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Psychosomatic Medicine 63:966-972 (2001)
© 2001 American Psychosomatic Society

ORIGINAL ARTICLE

Sex Differences in Glucocorticoid Sensitivity of Proinflammatory Cytokine Production After Psychosocial Stress

Nicolas Rohleder, Dipl-Psych, Nicole C. Schommer, Dipl-Psych, Dirk H. Hellhammer, PhD, Renate Engel, MTA and Clemens Kirschbaum, PhD

From the Center for Psychobiological and Psychosomatic Research (N.C.S., D.H.H., R.E., C.K.), University of Trier, Trier, Germany; and Institute of Physiological Psychology II (N.R., C.K.), University of Düsseldorf, Düsseldorf, Germany.

Address reprint requests to: Clemens Kirschbaum, PhD, Institute of Physiological Psychology II, University of Düsseldorf, Universitätsstrasse 1, D-40225 Düsseldorf, Germany. Email: ck{at}uni-duesseldorf.de


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: Men and women show marked differences in susceptibility to disorders related to the immune system. These gender differences have been proposed to be mediated by functional interactions of the hypothalamus-pituitary-adrenal (HPA) and hypothalamus-pituitary-gonadal (HPG) axes. A potential mechanism involved in this interaction is the glucocorticoid (GC) sensitivity of relevant target tissues for GC. Therefore, the aim of the study reported here was to investigate the impact of psychosocial stress and HPA axis activation on the GC sensitivity of proinflammatory cytokine production in men and women.

METHODS: A total of 45 healthy subjects were investigated. Eighteen women in the luteal phase of their menstrual cycle and 27 men were exposed to a psychosocial stress test (Trier Social Stress Test). Salivary free cortisol levels were measured repeatedly after exposure to the stressor. GC sensitivity was assessed in vitro by dexamethasone inhibition of lipopolysaccharide-stimulated production of interleukin-6 and tumor necrosis factor-{alpha}.

RESULTS: The stress test induced significant increases in salivary free cortisol with no significant differences between men and women. In contrast, GC sensitivity and lipopolysaccharide-stimulated cytokine production showed large gender differences. In men GC sensitivity was markedly increased 1 hour after stress, whereas GC sensitivity decreased significantly in women. Similarly, lipopolysaccharide-induced cytokine production decreased in response to stress in men but increased in women.

CONCLUSIONS: These results demonstrate that despite similar free cortisol responses of men and women (studied in the luteal phase) to psychosocial stress, gender may exert differential effects on the immune system by modulating GC sensitivity of proinflammatory cytokine production.

Key Words: psychosocial stress, • HPA axis, • sex differences, • salivary cortisol, • Trier Social Stress Test, • inflammatory disease.

Abbreviations: ANCOVA = analysis of covariance;; ANOVA = analysis of variance;; BMI = body mass index;; DEX = dexamethasone;; EDTA = ethylenediaminetetraacetic acid;; ELISA = enzyme-linked immunosorbent assay;; GC = glucocorticoid;; HPA axis = hypothalamus-pituitary-adrenal axis;; HPG axis = hypothalamus-pituitary-gonadal axis;; IC50 = 50% inhibition concentration;; IL = interleukin;; LPS = lipopolysaccharide;; NF-{kappa}B = nuclear factor-{kappa}B;; TSST = Trier Social Stress Test;; TNF-{alpha} = tumor necrosis factor {alpha}.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
The immune system shows a marked gender dimorphism, which is reflected by different susceptibilities of women and men to specific immunological disorders. Men have a higher general susceptibility to a variety of bacterial and viral infections (1, 2). Women, in contrast, have a lower risk of infections but seem to be more susceptible to autoimmune or inflammatory diseases, with female-to-male ratios of 4:1 for rheumatoid arthritis (3), 9:1 for systemic lupus erythematosus (4), and 19:1 for autoimmune thyroid disease (5). Because the severity of these diseases largely varies with sex hormone status (menstrual cycle phase, pregnancy, menopause), it is likely that gonadal steroids are at least partially involved in the pathogenesis. This dimorphism has been hypothesized to be mediated by interactions of various endocrine systems, with the HPA and HPG axes as prime candidates (6).

The HPA axis can be activated by a wide variety of psychosocial and physiological stressors, which result in the secretion of GCs and modulation of specific immune responses. Psychosocial stress, such as academic examinations (7–10), leads to decreased cellular immune function, which is mediated by profound changes in cytokine secretion. The major type 1 cytokines, interferon-{gamma} and IL-2, produced by TH1 helper cells, are suppressed by GCs, whereas type 2 cytokines, IL-4 and IL-10, remain unchanged. This shift toward a type 2 cytokine pattern favors humoral immune responses while suppressing cell-mediated immunity (11). In monocytes and macrophages, GCs specifically inhibit the production of proinflammatory cytokines (IL-6, IL-1, and TNF-{alpha}), whereas antiinflammatory cytokines remain unaffected or are even stimulated (12). By these effects the HPA axis acts as a regulatory feedback loop that shuts off inflammatory responses to invading antigens after the initial response or in a state of stress. In rats, an impaired HPA axis response to an inflammatory agent is associated with increased susceptibility to experimental models of chronic inflammatory diseases. This susceptibility can be reversed by treatment with GCs or transplantation of hypothalamic tissue of resistant strains.

In contrast, disruption of HPA axis responsiveness renders previously resistant strains highly susceptible (13–15). In humans, a defective HPA axis response has been found in patients suffering from rheumatoid arthritis (16).

The HPG axis exerts direct and indirect effects on the immune system. The direct effects of HPG axis steroids are mediated through respective receptors on various immune tissues. Estrogens induce a shift in cytokine balance toward a type 2 cytokine response, thereby inhibiting cellular immunity (17). The effects on monocytes and macrophages are dose dependent, with inhibition of proinflammatory cytokine production at higher concentrations and stimulation at lower concentrations (1). Progesterone has also been reported to inhibit proinflammatory cytokine production through competitive binding to the glucocorticoid receptor (18). Although in general the effects of androgens are less clear, testosterone seems to inhibit immune functions to some extent (17, 19).

Indirect effects of gonadal steroids on immune tissues are mediated through their impact on HPA axis reactivity. In animals, the female sex steroids, especially estrogens, stimulate GC secretion, whereas the male sex steroid testosterone has an inhibitory impact (20, 21). In humans, however, no such clear-cut sex differences can be found. Total plasma cortisol responses are higher in women in response to pain (22) or pharmacological stimuli like corticotropin-releasing hormone (23). After psychosocial stress, free cortisol responses of men are comparable with those of women in the luteal phase of the menstrual cycle. Both show greater free cortisol responses than women during the follicular phase or women using estrogen-containing contraceptive medication, respectively (24–26).

To further explore the complex interactions between gender, HPA axis, and the immune system, we investigated HPA axis hormones and GC sensitivity of proinflammatory cytokine production in response to psychosocial stress in healthy women and men. GC sensitivity was recently shown to be a rather dynamic phenomenon and subject to changes associated with activation of the HPA axis (27, 28).


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects
A total of 45 healthy young subjects were recruited at the University of Trier. The sample consisted of 18 women in the luteal phase of the menstrual cycle (mean age ± SEM, 25.61 ± 1.78 years) and 27 men (24.57 ± 0.88 years). BMI was 21.93 ± 0.51 for the women and 22.21 ± 0.40 for the men. Age and BMI did not differ significantly between groups (age, F(1,44) = 0.33, p < .57; BMI, F(1,43) = 0.18, p < .67). Women in the luteal phase of the menstrual cycle were studied between days 22 and 27 of their cycle. Luteal phase was confirmed by measurement of progesterone in baseline blood samples. Progesterone levels higher than 4 ng/ml were considered indicative of the luteal phase. No subjects had to be excluded because of low progesterone levels (Table 1 for progesterone and estrogen levels). All subjects underwent a comprehensive medical examination for past or current health problems. Subjects with psychiatric, endocrine, cardiovascular, or other chronic diseases or those medicated with psychoactive drugs, ß-blockers, or GCs were excluded from participation. Blood glucose level at the beginning of the experiment did not differ significantly between groups (F(1,44) = 0.00, p < .97).


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  		Table 1. Baseline Progesterone and Estradiol Levelsa
 
Experimental Protocol
Subjects reported to the laboratory between 11:00 AM and 1:00 PM. After catheter insertion and a resting period of 45 minutes, the first blood and saliva (Salivette, Sarstedt, Rommelsdorf, Germany) samples were collected. Subjects were then exposed to the TSST, which consists of a free speech and mental arithmetic task in front of an audience. The TSST takes approximately 15 minutes, including preparation for the speech (29). Additional blood and saliva samples were collected 1, 10, 20, 30, 45, 60, and 90 minutes after exposure to the stressor. Blood samples for the GC sensitivity assay (see below) were obtained immediately before and 60 minutes after the stressor. The study protocol was approved by the ethics committee of the University of Trier.

Glucocorticoid sensitivity assay.
Venous blood was collected in heparinized tubes and diluted 10:1 with saline. The blood was then incubated with LPS (E. coli, Difco, Augsburg, Germany) and five different concentrations of DEX (Sigma, Deisenhofen, Germany), both dissolved in saline, on a 24-well plate (Greiner, Nuertingen, Germany). Diluted whole blood (400 µl) was added to 50 µl of LPS and 50 µl of various concentrations of DEX. The final concentration on the plate was 30 ng/ml LPS and 0, 10-10, 10-9, 10-8, and 10-7 mol/liter DEX. After 6 hours of incubation at 37°C in 5% CO2, the plates were centrifuged for 10 minutes at 2000 g and 4°C. The supernatant was collected and stored at -80°C until assayed.

Biochemical analysis.
Free cortisol in saliva was measured using a time-resolved immunoassay with fluorometric detection as described previously (30). TNF-{alpha} and IL-6 were determined using commercial ELISA kits (Pharmingen, San Diego, CA). Briefly, 96-well plates were coated with capture antibody (monoclonal anti-TNF-{alpha} or anti-IL-6) and incubated overnight. Then plates were blocked with 200 µl of assay diluent and washed. After that, 100 µl of the standard or plasma sample were added to each well (diluted 1:600 for IL-6 and 1:50 for TNF-{alpha}) and incubated for 2 hours at room temperature. After another wash step, 100 µl of detection antibody was added (1-hour incubation). After incubation with 100 µl of substrate solution (tetramethylbenzidine and hydrogen peroxide) for 30 minutes, 50 µl of stop solution (2N H2SO4) was added and the plates were read by an ELISA reader at 450 nm. Estradiol and progesterone were measured from baseline blood samples with use of commercial ELISA kits obtained from DRG Instruments (Marburg, Germany).

Blood cell counting.
Two blood samples were collected for determination of leukocyte and monocyte counts 1 minute before and 60 minutes after the TSST in 2.7-ml EDTA-coated tubes (Sarstedt). Cell counting was performed with use of a SE-9000 cell counter (Sysmex, Norderstedt, Germany).

Statistical Analysis
ANOVAs for repeated measures were calculated for salivary free cortisol, number of monocytes, and DEX inhibition of LPS-stimulated cytokine production. Greenhouse-Geisser corrections for repeated measures were calculated where appropriate. Data are presented as mean ± SEM.

As an index of GC sensitivity, we calculated the IC50 of the dose-response curve for DEX inhibition of LPS-induced cytokine production. The IC50 reflects the specific DEX concentration required for 50% inhibition of cytokine production observed after LPS stimulation without DEX. To calculate IC50 values, we used an exponential function with a mean determination coefficient of r2 = 0.98. ANOVAs for repeated measures were used to calculate the differences in IC50 values. Because monocytes are the main source of proinflammatory cytokine production if stimulated with LPS (31), the cytokine levels were standardized by number of monocytes for calculation of IC50 values.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Exposure to the psychosocial stressor (TSST) induced significant increases in salivary free cortisol in the total group, with peak levels 20 minutes after cessation of the stressor (time effect: F(2.36,87.36) = 21.60, p < .0001). Despite slightly higher baseline levels in men, the net cortisol response was similar in men and women (mean response, women vs. men: +5.7 vs. +5.8 nmol/l, NS). The cortisol stress response was not significantly correlated with the individual cortisol baseline (r = -0.19, NS) Both ANOVA and ANCOVA (with the baseline cortisol level as covariate) supported this: There was no significant sex difference in cortisol response to the TSST (group by time interaction: F(7,259) = 1.16, p = .32; Figure 1). Moreover, ANOVAs with subsets of the total group of subjects with numerically identical baseline cortisol levels did not change any of the results described below (data not shown).



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  		Fig. 1. Salivary free cortisol levels before and after psychosocial stress (TSST) in men and women. Values are means ± SEM.

 
The total number of monocytes decreased significantly in response to psychosocial stress (time effect: F(1,42) = 5.64, p = .0223), whereas no sex-specific differences were observed (sex effect: F(1,42) < 1; Figure 2).



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  		Fig. 2. Absolute numbers of monocytes before and after psychosocial stress (TSST) in men and women.

 
Stimulation of whole blood with LPS induced marked increases in TNF-{alpha} and IL-6 production and was significantly inhibited by increasing concentrations of DEX (DEX effect, TNF-{alpha}: F(4,144) = 131.62, p < .0001; IL-6: F(4,152) = 250.99, p < .0001). LPS-stimulated cytokine production as well as inhibition by DEX did not differ between men and women at baseline. However, 1 hour after stress, cytokine production was decreased in men but unchanged in women (sex by time interaction, TNF-{alpha}: F(1,36) = 1.85, p = .17; IL-6: F(1,38) = 4.98, p < .03; Figures 3, A, and 4, A).



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  		Fig. 3. A, DEX inhibition of LPS-stimulated production of TNF-{alpha} before and after TSST in men and women. B, Glucocorticoid sensitivity of LPS-stimulated TNF-{alpha} production before and after psychosocial stress (TSST) in men and women. The IC50 indicates the concentration of DEX required for 50% inhibition of cytokine production.

 


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  		Fig. 4. A, DEX inhibition of LPS-stimulated production of IL-6 before and after TSST in men and women. B, Glucocorticoid sensitivity of LPS-stimulated IL-6 production before and after psychosocial stress (TSST) in men and women.

 
The relative GC sensitivity of proinflammatory cytokine production is represented by the IC50 of the dose-response curve of DEX inhibition of LPS-induced cytokine production. The IC50 is inversely related to GC sensitivity (ie, a higher IC50 indicates a lower sensitivity, and a lower IC50 indicates a higher sensitivity). The IC50 for DEX inhibition of LPS-stimulated cytokine production showed similar patterns for IL-6 and TNF-{alpha}; however, only the differences for IL-6 were statistically significant. As depicted in Figures 3, B, and 4, B, basal GC sensitivity was lower in the men than in the women. Exposure to the psychosocial stress test led to sex-specific response patterns. In men, GC sensitivity increased 1 hour after stress, whereas the small decrease observed in women did not reach statistical significance (sex by time interaction, TNF-{alpha}: F(1,41) = 2.01, p = .16; IL-6: F(1,42) = 5.44, p = .025; post hoc contrasts for time effects in men, TNF-{alpha}: F(1,41) = 1.99, p = .16; IL-6: F(1,42) = 4.09, p < .05; post hoc contrasts for time effects in women, TNF-{alpha}: F(1,41) = 0.49, NS; IL-6: F(1,42) = 1.95, p = .16).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
Marked and rather complex sex differences exist in human immune function and HPA axis responsiveness. In women free cortisol stress responses covary with menstrual cycle phase, with blunted responses in the follicular phase and increased responses similar to those of men in the late luteal phase (24). Therefore, the present study investigated women in the late luteal phase of the menstrual cycle to determine whether sex differences in immune parameters still exist despite similar GC levels in both sexes.

The present results confirm previous observations that HPA axis reactivity to psychosocial stress does not differ significantly between women in the luteal phase of the menstrual cycle and men. In contrast, marked sex differences can be found in target tissues for GCs. In response to the TSST, the GC sensitivity of proinflammatory cytokine production increased in men but remained unchanged (or even decreased) in women.

These findings add important insight into the difficulties of linking HPA and HPG axis steroids and their interaction on immune function in humans. In the absence of inflammatory stimuli or stress, the female immune system is under varying influence of estrogens, favoring type 2 or humoral immune responses (5, 17). The male immune system, on the other hand, seems to be under rather inhibitory control of androgens (17, 32, 33), which might contribute to the increased susceptibility to infections of men.

If the present findings on responses to psychosocial stress can be applied analogously to inflammatory stimuli (eg, invading pathogens), the female immune system may be able to mount a sufficient HPA axis response while the sensitivity of the relevant target tissue decreases or remains unchanged, as suggested by the present findings. In this state of low sensitivity, the secreted GCs would probably not subserve their function, namely to shut off the inflammatory response after antigen stimulation, as proposed by Sapolsky et al. (34). Such an unrestrained inflammatory response may lead to tissue damage and autoimmune or inflammatory reactions or favor symptoms like fever or fatigue (15, 35, 36).

Although stress and invading pathogens induce a similar HPA axis response, there seems to be a sex difference in GC sensitivity of proinflammatory cytokine production in response to acute stress. Even though men and women had similar free cortisol responses, men showed a significant increase in GC sensitivity 1 hour after the stressor, whereas women showed a slight decrease. This response may facilitate a sufficient inhibition of proinflammatory cytokine production, and thereby terminate an inflammatory response timely in men. As a consequence, the male response pattern may protect the body from tissue damage and other adverse effects of systemic elevations of proinflammatory cytokines, whereas women are rendered more susceptible (35, 36). On the other hand, together with the tonic immune inhibition by androgens, it could contribute to the higher susceptibility of men to infectious diseases (1, 2).

No data are currently available on the precise mechanism of GC and gonadal steroid interaction in peripheral inflammatory sites, but the effects of each steroid alone are well documented. Estrogen receptors have been found on various immune cells, including monocytes and macrophages (1, 37). Some authors could show that the activated estrogen receptor exerts effects similar to those of the activated glucocorticoid receptor (eg, compromising the DNA-binding activity of the transcription factors NF-{kappa}B and activator protein-1), thereby inhibiting proinflammatory cytokine production (38, 39). On the other hand, estrogens enhance the production of peripheral corticotropin-releasing hormone, which in turn stimulates secretion of proinflammatory cytokines (6, 40). Progesterone can also exert inhibitory effects on proinflammatory cytokine production by increasing cytosolic levels of inhibitory {kappa}B (I{kappa}B-{alpha}) mRNA, which inhibits the proinflammatory activity of the transcription factor NF-{kappa}B. This effect may be mediated by cross-binding of progesterone to the glucocorticoid receptor, because progesterone receptors have not yet been found on human monocytes (18).

Additional mechanisms for interactions between sex steroids and GCs in peripheral inflammatory sites have been proposed by Da Silva (6). Sex steroids can modulate glucocorticoid receptor expression and kinetics, and sex steroids can modulate the expression of heat shock protein 90, which restrains the unbound glucocorticoid receptor in a responsive state to the cytoplasm (41).

In summary, the present study demonstrates that the GC sensitivity of proinflammatory cytokine production shows sex-specific patterns in response to a psychosocial stress test. These differences are in accordance with the sexual dimorphism observed in immune functioning (ie, the increased susceptibility to autoimmune or inflammatory processes in women and a higher susceptibility to infections in men). However, to extend the present results, women should be studied in other phases of the menstrual cycle, in which lower levels of progesterone, estrogens, and glucocorticoids would be expected. Furthermore, to explore the kinetics of these processes, measurement of GC sensitivity should be extended for a longer period after cessation of the stressor. Because the exact mechanisms by which the changes in GC sensitivity are mediated are still unknown, additional studies focusing on intracellular processes are warranted. In addition, we suggest concurrent measurement of GC sensitivity and HPA (re)activity in patients with chronic inflammatory diseases like rheumatoid arthritis or systemic lupus erythematosus to understand the underlying pathophysiological processes of these diseases in more detail.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
This study was supported by the Deutsche Forschungsgemeinschaft (Ki 537/6-1, He 1013/13-1/2).

Received for publication July 5, 2000.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

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