Physiol Behav. 2018 Feb 1;184:108-115. doi: 10.1016/j.physbeh.2017.11.009.

Distinct inflammatory response patterns are evident among men and women with higher depressive symptoms


Marzieh Majda, Jennifer E. Graham-Engelanda,b, Joshua M. Smytha,b,c, Martin J. Sliwinskib,d, Richard B. Liptone, Mindy J. Katzf, Christopher G. Engelanda,b,g.

a Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, USA.

b Center for Healthy Aging, The Pennsylvania State University, University Park, PA, USA.

c Penn State Milton S. Hershey Medical Center, The Pennsylvania State University, PA, USA.

d Department of Human Development and Family Studies and Center for Healthy Aging, The Pennsylvania State University, University Park, Pennsylvania, USA.

e Department of Neurology, Department of Psychiatry and Behavioral Sciences, Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, USA.

f Department of Neurology, Albert Einstein College of Medicine, Bronx, USA.

g College of Nursing, The Pennsylvania State University, University Park, Pennsylvania, USA.

Corresponding author: Dr. Christopher G. Engeland, Associate Professor, Department of Biobehavioral Health, 229 Biobehavioral Health Building, The Pennsylvania State University, University Park, PA 16802; 814-865-4694, email:



Extensive research links depression and inflammation, with emerging evidence suggesting some differences between males and females in these associations. However, relatively few studies have examined stimulated inflammatory responses (ex vivo) in depression. The present research investigated the associations between depressive symptoms, basal inflammation, and LPS-stimulated production of pro- (IL-1β, IL-6, IL-8, TNF-α) and an anti-inflammatory cytokine (IL-10), with a focus on the extent to which gender moderates these relationships. As part of a larger study, 162 socio-economically and racially diverse subjects (ages 25-65, 67% women) completed extensive self-report measures, including depressive symptoms. Whole blood was quantified for basal inflammation, or incubated with 1μg/mL lipopolysaccharide (LPS) for 2h (at 37°C, 5% CO2) to quantify inflammatory responses to bacterial challenge. We examined the associations between depression and inflammatory markers in regression analyses, controlling for age, BMI, race/ethnicity, income, education, and use of medications. No main effects were observed between depressive symptoms and basal or stimulated levels of inflammation. Moderation analyses revealed a significant interaction between depressive symptoms and gender for stimulated TNF-α, stimulated IL-6 (p < 0.05), and a marginally significant interaction for stimulated IL-10 (p = 0.07). For men, higher depressive symptoms were associated with significantly higher production of TNF-α (p < 0.05) and marginally higher IL-6 (p = 0.07), but not with the anti-inflammatory cytokine IL-10. For women, higher depressive symptoms were associated with significantly lower production of TNF-α and IL-10 (ps <0.05), and marginally lower IL-6 (p = 0.06). These findings provide evidence for gender differences in the association of depressive symptoms with inflammatory response patterns, and highlight the utility of assessing ex vivo immune responses in blood. Implications for health are discussed.

Keywords: cytokine; depression; endotoxin; inflammation; inflammatory response; LPS 



The majority of studies relating depression to inflammation have focused on systemic inflammation (e.g., basal cytokine levels in blood) and have generally shown positive correlations, even at subclinical levels of depression (1,2). An alternate approach is to examine inflammatory responses ex vivo. Blood samples in such studies are incubated (at 37°C, 5% CO2, 2 to 24h) with a mitogen, such as lipopolysaccharide (LPS) and/or phytohemagglutinin (PHA), to examine the capacity of immune cells to produce cytokines. Under normal physiological conditions, cytokines often occur at such low concentrations that basal levels cannot be easily detected in blood; the examination of stimulated cytokines ex vivo yields higher detectability and allows for the determination of abnormal patterns of cytokine production (3). Inflammatory responses ex vivo provide an immune measure that is distinct from basal inflammation (i.e., these two measures often do not correlate). Relatively few studies have examined the association between depression and ex vivo inflammatory responses, and these studies have yielded contradictory results. These studies are discussed in the original paper. Some possible reasons for the inconsistencies in past studies include: (1) heterogeneity of the sample (i.e., clinical depressed inpatients or outpatients, different types of clinical depression, non-clinically depressed individuals), (2) different methodologies for cytokine stimulation (e.g., type of mitogen used [LPS, PHA, both], incubation period), (3) cytokines measured (i.e., pro- and/or anti-inflammatory cytokines), (4) some studies included a single gender, some controlled for gender, some did not report gender differences, (5) small sample sizes. It is important to note that the present study would have reported a null finding if gender was not specifically examined, which highlights the utility and importance of assessing the depression-inflammation relationship separately within men and women.

The finding in men, of higher depressive symptoms being associated with greater inflammatory responses without a concordant increase in anti-inflammatory cytokines (Figure A), suggests heightened/exaggerated inflammation in the face of immune challenge in men with depression. Such elevated inflammatory responses may help explain the reported negative health outcomes (e.g., cardiovascular disease, mortality) that have been associated with depression in men (4). Conversely, a blunted inflammatory response was observed in women reporting more depressive symptoms (Figure B). Lower inflammatory responses in women with higher depressive symptoms may be indicative of a reduced ability of immune cells to mount an appropriate response to challenge (5). Overall, these findings provide evidence of divergent patterns of inflammatory responses across depressive symptomatology in men and women. This study highlights the importance of examining both between-gender and within-gender effects when studying depression and inflammation. Examining inflammation in a dynamic fashion (e.g., via antigen-stimulated immune responses) as it relates to depression may yield meaningful data beyond what can be learned from more static measures such as basal (systemic) inflammation.






Figure: Associations between depressive symptoms and log-transformed LPS-stimulated levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10 in men (A) and women (B). (A) In men, higher depressive symptoms were associated with significantly higher levels of TNF-α and marginally higher IL-6 (p = 0.07), with no association observed for IL-10 (p = 0.7). (B) In women, higher depressive symptoms were associated with significantly lower levels of TNF-α, IL-10 and marginally lower IL-6 (p = 0.06).

Depressive symptoms were assessed using the Patient Reported Outcome Measurement Information System – Depression (PROMIS Depression) short-form scale. The total summed raw score (ranging from 8 to 40) was converted to a standardized T-score (ranging from 38.2 to 81.3). This T-score is a well-established metric which is centered based on the U.S. general population, with a mean of 50 and a standard deviation of 10.

Multiple linear regression analyses were conducted to determine the relationship between reported depression scores and each stimulated cytokine level.

Covariates: age, BMI, income, education, race/ethnicity, corticosteroids, statins, non-steroidal anti-inflammatory agents, oral contraceptives, and antidepressants.



  1. Y. Dowlati, N. Herrmann, W. Swardfager, H. Liu, L. Sham, E.K. Reim, K.L. Lanctôt, A Meta-Analysis of Cytokines in Major Depression, Biol. Psychiatry. 67 (2010) 446–457.
  2. M.B. Howren, D.M. Lamkin, J. Suls, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis., Psychosom. Med. 71 (2009) 171–186.
  3. D. De Groote, P.F. Zangerle, Y. Gevaert, M.F. Fassotte, Y. Beguin, F. Noizat-Pirenne, J. Pirenne, R. Gathy, M. Lopez, I. Dehart, Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole blood. I. Comparison with isolated PBMC stimulation., Cytokine. 4 (1992) 239–248.
  4. S. Lawes, P. Demakakos, A. Steptoe, G. Lewis, L. Carvalho, Combined influence of depressive symptoms and systemic inflammation on all-cause and cardiovascular mortality: evidence for differential effects by gender in the English Longitudinal Study of Ageing., Psychological medicine, 49 (2019) 1521-1531.
  5. J.K. Kiecolt-Glaser, P.T. Marucha, W.B. Malarkey, a M. Mercado, R. Glaser, Slowing of wound healing by psychological stress., Lancet. 346 (1995) 1194–1196.