuals (28). Similarly, MCP-1 has been linked to the acceleration of disease (29), and the targeted deletion of either the gene for MCP-1 (30, 31) or its receptor (32) has been related to the reduced formation of the fatty streak. Lastly, increases in IL-8 have been observed in macrophages isolated from atherosclerotic plaque and in blood monocytes from patients with coronary disease (33).


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects
Participants were 53 healthy, nonsmoking men (age range = 18–43 years, mean = 25.8, SD = 6). Subjects were recruited from the community through advertisements placed in local newspapers and fliers distributed throughout the area. Subjects were compensated for their participation. Participants were healthy males with no past or present history of any chronic medical and psychiatric conditions that could alter cytokine expression (eg, asthma, allergies, arthritis, diabetes, cardiovascular disease, and psychiatric conditions). Moreover, none of the participants had ever taken medications for psychiatric conditions. Lastly, none of the subjects reported taking any over-the-counter preparations (eg, omega-3 supplements), prescription medications, or low-dose aspirin in the 2 weeks before study participation. The sample was composed of 33 whites, 13 blacks, 4 Asians, 2 Hispanics, and 1 person of "other" race. Written informed consent was obtained before study participation. This protocol was approved by the Duke University Medical Center Institutional Review Board.

Procedure
Subjects arrived between the hours of 8:00 AM and 9:00 AM at the Psychophysiology Laboratory at Duke University Medical Center. Subjects fasted for 12 hours before their appointment. On arrival, subjects were seated in a reclining chair, and a 21-gauge catheter was inserted into a forearm vein. Subjects then rested for 30 minutes before the collection of blood samples. After blood samples were collected, subjects completed the 21-item BDI (38). For the BDI, participants were instructed to rate their level of depressive symptoms for the week before study participation.

Blood Collection and Flow Cytometry Procedures
Blood samples were collected in two 4-ml tubes containing lithium heparin. Fasting blood samples were drawn between 8:30 and 9:30 AM to control for potential diurnal variation in the proteins measured (34). To reduce the possibility of protein degradation, samples were stored on ice for approximately 50 minutes until transferred to the flow cytometry laboratory. At the flow cytometry laboratory, the two samples were combined, and the pooled sample was used to determine the level of expression for each of the monocyte proteins. Dual-color flow cytometry (FACscan, Becton-Dickinson) using CellQuest (version 3.1) computer software for analysis was used to determine monocyte-associated protein expression. In contrast to techniques used to measure serum or plasma concentrations of cytokines, such as enzyme-linked immunosorbent assay systems, flow cytometry allowed for the measure of the selected proteins at the individual cell level, in this case blood monocytes.

Undiluted whole blood was incubated for 4 hours at 37°C alone or stimulated by the addition of lipopolysaccharide (LPS) (1 µg/ml). The use of LPS is a well-established and frequently used in vitro model to assess monocyte-associated cytokines and chemokines (55). It has been shown that LPS stimulates CD-14, a protein that contributes to the adherence of human monocytes to cytokine-stimulated endothelial cells (56). Monensin (1 µg/ml), an inhibitor of protein transport and secretion (35), was also added to both cultures to inhibit the secretion of synthesized proteins.

Mean fluorescent intensity (MFI) for each monocyte protein was measured only in cells that were positive for the monocyte marker CD-14. Levels of monocyte protein expression were calculated by subtracting the mean background fluorescence from the mean fluorescence of experimental samples. Reproducibility of flow cytometry was ensured by regular measurement of calibrated standards. In previous studies, experimentally induced changes in serum cytokine concentrations have been shown to mirror induced changes in stimulated expression of cytokines by blood monocytes (54). Thus, it is likely that the MFI obtained from flow cytometry is highly correlated with quantitative measures of serum or plasma concentrations of the same or related cytokines.

Cell-associated total IL-1{alpha}, IL-1ß, TNF-{alpha}, IL-8, and MCP-1 expression are presented as MFI determined from approximately 10,000 CD-14++ monocyte observations. Two subjects had missing data for MCP-1 because of technical problems.

Data Analyses
Inspections of MFI values for each monocyte marker indicated skewed distributions; therefore, logarithmic transformations were applied. Kirk suggests using the logarithmic transformation formula log10 (x + 1) when some scores are zero or very small (36).

Analyses were performed using the general linear model and correlation procedures from SAS (37). Given our a priori directional predictions, a one-tail test was used to determine statistical significance. The data were subjected to two separate series of analyses. The first set of analyses used univariate techniques to examine the relation of BDI total score and BDI depression group to levels of monocyte protein expression. The second set of analyses used multivariate procedures to examine the relation of protein expression to total BDI score and BDI group while statistically controlling for age, body mass index (BMI), race, and alcohol use.

BDI groups were established using an a priori scoring criteria for a BDI score of 10 or higher (38). A score of 10 or above indicates a preponderance of depressive symptoms above normal variation (38). BDI scores below 10 represent normal variations in symptoms (38).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
Table 1 presents the subject characteristics of the men in this sample. BDI total score was not associated with age (r = 0.07, NS) or BMI (r = 0.09, NS). BDI was not associated with either race (F(4,48) = 1.20, NS) or alcohol use (F(4,48) = 0.35, NS).


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  		TABLE 1. Sample Characteristics
 
Univariate Analyses
BDI total score was positively and significantly correlated with LPS-stimulated expression of IL-1ß (r = 0.37, p = .006), TNF-{alpha} (r = 0.48, p < .001), IL-8 (r = 0.45, p < .001), and MCP-1 (r = 0.35, p = .010). Although BDI total score was also positively associated with IL-1{alpha} (r = 0.23, p = .10), the correlation was not significant. Univariate results also indicated that age was associated with TNF-{alpha} (r = 0.30, p = .03) and IL-8 (r = 0.28, p = .04). No other Pearson correlations were found to be significant.

Results of univariate t tests showed significant group differences between BDI groups. Relative to men with a BDI score of less than 10, men with a BDI score of 10 or above exhibited greater expression of IL-1ß (t(51) = -2.94, p = .003), TNF-{alpha} (t(51) = -3.51, p < .001), IL-8 (t(51) = -3.49, p < .001), and MCP-1 (t(23.7) = -2.07, p = .025). BDI group differences in IL-1{alpha} (t (51) = -1.55, p = .054) were not significant.

Multivariate Analyses
We conducted a series of regression analyses with BDI score as a continuous predictor variable and age, race, BMI, and alcohol use as covariates. Results revealed that BDI significantly predicted IL-1{alpha} (ß = 0.028, p = .018, total R2 = 0.288), IL-1ß (ß = 0.041, p < .001, total R2 = 0.365), TNF-{alpha} (ß = 0.052, p < .001, total R2 = 0.413), IL-8 (ß = 0.054, p < .001, total R2 = 0.423), and MCP-1 (ß = 0.019, p = .026, total R2 = 0.319). To further characterize these associations, we performed Pearson partial correlations controlling for age, race, BMI, and alcohol use. BDI was associated with IL-1{alpha} (partial r = 0.27, p = .057), IL-1ß (partial r = 0.44, p = .001), TNF-{alpha} (partial r = 0.57, p < .001), IL-8 (partial r = 0.52, p < .001), and MCP-1 (partial r = 0.33, p = .025).

Parallel analyses were conducted using analysis of covariance with BDI groups. As in the above analyses, age, race, BMI, and alcohol use were entered as covariates. For IL-1ß, results indicated a significant main effect for BDI group (F(1,41) = 11.28, p = .008). Post hoc inspection of group means indicated that men with BDI scores of 10 and above showed significantly greater expression of IL-1ß (see Fig. 1).1



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  		Fig. 1. Log-normalized means (±SEM) for MCP-1, IL-1ß, TNF-{alpha}, and IL-8 by BDI group, adjusting for age, race, BMI, and alcohol use.1

 
Similarly, analysis of TNF-{alpha} revealed a significant BDI group effect (F(1,41) = 11.29, p = .009). Inspection of group means indicated that men with high BDI scores showed greater TNF-{alpha} expression (see Fig. 1). Analysis of MCP-1 also revealed a significant BDI group effect (F(1,39) = 5.54, p = .012), with men with high BDI scores showing greater MCP-1 expression. Similarly, men with high BDI scores showed greater expression of IL-8 (F(1,41) = 9.64, p = .003). Lastly, analysis of IL-1{alpha} showed that the BDI group effect approached significance (F(1,41) = 3.68, p = .062), with men with higher BDI scores showing greater expression of IL-1{alpha}.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 
The present studies shows that severity of depressive symptoms is significantly and positively associated with an over-expression of proinflammatory cytokines by LPS-stimulate blood monocytes. In healthy, nonsmoking men, higher BDI scores were associated with greater expression of monocyte-associated IL-1{alpha}, IL-1ß, TNF-{alpha}, IL-8, and MCP-1. Significant differences were also noted when the analyses were conducted using BDI groups established by a priori scoring criteria. Indeed, relative to men with minimal or no depressive symptoms (ie, BDI < 10), men reporting mild to moderate levels of depressive symptoms (ie, BDI >= 10) exhibited an overexpression of monocyte-associated proinflammatory cytokines and chemokines after LPS stimulation. To the best of our knowledge, this is the first study to indicate that severity of depressive symptoms is associated with monocyte-associated overexpression of proinflammatory cytokines and chemokines in healthy, nonmedicated men without a diagnosis of MDD or ASCVD.

The current findings parallel previous observations of an increase in IL-1ß, TNF-{alpha}, and IL-8 in persons with MDD (for review see Ref. 10). The current data, however, extend previous observations by suggesting that even low to moderate levels of depressive symptoms are associated with an overexpression of proinflammatory cytokines. Although novel, the current findings seem to be consistent with the observed gradient between severity of depressive symptoms and increased risk of cardiovascular disease in initially healthy persons (3). Thus, if overexpression of monocyte-associated cytokines and chemokines plays a role in the pathogenesis of atherosclerosis, it would explain in part the reported gradient between cardiovascular disease risk and magnitude of depressive symptoms (3).

A unique aspect of this study is the assessment of protein expression by blood monocytes. It is well recognized that various leukocytes and other cells produce the cytokines and chemokines measured in this study. Blood monocytes, however, are known to be one of the major cellular components in the initiation and evolution of atherosclerotic lesions (39). It is thought that production of proinflammatory cytokines by blood monocytes contributes to the adherence of monocytes to the endothelium, the first step in the sequence of cellular events leading to the development of foam cells (5, 6). That our observations are specific to the expression of cytokines and chemokines by blood monocytes promotes the hypothesis of inflammation as a link between severity of depressive symptoms and ASCVD.

The current findings were observed in both univariate and multivariate analyses. The latter set of analyses is particularly important because it controlled for potential confounding variables, such as age, BMI, and alcohol intake, all shown to alter cytokine expression (40). In addition to statistical controls, we excluded smokers, men with preexisting medical and psychiatric conditions, and men who had taken or were taking any medications and low-dose aspirin, all factors known to affect cytokines (41). Implementation of these exclusionary conditions removed the possibility that these factors could account for our findings. Nevertheless, other factors not measured may have contributed to our findings. For example, increases in depressive symptoms may be accompanied by sleep disturbance, a factor known to influence cytokine production (42). Although we did not directly assess number of hours slept, subjects were asked to compare hours slept during the week before participation to an "average" week in their lives. Most subjects reported sleeping the "same as usual" (N = 25) or "less than usual" (N = 16) with a smaller number reporting "more than usual" (N = 12). In our sample, however, BDI scores were not significantly different between these three classifications (p = .45). Thus, changes in sleep pattern, although often associated with increases in depressive symptoms and cytokine production, may not account for our findings.

The current study has several limitations. First, the nature of the observations does not establish the directionality of these associations. Directionality is particularly relevant due to speculations about the potential role of proinflammatory cytokines in the onset of depression (43). Specifically, Smith (43) proposed that excessive secretion of proinflammatory cytokines such as IL-1ß and TNF-{alpha} may cause depression. He further suggested that some depressive patients might show immune abnormalities that precipitate hormonal and behavioral changes associated with depression. Direct evidence for the behavioral effects of cytokines have mostly come from a number of animal studies (44) and studies of cancer patients (45). However, one recent study of healthy young men showed that the intravenous administration of LPS produced increases in TNF-{alpha} and IL-6 that were strongly associated with increased anxiety and depressive mood (46). Although these issues are beyond the scope of this study, the role that inflammatory cytokines play in the onset of depressive symptoms, and their relation to depression associated with other inflammatory diseases such as cancer and arthritis, is an important area for future research.

Second, we did not assess potential mechanisms that could explain our findings. For example, psychological stress, whether characterized as acute or chronic, is associated with both depression and proinflammatory cytokine regulation (47–49). Thus, one possibility is that psychological stress among men reporting depressive symptoms contributed to our findings. Similarly, biological parameters such as hypothalamic-pituitary-adrenal axis activation (50), neurotransmitters (51), activity of the adrenergic receptor/adenylase cyclase unit (52), and substance P (53) are associated with depression and are also known to affect cytokines. Thus, one or a combination of any of the above factors may underlie the increased expression of monocyte-associated cytokines and chemokines among men exhibiting depressive symptoms.

Lastly, the current study assessed only a limited number of cytokines and chemokines implicated in the pathogenesis of ASCVD. Recent evidence has indicated that IL-6 is a significant predictor of future MI in initially healthy men (57). In two previous studies, IL-6 was linked to severity of depressive symptoms and depressed mood in older healthy adults (21, 22) and to MDD in psychiatric patients (10). Thus, it may be the case that severity of depressive symptoms is also associated with IL-6. In light of this possibility, we are currently collecting new data that will be used to examine whether severity of depressive symptoms is also associated with IL-6 in younger (<50 years) men and women.

Clearly the weight of the evidence suggests that in initially healthy individuals, severity of depressive symptoms in the absence of diagnosed MDD is associated with increased risk of cardiovascular disease along a continuum (1, 3). At this time, however, it is not well understood how depressive symptoms contribute to cardiovascular disease (3, 9). The current study observed an association between severity of depressive symptom and overexpression of proinflammatory cytokines and chemokines by blood monocytes. These observations may explain in part the relation of severity of depressive symptoms to cardiovascular disease given that an increased in proinflammatory cytokines and chemokines characterize the inflammatory process, leading to the onset and progression of ASCVD. Future studies should examine whether psychological, behavioral, and biological factors could moderate the production of proinflammatory cytokines and chemokines in persons exhibiting depressive symptoms.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
REFERENCES
 
The authors are grateful to Karen Achanzar, Kenneth Young, and the Comprehensive Cancer Center for Flow Cytometry under the direction of Michael J. Cook, PhD, for conducting the flow cytometry. We also wish to thank Melanie Tirronen, Sarah S. Rush, and Tara N. Pennington for their efforts in data collection. This work was supported by National Heart, Lung, and Blood Institute Grants HL-56105 and HL-67459 (to E.C.S.).


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
ACKNOWLEDGMENTS
 REFERENCES
 
1 Adjusted raw means (±SEM) for each BDI group (BDI <10 and BDI >=10, respectively): IL-1ß, 24.6 (7.4) vs. 67.7 (9.5); TNF-{alpha}, 14.5 (9.8) vs. 55.0 (12.7); MCP-1, 0.99 (0.35) vs. 2.42 (0.48); and IL-8, 96.3 (78.4) vs. 303.23 (101.2). Back

Received for publication July 11, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 ACKNOWLEDGMENTS
 REFERENCES
 

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