Psychoneuroendocrinology (2004) 29, 1119–1128
Enhanced expression of cytokines and
chemokines by blood monocytes to in vitro
lipopolysaccharide stimulation are associated
with hostility and severity of depressive
symptoms in healthy women
Edward C. Suareza,*, James G. Lewisb, Ranga R. Krishnana,
Kenneth H. Youngb
aDepartment of Psychiatry and Behavioral Sciences, Duke University Medical Center,
P.O. Box 3328, Durham, NC 27710, USA
bDepartment of Pathology, Duke University Medical Center, P.O. Box 3712, Durham,
NC 27710, USA
Received 1 July 2003; received in revised form 30 December 2003; accepted 5 January 2004
Summary The current study investigated the relation of hostility and severity of
depressive symptoms, separately and jointly, to the capacity of blood monocytes
to secrete an array of cytokines when stimulated by bacterial lipopolysaccharide
(LPS). Subjects were 44 healthy, non-smoking, premenopausal women (aged 23–
49 years) not currently taking oral contraceptives. Data were collected during
the follicular phase of the menstrual cycle. The Cook–Medley Hostility (Ho) scale
and the Beck Depression Inventory (BDI) were used to assess hostility and sever-
ity of depressive symptoms, respectively. Dual-color flow cytometry was used to
measure the total expression of interleukin (IL)-1a, IL-1b, IL-8, tumor necrosis
factor (TNF)-a, monocyte chemotactic protein (MCP)-1 and monocyte inflamma-
tory protein (MIP)-1a in blood monocytes following 4 h in vitro LPS stimulation
of whole blood. In analyses adjusting for age, body mass index (BMI), fasting
cholesterol, alcohol use, race and 17b-estradiol (E2), higher Ho scores were
associated with greater LPS-stimulated expression of IL-1a (b ¼ 0:033, p ¼ 0:02),
IL-8 (b ¼ 0:046, p ¼ 0:01) and IL-1b (b ¼ 0:024, p ¼ 0:06). Higher BDI scores were
associated with greater expression of TNF-a (b ¼ 0:042, p ¼ 0:02) and IL-8
(b ¼ 0:045 p ¼ 0:04). The linear combination of Ho and BDI scores was signifi-
cantly associated with IL-1b (b ¼ 0:18 p ¼ 0:057), IL-8 (b ¼ 0:36, p ¼ 0:01), TNF-a
(b ¼ 0:25, p ¼ 0:03), and IL-1a (b ¼ 0:18, p< 0:07). Thus, in healthy women,
these psychological risk factors, alone and in combination, induce a proin-
flammatory phenotype in circulating monocytes characterized by the up-regu-
lation of proinflammatory cytokines, supporting the hypothesis that inflammation
*Corresponding author. Tel.: +1-919-684-2941; fax: +1-919-
E-mail address: email@example.com (E.C. Suarez).
0306-4530/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
may be a key pathway whereby hostility and depressive symptoms contribute to
atherosclerosis and subsequent coronary heart disease (CHD).
# 2004 Elsevier Ltd. All rights reserved.
Hostility and severity of depressive symptoms
have been independently
increased risk of coronary heart disease (CHD) in
community samples of initially healthy women
with no known cardiovascular disease (Ford et al.,
1998; Knox et al., 1998; Ferketich et al., 2000;
Myrtek, 2001; Wuslin and Singal, 2003). It has also
been demonstrated that even subclinical levels of
depressive symptoms are associated with future
CHD risk (Ferketich et al., 2000; Penninx et al.,
2001). For the most part, the relations of hostility
and severity of depressive symptoms to CHD
appear to be independent of established risk fac-
tors, such as age, gender, diabetes, hypertension,
and cholesterol (Jiang and Blumenthal, 2003).
Although it is not well understood what mechan-
isms underlie these associations, both behavioral
(e.g., increased smoking, decreased physical fit-
ness, poor diet) and biological factors (e.g.,
excessive sympathetic nervous system and hypo-
thalamic–pituitary activation to stressors) have
been implicated (Smith, 1994; Musselman et al.,
1998). It is now recognized, however, that CHD is
an inflammatory disease characterized by the
accumulation of inflammatory cells at the site of
atherosclerotic plaque and the up-regulation of
proinflammatory cytokines and chemokines (Ross,
1999). One critical cell contributing to CHD is the
blood monocyte/macrophage. It has been shown
that blood monocytes/macrophages (a) are key
cellular components in every phase of the inflam-
matory process leading to cardiovascular disease
(Stary et al., 1994; Ross, 1999; Lessner et al.,
2002); (b) predict premature occurrence of coron-
ary events (Olivares et al., 1993); (c) are parti-
cularly important in early lesion development
(Gerrity, 1981); and (d) are recruited by cytokines
(Kim et al., 2000; Litovsky et al., 2003). Studies
have shown that circulating inflammatory cyto-
kines and monocyte-associated responses to in
vitro stimulation are associated not only with cor-
onary syndromes (Liuzzo et al., 2001) but also
(Bermudez et al., 2002) and increased risk of CHD
(Ridker et al., 1997) in initially healthy women.
Recently our group has presented data showing
that, in healthy men, severity of depressive symp-
stimulated expressions of monocyte-associated
cytokines and chemokines (Suarez et al., 2003)
and, in conjunction with hostility, circulating
levels of plasma IL-6 (Suarez, 2003a,b). We also
have presented data to demonstrate that in men,
hostility alone is associated with an enhanced
monocytes (Suarez et al., 2002). Although prelimi-
nary, these observations support the hypothesis of
an association between proinflammatory cytokines
and psychological coronary risk factors of hostility
and severity of depressive symptoms in men. To
date, parallel studies in women have not been
conducted. Given our prior observations in men
and the relative importance of proinflammatory
cytokines and monocytes in the development of
CHD (Bermudez et al., 2002), we hypothesized
that hostility and severity of depressive symptoms
would be similarly associated with greater mono-
chemokines in healthy women. The purpose of the
present study, therefore, was to critically test this
hypothesis by examining the separate and com-
bined effects of hostility and severity of depress-
ive symptoms on the expression of interleukin
(IL)-1a, IL-1b, IL-8, TNF-a, monocyte chemotactic
protein (MCP)-1 and monocyte inflammatory pro-
tein (MIP)-1a following in vitro stimulation of
women with a mean age of 33.5 years (range:
23–49) who were recruited via advertisements
placed in local newspapers. Interested individuals
psychological conditions and use of medications
that could alter the expression of monocyte mar-
kers. None of the participants reported a history
or current diagnosis of cardiovascular disease,
immune-related conditions, hypertension, sub-
stance abuse problems, oral/dental conditions or
any other medical/psychiatric conditions. None of
E.C. Suarez et al. 1120
the women were taking oral contraceptives, or
any prescription or over-the-counter medications,
including low-dose aspirin and/or vitamin supple-
ments. Lastly, individuals who smoked in the last
2 years or had irregular menstrual cycles were
excluded. Subjects who met eligibility criteria
between 08:00 and 09:00 h following a 12 h over-
night fast. Participants were scheduled during the
follicular phase (days 5–10) of the menstrual cycle
in order to minimize the influence of menstrual
cycle phase on expression of monocyte markers
follicular phase was done via assessment of 17b-
estrodial (E2) and progesterone (P) on blood sam-
ples collected on the day of the study.
On the day of the laboratory session, all sub-
jects gave written informed consent to participate
in the study, approval of which was granted by the
Institutional Review Board of Duke University
Medical Center. After consent was completed,
blood samples were drawn using a 21-gauge but-
psychological scales and a short personal back-
ground questionnaire. Participants received mon-
etary compensation for their participation.
2.2. Assessment of hostility and severity
of depressive symptoms
Assessment of severity of depressive symptoms
and hostility was performed using the 21-item
Beck Depression Inventory (BDI) (Beck et al.,
1999) and the 50 item Cook–Medley Hostility (Ho)
scale (Cook and Medley, 1954), respectively. Sub-
jects also completed a short background question-
naire that included questions on health and
health-related behaviors (e.g., exercise, alcohol
consumption). It has been suggested that the BDI
reflects such dimensions as negative attitude
toward self, performance impairment and somatic
disturbance (Dozois et al., 1998). The Ho scale, on
the other hand, is purported to measure cynical
beliefs and mistrust of others (Barefoot and Lip-
kus, 1994) as well as neurotic and antagonistic
hostility (Suarez and Williams, 1990). The BDI and
the Ho have been reported to have good psycho-
metric properties including adequate internal val-
idity, good test–retest reliability and construct
validity (Cook and Medley, 1954; Barefoot and Lip-
kus, 1994; Beck et al., 1999). Evidence suggests
that BDI scores are positively correlated with
clinical ratings of depression (Brown et al., 1995;
Beck et al., 1999).Similarly, evidence for conver-
gent validity has been reported for the Ho scale
(Smith and Frohm, 1985). It has also been repor-
ted that the BDI and Ho scales are significantly
correlated in non-clinical samples (Felsten, 1996;
Suarez, 2003a,b). Other studies have shown that
depression is related to hostility (Weissman et al.,
1971; Schless et al., 1974). For the BDI, parti-
cipants were instructed to reflect on the week
prior to study participation in responding to the
2.3. Blood collection and flow cytometry
Procedures for assessment of total cell-associated
cytokines and chemokines have been previously
described elsewhere (Schultz, 2003; Suarez et al.,
2003). Briefly, following an overnight fast, blood
samples were drawn between 08:30 and 09:30 h
into two 4 ml tubes containing lithium heparin.
Samples were placed on ice for approximately 50
min until transferred to the flow cytometry lab-
oratory. At the flow cytometry laboratory, undi-
luted whole-blood culture was incubated for 4 h
Monensin (1 lg/ml), an inhibitor of protein trans-
port and secretion (Mollenhauer et al., 1990), was
simultaneously added to both cultures to inhibit the
secretion of synthesized proteins. After stimulation,
leukocytes were fixed with paraformaldehyde and
permeabilized with saponin. Erythrocytes were
lysed with lysing solution. Samples were then sepa-
rated into 200 ll aliquots where cells were incu-
bated with anti-CD14 flourescein isothiocyanate
(FITC)-conjugated monoclonal antibody (mAb). For
determining cell-associated expression, cells were
incubated with phycoerythrin (PE) conjugated anti-
cytokines and -chemokines specific mAb. Controls
consisted of samples exposed to equal concentra-
tions of tagged irrelevant antibodies of the same
Dual-color flow cytometry (FACScan, Beckton
Dickinson) was done using CellQuest (ver. 3.1)
computer software and gating on CD14-positive
cells. Results were expressed as the relative mean
fluorescent intensity (MFI) derived from at least
10,000 CD14-positive monocytes. MFI was calcu-
lated for total cell-associated IL-1a, IL-1b, TNF-a,
IL-8, MCP-1 and MIP-1a. Reproducibility of flow
cytometry was ensured by regular measurement of
Blood samples for lipid assessment were collected
in standard chemistry tubes (Serum separator Tubes)
and fasting total cholesterol was determined enzy-
matically (Hitachi 704 Analyzer, Boehringer Man-
nhein Diagnostics, Indianapolis, ID).
?C alone or stimulated with LPS (1 lg/ml).
1121Hostility, depression and monocyte-associated inflammatory proteins in women
Initial inspection of MFI values for all monocyte
markers revealed a skewed distribution, thus log-
arithmic transformations were performed using
the formula Log10ðXþ1Þ (Kirk, 1968). Multivariate
regression analysis was conducted separately for
Ho and BDI scores entered as continuous vari-
ables. To examine the combined effect of Ho and
BDI, a principal component analysis was per-
formed and a psychological risk factor (PRF) score
was generated. The PRF score is the linear combi-
nation of Ho and BDI. The continuous PRF score
was used in subsequent analyses examining the
combined effect of Ho and BDI on monocyte mar-
included age, body mass index (BMI), fasting total
cholesterol (TC), race and alcohol use as covari-
ates. These covariates were selected on the basis
of previous observations suggesting an association
between these factors and elevations in proin-
flammatory cytokines (Elneihoum et al., 1997;
Mendall et al., 1997) as well as to adjust for poss-
ible confounding with measures of hostility and
severity of depressive symptoms. In addition, E2
was also used as a covariate in all analyses given
the reported effect of E2on production of cyto-
(Rogers and Eastell, 2001). Given the expected
direction of the hypothesized relationships, a one-
tail test was used to determine significance of
in peripheralblood mononuclearcells
Table 1 presents sample characteristics. Overall,
97% of the participants described their health sta-
tus as good or excellent in the week preceding
their participation. Mean levels of E2 and pro-
gesterone (P) were consistent with the follicular
phase of the menstrual cycle. As expected, scores
on the Ho and BDI scales were significantly corre-
lated (r ¼ 0:61, p< 0:001). Using established a
priori criteria for the BDI, 25% of the participants
scored 10 and above, suggesting mild to moderate
intensity of depressive symptoms (Beck, 1967;
Beck et al., 1999).
psychological risk factors to monocyte count.
Pearson partial correlations revealed that mono-
cyte count was not associated with either BDI
Body mass index (kg/m2)
Total cholesterol (mg/dl)
health status (%)
Exercise regularly (%)
Alcohol use (%)
Tumor necrosis factor-a
Monocyte chemotactic protein-1
Monocyte inflammatory protein-1a
Due to skewness, mean fluorescent intensity (MFI) for monocyte markers are presented as median and
E.C. Suarez et al.1122
(partial r ¼ ?0:15, ns) or Ho (partial r ¼ ?0:11, ns)
Regression models using Ho score as a continu-
ous variable revealed significant Ho effects for IL-
1a (b ¼ 0:033, SE ¼ 0:015, tð29Þ ¼ 2:17, p ¼ 0:02),
IL-1b (b ¼ 0:024, SE ¼ 0:015, tð29Þ ¼ 1:60, p ¼
0:06), and IL-8 (b ¼ 0:046, SE ¼ 0:021, tð29Þ ¼
2:24, p ¼ 0:01). Inspection of b-coefficients indi-
cated that increases in Ho scores were associated
with greater expression of these monocyte-asso-
Similarly, analyses of BDI score entered as a
effects for IL-8 (b ¼ 0:045, SE ¼ 0:025, tð31Þ ¼
1:82, p ¼ 0:04), and TNF-a (b ¼ 0:042, SE ¼ 0:02,
tð31Þ ¼ 2:09, p ¼ 0:02). Higher BDI scores were
associated with greater expression of IL-8 and
TNF-a following LPS stimulation.
Lastly, analyses were performed to examine
the combined effect of hostility and severity of
analysis yieldeda single
(Eigenvalue ¼ 1:61) that accounted for 81% of
the variance. As with
derived scores, the PRF score has a mean of 0
and a standard deviation of 1. As with Ho and
revealed that PRF was not associated with mono-
cyte count (partial r ¼ ?0:15, ns). Complete
results for regression analyses are presented in
Results of regression analyses revealed a signifi-
cant PRF-effect for IL-1b (b ¼ 0:18, SE ¼ 0:11,
tð29Þ ¼ 1:60, p ¼ 0:057), IL-8 (b ¼ 0:36, SE ¼ 0:15,
tð29Þ ¼ 2:34,
SE ¼ 0:12, tð29Þ ¼ 2:03, p ¼ 0:032) and marginally
significant effects for IL-1a (b ¼ 0:18, SE ¼ 0:12,
tð29Þ ¼ 1:56, p ¼ 0:070). As illustrated in Fig. 1a–c,
higher PRF scores were associated with greater
LPS-stimulated expression of monocyte markers.
p ¼ 0:011),TNF-a
(b ¼ 0:25,
The results of the present study showed that hos-
tility and severity of depressive symptoms, separ-
ately and in combination, significantly predict
LPS-stimulated expression of monocyte-associated
menopausal women. Moreover, with the exception
of MCP-1, the pattern of individual cytokine
expressions associated with hostility and severity
of depressive symptoms in women is the same as
that previously observed for men whereby higher
BDI scores were associated with LPS-stimulated
expression of IL-1b, TNF-a, IL-8 and MCP-1 by
blood monocytes (Suarez et al., 2003). As with our
previous study of healthy men, the current obser-
vations were observed in multivariate analyses
controlling for various factors such as age, BMI,
fasting cholesterol, alcohol use, as well as E2, all
cytokines.1In addition to statistical adjustments,
exclusionary criteria insured that these observa-
tions were not confounded with the presence of
established risk factors such as smoking, hyper-
tension and diabetes. Thus, these data support
mechanisms may be one pathway whereby these
empirically supported psychological risk factors
lead to an increased risk of CHD.
We previously have demonstrated that scores on
the Ho scale significantly and positively predicted
LPS-stimulated expression of TNF-a in circulating
monocytes from healthy men (Suarez et al.,
2002). The current study is the first to our knowl-
edge to indicate that hostility, assessed via the Ho
scale, is also associated with greater stimulated
expression of monocyte-associated cytokines. Pre-
vious studies have reported that the Ho scale pre-
dicts incidence of CHD (Haynes et al., 1980) as
well as risk of myocardial infarction (MI) in
initially healthy women (Barefoot et al., 1995). In
postmenopausal women with CHD, hostility has
been shown to significantly predict recurrent MI in
a 4-year follow-up (Chaput et al., 2002). Although
previous studies of healthy women have also indi-
cated that the Ho scale is associated with (a)
excessive cardiovascular responses to anger arou-
sal (Suarez et al., 1993), and (b) elevations in
fasting lipids (Suarez et al., 1998), both known or
suspected of leading to increased risk of CHD, the
current findings provide preliminary evidence indi-
cating that inflammatory mechanisms may be one
pathway whereby hostility contributes to the
development and progression of CHD in women.
1The rationale for including these variables as covariates was
to reduce the possibility of confounding as reported in other
studies (e.g., Kop et al., 2002; Miller et al., 2002). However,
not all of the covariates included in the regression analyses sig-
nificantly predicted expressions of monocyte markers. Results
of regression analyses showed that fasting TC significantly pre-
dicted IL-1a (b ¼ 0:01, p ¼ 0:002); IL-1b (b ¼ 0:008, p ¼ 0:03);
IL-8 (b ¼ 0:01, p ¼ 0:01); TNF-a (b ¼ 0:009, p ¼ 0:02). 17b-
estradiol predicted IL-8 (b ¼ ?0:005, p ¼ 0:039) and race pre-
dicted MIP-1a ðFð3; 18Þ ¼ 3:23, p ¼ 0:046). Although BMI, age
and alcohol use failed to predict expression of monocyte mar-
kers, these variables have been previously shown to alter the
relation of depression to proinflammatory biomarkers (e.g.,
Kop et al., 2002; Miller et al., 2002), thus it was important to
retain these variables in the analyses.
1123Hostility, depression and monocyte-associated inflammatory proteins in women
b-coefficients (SE) for regression models with psychological risk factor (PRF) score. PRF represents the linear combination of the scores on the Beck
Depression Inventory and Cook–Medley Hostility Inventory. All cytokine values were logarithmically transformed
*p < 0:01.
**p < 0:05.
***p < 0:10.
E.C. Suarez et al.1124
Greater LPS-stimulated expressions of mono-
cyte-associated markers were also significantly
associated with greater severity of depressive
symptoms as indicated by higher BDI scores.
Although previous studies have indicated that both
severity of depressive symptoms and clinical
depression are associated with higher circulating
levels of proinflammatory cytokines, multivariate
analyses controlling for traditional risk factors of
CHD have led to diminished and non-significant
associations (Kop et al., 2002; Miller et al., 2002).
In these data, however, the relations of BDI scores
to monocyte-associated inflammatory cytokines
were significant in multivariate analyses that con-
trolled for various factors. That we excluded indi-
viduals with preexisting chronic and acute medical
conditions and those women taking prescribed or
over-the-counter medications insured that the
current results do not reflect potential confounds.
Thus, these data suggest that independent of
depressive symptoms is significantly and indepen-
dently associated with greater expression of mono-
cyte-associated inflammatory markers in healthy
Lastly, the linear combination of hostility and
severity of depressive symptoms significantly pre-
dicted greater expression of monocyte-associated
cytokines and chemokines. Not only do these data
show an association of the combination of hos-
tility and severity of depressive symptoms with
increased expression of proinflammatory cyto-
kines in monocytes, but these results also indicate
a quantitative correlation; the more severe the
depressive symptoms and greater hostility the
greater the production of cytokines (see Fig. 1).
Although similar analyses have not been conduc-
ted in men, the same linear combination of sever-
ity of depressive symptoms and hostility predicts
higher levels of plasma IL-6 in healthy, non-smok-
ing men (Suarez, 2003a,b). Taken together, the
data from our laboratory underscore the impor-
tance of examining the effect of clustering of
psychological risk factors on inflammatory bio-
makers with the comorbidity of hostility and
severity of depressive symptoms as a potentially
There is abundant evidence to indicate that
exposure of monocytes and macrophages to LPS
induces a reproducible pattern of changes including
the up-regulation and secretion of a various cyto-
kines (Kang et al., 1992). In the current study,
the same pattern was observed in that all cyto-
kines showed up-regulation following exposure to
LPS. However, it is important to note that the
enhanced expression of cytokines following LPS
significantly varied by level of hostility, severity
of depressive symptoms, and their combination.
Hostility enhanced expression of IL-1a, IL-1b, IL-
8, and MIP-1, whereas severity of depressive
expression of TNF-a and IL-8, and the combi-
factor (PRF) score and predicted values of logarithmic-
transformed mean fluorescent intensity (MFI) for mono-
cyte-associated total expression of interleukin (IL)-1b,
tumor necrosis factor (TNF)-b and IL-8 following 4 h of
LPS-stimulation. Log-transformed MFI values are adjus-
ted for age, body mass index, fasting total cholesterol,
race, 17b-estradiol and alcohol use.
(a–c) Associations between psychological risk
1125Hostility, depression and monocyte-associated inflammatory proteins in women
expression of IL-1b, IL-8, and TNF-a; three dis-
tinct but yet over-lapping patterns of enhance-
ment. The most likely interpretation of these
data is that severity of depressive symptoms and
hostility do not simply up-regulate the overall
response of monocytes to LPS but, via some
unknown mechanism, act on enhancing LPS-sti-
mulated expression of individual cytokines. The
novelty of these observations does not allow us
to conclude that only certain cytokines are more
The cross-sectional design of the current study
also does not allow for any conclusion to be made
regarding the directionality of the observed asso-
ciations. Nevertheless, our observations are in-
line with the hypothesis proposed by Smith, who
suggested that excessive secretion of macrophage
products, such as IL-1, causes depression (Smith,
1991). Recent reviews by both Seidel et al. (1999)
and Capuron and Dantzer (2003), however, have
concluded that while a number of studies report
increases in circulating levels of inflammatory
cytokines in patients with clinical depression, this
has not always been the case. These authors have
suggested that the observations of increased cir-
culating levels of cytokines in depressed patients
may be due to various confounding factors (e.g.,
age, BMI, ongoing or recent infections, smoking
habits, and prior medications) as well as diagnosis
(Haack et al., 1999). Clearly, this is not the case
in the current study since all of these factors were
either adjusted for in the analyses (e.g., age, BMI)
or controlled methodologically via the selection
criteria (e.g., no ongoing or recent infection(s),
non-smokers, no current or prior medication use
including low-dose aspirin, oral contraceptives,
vitamin supplements). Thus, while conclusions
about causality are not possible, the current data
are consistent with the hypothesis of cytokine-
induced depressive symptoms independent of vari-
ous confounding factors.
Although the current findings are similar to our
previous observations in healthy men, it is well
recognized that premenopausal women are rela-
tively protected from atherosclerosis and CHD
(Higgins and Thom, 1993). Nevertheless, one
recent study has suggested the importance of
modifying risk factors during the pre- and perime-
nopausal years of a woman’s life and that the lack
of modification may lead to greater numbers of
women requiring more aggressive treatment dur-
ing their postmenopausal years (Derby et al.,
2003). The extent to which inflammation plays a
role in future risk of CHD combined with evidence
from prospective and case-control studies of the
relation of hostility and severity of depressive
symptoms to CHD in women leads to the con-
reduction of depressive symptoms may subse-
quently contribute to lower risk of CHD later in
life via reduction in inflammation.
In conclusion, these findings show that hostility
and severity of depressive symptoms, separately
and in combination, predict greater expression of
monocyte-associated cytokines and chemokines
following in vitro stimulation of whole blood by
LPS. These associations were significant in multi-
variate analyses that adjusted for age, BMI, fast-
ing total cholesterol, alcohol use, and race and
with methodological criteria insuring that parti-
cipants were free of ongoing or previous medical
conditions associated with inflammation and were
also non-smokers. Given these observations, the
findings indicate that inflammatory mechanisms
whereby hostility and severity of depressive symp-
toms contribute to the atherosclerotic process
leading to CHD in women.
The authors are grateful to Karen Achanzar and
the Comprehensive Cancer Center for Flow Cyto-
metry under the direction of Michael J. Cook,
Ph.D. for conducting the flow cytometry studies.
We also wish to thank Melanie Tirronen, Sarah S.
Rush, and Tara N. Pennington for their efforts in
data collection. The authors also wish to acknowl-
edge the initial contributions of Dolph O. Adams,
M.D. who was instrumental in initiating these stu-
dies. Dr. Adams passed away prior to the collec-
tion of data. This work was supported by National
Heart, Lung, and Blood Institute grants HL-56105
and HL-67459 (to E.C.S.)
Barefoot, J.C., Lipkus, I.M., 1994. The assessment of anger and
hostility. In: Sigman, A.W., Smith, T.W. (Eds.), Anger, Hos-
tilityand theHeart. Lawrence
Hillsdale, NJ, pp. 43–66.
Barefoot, J.C., Larsen, S., von der Lieth, L., Schroll, M., 1995.
Hostility, incidence of acute myocardial infarction, and
mortality in a sample of older Danish men and women. Am.
J. Epidemiol. 142, 477–484.
University of Pennsylvania Press, Philadelphia.
Beck, A.T., Steer, R.A., Garbin, M.G., 1999. Psychometric
properties of the Beck Depression Inventory: twenty-five
years of evaluation. Clin. Psychol. Rev. 89, 757–760.
Bermudez, E.A., Rifai, N., Buring, J., Manson, J.E., Ridker,
P.M., 2002. Interrelationships among circulating interleukin-
E.C. Suarez et al.1126
6, C-reactive protein, and traditional risk factors in women.
Arterioscler. Thromb. Vas. Biol. 22, 1668–1673.
Brown, C., Shulberg, H.C., Madonia, M.J., 1995. Assessing
depressionin primary care
Depression Inventory and the Hamilton Rating Scale for
Depression. Psychol. Assess. 7, 59–65.
Capuron, L., Dantzer, R., 2003. Cytokines and depression:
the need for a new paradigm. Brain Behav. Immun. 17,
Chaput, L.A., Adams, S.H., Simon, J.A., Blumenthal, R.S., Vit-
tinghoff, E., Lin, F., Loh, E., Matthews, K.A., 2002. Hos-
tility predicts recurrent events among postmenopausal
women with coronary heart disease. Am. J. Epidemiol. 156,
Cook, W.W., Medley, D.M., 1954. Proposed hostility and phar-
isaic-virtue scales for the MMPI. J Appl. Psych. 38, 414–418.
Derby, C.A., Fitzgerald, G., Pasternak, R.C., 2003. Application
of Adult Treatment Panel III (ATPIII) guidelines to a multi-
ethnic cohort of perimenopausal women: inclusion of
age > 55 will produce an important shift in the proportions
requiring intervention. In: Paper Presented at the 43rd
Annual Conference on Cardiovascular Disease Epidemiology
and Prevention, Miami, FL.
Dozois, D.J., Dobson, K.S., Ahnberg, J.L., 1998. The psycho-
metric evaluation of the Beck Depression Inventory—II. Psy-
chol. Assess. 10, 83–89.
Elneihoum, A.M., Falke, P., Hedblad, B., Lindga ¨rde, F.,
Ohlsson, K., 1997. Leukocyte activation in atherosclerosis:
correlation with risk factors. Atherosclerosis 131, 79–84.
depression. Person. Indiv. Differ. 21, 461–467.
Ferketich, A., Schwartzbaum, J., Frid, D., Moeschberger, M.,
2000. Depression as an antecedent to heart disease among
women and men in the NHANES I study. Arch. Intern. Med.
Ford, D.E., Mead, L.A., Chang, P.P., Cooper-Patrick, L., Wang,
N.Y., Klag, M.J., 1998. Depression is a risk factor for coron-
ary artery disease in men: the precursors study. Arch.
Intern. Med. 158, 1422–1426.
Gerrity, R.G., 1981. The role of the monocyte in atherogenesis.
I Transition of blood-borne monocytes into foam cells in
fatty lesions. Am. J. Pathol. 103, 181–190.
Haack, M., Hinze-Selch, D., Fenzel, T., Kraus, T., Kuhn, M.,
Schuld, A., Pollmacher, T., 1999. Plasma levels of cytokines
and soluble cytokine receptors in psychiatric patients upon
hospital admission: effects of confounding factors and diag-
nosis. J. Psychiatry Res. 33.
Haynes, S.G., Feinleib, M., Kannel, W.B., 1980. The relation-
ship of psychosocial factors to coronary heart disease in the
Framingham Study. III. Eight-year incidence of coronary
heart disease. Am. J. Epidemiol. 111, 37–58.
Higgins, M., Thom, T., 1993. Cardiovascular disease in women
as a public health problem. In: Packard, B. (Ed.), Cardio-
vascular Health and Disease in Women. LeJacp Communica-
tions, Inc, Greenwich, CT, pp. 33–41.
Jiang, W., Blumenthal, J.A., 2003. Depression and ischemic
heart disease: overview of the evidence and treatment
implication. Curr. Psychiatry Rep. 5, 47–54.
Kang, Y.H., Lee, C.H., Monroy, R.L., Dwivedi, R.S., Odeyale,
C., Newball, H.H., 1992. Uptake, distribution, and fate of
bacterial lipopolysaccharides in monocytes and macro-
phages: an ultrastructural and functional correlation. Elec-
tron Microsc. Rev. 5, 381–419.
Kim, C.J., Khoo, J.C., Gillote-Taylor, K., et al., 2000. Poly-
recruitment of monocytes to mouse atherosclerotic lesions
in vivo: enhancement by tumor necrosis factor-alpha and
interluekin-1 beta. Arterioscler. Thromb. Vas. Biol. 20,
Kirk, R.E., 1968. Experimental Design: Procedures for the
Behavioral Sciences. Brooks/Cole Publishing, Belmont, CA.
Knox, S.S., Siegmund, K.D., Weidner, G., Ellison, C., Adelman,
A., Catherine, P., 1998. Hostility, social support, and coron-
ary heart disease in the National Heart, Lung and Blood
Institute Family Heart Study. Am. J. Cardiol. 82, 1192–1196.
Kop, W.J., Gottdiener, J.S., Tangen, C.M., Fried, L.P.,
McBurnie, M.A., Walston, J., Newman, A., Hirsch, C.,
Tracy, R.P., 2002. Inflammation and coagulation factors in
persons > 65 years of age with symptoms of depression but
without evidence of myocardial ischemia. Am. J. Cardiol.
Lessner, S.M., Prado, H.L., Waller, E.K., Galis, Z.S., 2002.
Atherosclerotic lesions grow through recruitment and pro-
liferation of circulating monocytes in a murine model. Am.
J. Pathol. 160, 2145–2155.
Litovsky, S., Madjid, M., Zarrabi, A., Casscells, W., Willerson,
J.T., Naghavi, M., 2003. Superparamagnetic iron oxide-
based method for quantifying recruitment of monocytes to
mouse atherosclerotic lesions in vivo: enhancement by
tissue necrosis factor-a, interleukin-1b, and interferon-c.
Circulation 107, 1545–1549.
Liuzzo, G., Angiolillo, D.J., Buffon, A., Rizzello, V., Colizzi, C.,
Ginnetti, F., Biasucci, L.M., Maseri, A., 2001. Enhanced
response of blood monocytes to in vitro lipopolysaccharide-
challenge in patients with recurrent unstable angina. Circu-
lation 103, 2236–2241.
Mendall, M.A., Patel, P., Asante, M., Ballam, L., Morris, J.,
Strachan, D., Camm, A., Northfield, T., 1997. Relation of
serum cytokine concentrations to cardiovascular risk factors
and coronary heart disease. Heart 78, 273–277.
Miller, G.E., Steller, C.A., Carney, R.M., Freedland, K.E.,
Banks, W.A., 2002. Clinical depression and inflammatory
risk markers for coronary heart disease. Am. J. Cardiol. 90,
Mollenhauer, H.H., Morre, D.J., Rowe, L.D., 1990. Alteration
of intracellular traffice by monensin: mechanism, speci-
ficity and relation to toxicity. Biochim. Biophys. Acta 1031,
Musselman, D.L., Evans, D.L., Nemeroff, C.B., 1998. The
relationship of depression to cardiovascular disease. Arch.
Gen. Psychiatry 55, 580–592.
Myrtek, M., 2001. Meta-analyses of prospective studies on cor-
onary heart disease, type A personality, and hostility. Int.
J. Cardiol. 79, 244–251.
Olivares, R., Ducimetiere, P., Claude, J.R., 1993. Monocyte
count: a risk factor for coronary heart disease? Am. J. Epi-
demiol. 137, 49–53.
Penninx, B.W., Beekman, A.T., Honig, A., Deeg, D.J., Scho-
evers, R.A., van Eijk, J.T., van Tilburg, W., 2001. Depression
and cardiac mortality: results from a community-based
longitudinal study. Arch. Gen. Psychiatry 58, 221–227.
Hennekens, C., 1997. Inflammation, aspirin, and the risk of
cardiovascular disease in apparently healthy men and
women. N. Engl. J. Med. 336, 973–979.
Rogers, A., Eastell, R., 2001. The effect of 17beta-estradiol on
production of cytokines in cultures of peripheral blood.
Bone 29, 30–34.
Ross, R., 1999. Atherosclerosis—an inflammatory disease. N.
Engl. J. Med. 340, 115–126.
Schless, A.P., Mendels, J., Kipperman, A., Cochrane, C., 1974.
Depression and hostility. J. Nerv. Ment. Dis. 159, 91–100.
flammatory cytokines and chemokines in monocytes by flow
1127Hostility, depression and monocyte-associated inflammatory proteins in women
cytometry. In: Korholz, D., Weiss, W. (Eds.), Cytokines and Download full-text
Colony Stimulating Factors: Methods and Protocols, 215.
Humana Press Inc, Totowa, NJ, pp. 29–39.
Seidel, A., Rothermundt, M., Rink, L., 1999. Cytokine pro-
duction in depressed patients. Adv. Exp. Med. Biol. 461,
Smith, R.S., 1991. The macrophage theory of depression. Med.
Hypotheses 35, 298–306.
Smith, T.W., 1994. Concepts and methods in the study of
anger, hostility, and health. In: Siegman, A.W., Smith, T.W.
(Eds.), Anger, Hostility and the Heart. Lawrence Erlbaum
Associates, Hillsdale, NJ, pp. 23–42.
Smith, T.W., Frohm, K.D., 1985. What’s so unhealthy about
hostility? Construct validity and psychological correlates of
the Cook and Medley Ho scale. Health Psychol. 4, 503–520.
Stary, H.C., Chandler, A.B., Glagov, S., Guyton, J.R., Insull,
W.J., Rosenfeld, M.E., Shaffer, S.A., Schwartz, C.J.,
Wagner, W.D., Wissler, R.W., 1994. A definition of initial,
fatty streak, and intermediate lesions of atherosclerosis: a
report from the Committee on Vascular Lesions of the
Council of Arteriosclerosis, American Heart Association.
Arterioscler. Thromb. 14, 840–856.
Suarez, E.C., 2003a. The joint effect of hostility and depress-
ive symptoms on plasma interleukin-6 in apparently healthy
men. Psychosom. Med. 65, 523–527.
Suarez, E.C., 2003b. Plasma interleukin-6 is associated with
psychological risk factors of atherosclerotic cardiovascular
Brain Behav. Immun. 17, 296–303.
Suarez, E.C., Williams, R.B., 1990. The relationships between
dimensions of hostility and cardiovascular reactivity as a
function of task characteristics. Psychosom. Med. 52,
Suarez, E.C., Harlan, E.S., Peoples, M.C., Williams, R.B., 1993.
Cardiovascular and emotional responses in women: the role
of hostility and harassment. Health Psychol. 12, 459–468.
Suarez, E.C., Bates, M.P., Harralson, T.L., 1998. The relation
of hostility to lipids and lipoproteins in women: evidence
for the role of antagonistic hostility. Ann. Behav. Med. 20,
Suarez, E.C., Lewis, J.G., Kuhn, C.M., 2002. The relation of
aggression, hostility, and anger to lipopolysaccharide-
stimulated tumor necrosis factor (TNF)-a by blood mono-
cytes of normal men. Brain Behav. Immun. 16, 675–684.
Suarez, E.C., Krishnan, R.R., Lewis, J.G., 2003. The relation of
severity of depressive symptoms to monocyte-associated
proinflammatory cytokines and chemokines in apparently
healthy men. Psychosom. Med. 65, 362–369.
Weissman, M., Klerman, G.L., Paykel, E.S., 1971. Clinical
evaluation of hostility in depression. Am. J. Psychiatry 128,
Wuslin, L.R., Singal, B.M., 2003. Do depressive symptoms
increase the risk for the onset of coronary disease? A system-
E.C. Suarez et al. 1128