Monocytes from depressed patients display an altered pattern of response to endotoxin challenge

Abstract

It is now well established that major depression is accompanied and characterized by altered responses of the immune-inflammatory system. In this study we investigated the pro-inflammatory activation of monocytes isolated from depressed patients as a parameter not influenced by such confounds as the time of day, the nutritional and exercise status or the age and gender of patients. Monocytes from depressed patients and from healthy controls were isolated in vitro; after 24-h incubation under basal conditions, cells were exposed for 24-h to 100 ng/ml of endotoxin (bacterial lipopolysaccharide, LPS). We found that monocytes from drug-free depressed patients and controls release the same amounts of prostaglandin E2 (PGE2) under basal conditions, whereas monocytes from patients are dramatically less reactive to LPS (8.62-fold increase vs previous 24 hrs) compared to healthy controls (123.3-fold increase vs previous 24 hrs). Such blunted prostanoid production was paralleled by a reduction in COX-2 gene expression, whereas other pro-inflammatory mediators, namely interleukin-1β (IL-1 β) and -6 (IL-6) showed a trend to increased gene expression. The above changes were not associated to increased levels of circulating glucocorticoids. After 8 months of antidepressive drug treatment, the increase in PGE2 production after the endotoxin challenge was partially restored, whereas the increase in IL-1 β and -6 levels observed at baseline was completely abolished. In conclusion, our findings show that the reactivity of monocytes from depressed patients might be considered as a marker of the immune-inflammatory disorders associated to depression, although the lack of paired healthy controls at follow-up does not allow to conclude that monocyte reactivity to endotoxin is also a marker of treatment outcome.

Figure 1. Prostaglandin E₂ release under basal conditions.

Data are expressed as pg/ml, the means ± SEM of 10 subjects per group. FU = Follow up.

Figure 2. Monocytes were activated for 24 hours with 100 ng/ml endotoxin.

Data are expressed as PGE₂ release, fold changes vs each paired unstimulated control. (A) Data are the means ± SEM (n = 10).^**P<0.01 vs. healthy controls; (B) Individual data of patients °P<0.05 vs patients at time 0; Mann Whitney test. FU = Follow up.

Figure 3. Total cytosolic RNA was prepared used for Q-PCR analysis of the expression of COX2.

Data are expressed as fold changes vs each paired unstimulated control, taken as calibrator for comparative quantitation analysis of mRNA levels. Each sample was measured in triplicate. (A) Data are the means ± SEM (n = 10).^**P<0.01 vs. healthy controls; (B) Individual data of patients °°°P<0.001 vs patients at time 0; Student's t-test. FU = Follow up.

Figure 4. Total cytosolic RNA was prepared used for Q-PCR analysis of the expression of IL-6.

Data are expressed as fold changes vs each paired unstimulated control, taken as calibrator for comparative quantitation analysis of mRNA levels. Each sample was measured in triplicate. (A) Data are the means ± SEM (n = 10). (B) Individual data of patients. FU = Follow up.

Figure 5. Total cytosolic RNA was prepared used for Q-PCR analysis of the expression of IL-1β.

Data are expressed as fold changes vs each paired unstimulated control, taken as calibrator for comparative quantitation analysis of mRNA levels. Each sample was measured in triplicate. (A) Data are the means ± SEM (n = 10). (B) Individual data of patients. FU = Follow up.

Figure 6. Salivary cortisol levels at 08.00, 16.00 and 23.00 for each experimental group.

Data are expressed as µg/Dl, the means ± SEM of 10 subjects per group. FU = Follow up.