Posttraumatic stress disorder is associated with an enhanced spontaneous production of pro-inflammatory cytokines by peripheral blood mononuclear cells

Repeated exposure to traumatic events such as rape, combat or natural disasters has dramatic effects on mental health [1‐3]. Frequent symptoms in the aftermath of such events include repetitive intrusive recollections of the trauma, persistent avoidance of trauma reminders, emotional numbing and hyperarousal – the core symptoms of posttraumatic stress disorder PTSD [4].

In addition to psychiatric morbidity, numerous studies have shown that traumatic stress and especially PTSD are associated with poor self-reported physical health, increased utilization of medical services, and an elevated risk for multiple comorbid medical disorders such as respiratory, gastrointestinal, musculoskeletal, inflammatory and autoimmune diseases [5‐7]. In particular, it has been found that cardiovascular disease and its risk factors are more prevalent among individuals with PTSD [5, 6, 8], with two recent studies even demonstrating a prospective relationship between PTSD symptoms and coronary heart disease [9] or PTSD and cardiovascular mortality, respectively [10].

Besides traditional behavioral cardiovascular risk factors such as smoking, alcohol abuse or low physical activity [11], chronic low-level inflammation has been discussed as a potential mechanism linking cardiovascular disease to PTSD [12]. This argumentation is supported by epidemiological and clinical studies demonstrating a strong and consistent relationship between markers of inflammation and risk of future cardiovascular events [13, 14].

However, studies investigating pro-inflammatory markers in PTSD patients have yielded mixed results. Some studies reported higher levels of IL-1β [15, 16], IL-6 [17], and TNF-α [12] in the plasma or elevated levels of IL-6 in the cerebrospinal fluid [18] of PTSD patients compared to control subjects. Furthermore, Spitzer et al. [19] found that, in a sample of 3049 adults, PTSD positive participants had significantly higher odds for elevated levels of C-reactive protein (CRP) than those without PTSD. In contrast, other studies did not find significant group differences with respect to circulating levels of IL-1β [12], IL-6 [12, 20], and CRP [12] or even reported lower levels of CRP [21] and IL-8 [20] in PTSD patients.

Likewise, ambiguous results have been obtained by studies investigating the production of pro-inflammatory cytokines in whole blood following ex vivo stimulation with lipopolysaccharide (LPS) and/or phytohemagglutinin (PHA). Whereas some studies reported higher LPS-stimulated IL-6 production [22] or increased LPS/PHA-induced production of IL-6 and TNF-α [23] in individuals with PTSD, other studies showed no group differences with respect to PHA-induced interferon (IFN)-γ [24] or LPS-induced TNF-α production [22]. One study by de Kloet et al. [24] even reported decreased TNF-α production in LPS-stimulated whole blood of PTSD patients compared to controls.

These inconsistent findings might partly be explained by variations in sample characteristics, such as differences with respect to the type of traumata experienced (e.g. childhood vs. adulthood trauma), time elapsed since the traumata (e.g. populations studied shortly after traumatic experiences or during ongoing threat vs. patients with chronic symptoms), comorbidities, and differences with respect to PTSD symptom severity (mild symptoms after a single trauma in comparison to severe symptoms after experiencing multiple traumata), as well as varying sample sizes. In particular studies investigating plasma cytokine levels consisted mostly of small patient groups, making the results error-prone.

Here we investigated plasma levels of pro- and anti-inflammatory cytokines in a well-defined group of 35 severely affected PTSD patients with war and torture experiences mainly experienced during late adolescence and adulthood and a chronic disease pattern, compared to 25 healthy ethnically matched control subjects. For a subsample of 16 PTSD patients and 18 control subjects, we additionally analyzed 1) LPS-stimulated production of IL-1β, IL-6 and TNF-α by peripheral blood mononuclear cells (PBMCs), as well as 2.) spontaneous cytokine production by these cells, as this has not been reported previously.

In the present study we investigated plasma levels of IL-6, IL-8, IL-10, TNF-α and MCP-1 as well as spontaneous and LPS-stimulated production of IL-1β, IL-6 and TNF-α by PBMCs from a group of severely affected PTSD patients compared to healthy control subjects.

While basal plasma concentrations of pro- and anti-inflammatory cytokines did not differ significantly in PTSD patients and controls, we found evidence for a heightened inflammatory state in PTSD patients when analyzing spontaneous ex vivo cytokine production. Concentrations of IL-1β, IL-6, and TNF-α in supernatants of unstimulated PBMCs were significantly higher in the PTSD compared to the control group. In addition, correlation analyses within the PTSD group revealed that levels of IL-6 and TNF-α were significantly related to the severity of PTSD symptoms as assessed with the CAPS; IL-1β was also positively associated, but significance was only at the level of a trend. The group differences reported above were not ascribable to differences in blood leukocyte distribution since lymphocyte and monocyte counts were comparable in both groups. Following the introduction of smoking as covariate to the model, the finding on TNF-α was reduced to a trend. The finding of an increased spontaneous production of pro-inflammatory cytokines in the PTSD patients group suggests that PBMCs of PTSD patients are already pre-activated in vivo. Furthermore, as in previous studies [22, 23], LPS-stimulated PBMCs from PTSD patients exhibited significantly higher IL-6 secretion compared to PBMCs from control subjects. However, when calculating the difference between LPS-stimulated and non-stimulated cytokine production to evaluate the net effect of LPS stimulation, no group differences were found, suggesting that the effect reported above mainly results from the enhanced spontaneous IL-6 secretion by PBMCs of PTSD patients. Our finding of a heightened spontaneous production of pro-inflammatory cytokines in the PTSD patient group is in agreement with reports that parameters normally suppressing inflammation are reduced in PTSD patients. For example, studies have reported lower cortisol levels [36] and a lower percentage of regulatory T cells [37] in those with PTSD, which are both crucial players in controlling inflammation thereby limiting immunopathological side effects of inflammatory processes [38, 39]. Consequently our results provide further evidence for a link between PTSD and low-grade inflammation, possibly representing one psychobiological pathway from PTSD to inflammatory diseases such as arteriosclerosis and its clinical manifestations, e.g., myocardial infarction, stroke, and peripheral vascular disease, often observed in patients with PTSD [5, 8]. Whereas arteriosclerosis has been formerly considered a simple lipid storage disease, current evidence supports a fundamental role for inflammation in mediating all stages of this disease. Inflammatory processes not only promote early atherogenesis and the progression of lesions, but also contribute decisively to precipitating acute thrombotic complications of atheroma. In addition, clinical studies affirm a correlation of circulating markers of inflammation with propensity to develop ischemic events and with prognosis after acute coronary syndromes [13, 14].

In conclusion, repeated exposure to traumatic events over the lifetime seems to induce long-lasting changes in the regulation of inflammatory processes that constitute a form of biological memory of the stressor and might lead in the long run due to self-perpetuating processes to the development of various physical diseases. However, the interpretation of our results is faced with several limitations of our study: 1) Groups differed significantly with respect to age. Unfortunately, correcting for age is only possible if groups do not differ in this variable see [33, 34]. But as a) spontaneous production of IL-1β, IL-6, and TNF-α was not significantly correlated with age, neither for controls nor for PTSD subjects and b) it was positively related to PTSD symptom severity within the PTSD group, older age in the PTSD group should not have accounted for the effects reported above 2) One third of the PTSD patients took psychotropic medication. 3) We did not control for the confounding effects of physical activity on the immune outcomes. Moreover, as earlier studies suggest, a heightened inflammatory state does not seem to hold true for all studied populations of PTSD patients [20, 21, 24]. Future studies should therefore investigate whether a heightened inflammatory profile is associated with a specific characteristic of PTSD, e.g., whether it can only be found in PTSD patients with chronic and severe symptoms or is modulated by the type of trauma experienced. Eventually, such findings could be the basis for the development of new trauma treatment approaches, paying more attention to the potential for improving physical, in addition to mental health.