Introduction
Traumatic events may trigger immune alterations, and this could lead to the development of post- traumatic stress disorder (PTSD). Therefore, it is important to understand and define the biological underpinnings of immune dysregulation in PTSD as it also plays a crucial role in helping us to understand the nature of the associations between PTSD and other medical and psychiatric illnesses. This is important, given that it is well established that PTSD is associated with the occurrence of co-morbid major depressive disorder (MDD) and other psychiatric illnesses.
Peripheral pro-inflammatory cytokines are capable of signaling the brain to induce behavioral symptoms like fatigue, sleep disturbance, and depressive mood (Dantzer, 2001a: Dantzer, 2004a: Dantzer & Kelley, 2007: Myers, 2008). Cytokine-to-brain signaling provides a theoretical base consistent with the evidence demonstrating an association between proinflammatory cytokines and behavioral symptoms of depressive disorders (Dantzer, 2001b: Dantzer, 2004b: Dantzer & Kelley, 2007: Myers, 2008). The result of a hyperactive pro-inflammatory state marked by excess production of the pro-inflammatory cytokines IL-6 may contribute to the pathophysiology of major depressive disorders (Sternberg, 2006).
Frink et al. (2009) have postulated that cytokines released in response to infection or inflammation alert the brain to any real or potential threats and initiate behaviors that are thought to be important for survival. Some scholars even refer to the ability of the immune system to alert or communicate with the brain as a “sixth sense” (for example, Fu, Zunich, O’Connor, Kavelaars, Dantzer & Kelley, 2010). Sickness behavior is believed to be adaptive in that it forces an individual to rest and withdraw from activities so that physiological processes can produce healing in an effective manner (Gudmundsdottir, Beck, Coffey, Miller & Palyo, 2004: Quale & Schanke, 2010). It is now known that pro-inflammatory cytokines released during infection, inflammation, injury, and even psychological stress can signal the brain to initiate behavioral changes that facilitate adaptation to these threats.
As mentioned earlier, cytokine-to-brain signaling has been implicated in mood disorders, particularly depression that accompanies illness (Dantzer, 2009). As such, a sufficient regulation of cytokine production is crucial for better physical and psychological outcomes (Gill, Saligan, Woods, & Page, 2009). Accordingly, it would be prudent to undertake an investigation of the acute circulating pro-inflammatory cytokines and their predictive values with a view to providing insight into the role of psychoneuroimmunological processes in trauma patients. The purpose of this critical literature review is to examine the literature that describes the association between PTSD and predictive value of the pro-inflammatory marker interleukin 6 (IL-6). At the end of this paper, conclusions and recommendations are discussed along with areas where further research may contribute to a broader understanding of this phenomenon.
Literature Review
A search of the databases (CINAHL, MEDLINE, and Pub Med) was used to locate articles relating to PTSD and the pro-inflammatory IL-6. The keywords used in searching the databases included PTSD, trauma, and IL-6 and depression. To further broaden the researcher, sources cited by the articles obtained were also tracked.
Review and Critique of Selected Articles
Cytokines have substantial psychological and physiological effects that are vital in understanding the immune dysregulations linked to the development of PTSD. Rohleder, Joksimovic, Wolf, & Kirschbaum, (2004) conducted a study to compare the production of pro-inflammatory cytokines and the glucocorticoid sensitivity of stimulated cytokine production among Bosnian war refugees. In the study, PTSD (n=12), age and gender matched German healthy control individuals (n=13). The researchers collected the samples on 2 consecutive days; saliva samples were collected at four different time points. Glucocorticoid (GC) sensitivity was measured by dexamethasone inhibition of lipopolysaccharide -induced IL-6 and tumor necrosis factor-alpha production measured in whole blood (Rohleder, Joksimovic, Wolf, & Kirschbaum, 2004)
Results of this study revealed that PTSD patients showed an increased sensitivity to pro-inflammatory cytokine production, along with a higher cytokine producing capacity in peripheral blood. However, the study also identified a number of limitations that need to be considered with a lot of caution. To start with, the health control subjects were not comparable because they were German and not Bosnian war refugees. Therefore, this diversity in regards to ethnicity variations could affect the results. Another limitation of the study is that the use of ex-vivo stimulation may not replicate in vivo changes in the organism. As such, result are not generalizable.
This is in line with a classic study conducted by Maes et al. (1999) to examine the inflammatory response system in patients with PTSD, with or without major depressive disorders (MDD), through measurements of serum IL-6, soluble IL-6 receptor (sIL-6R), sgp130 (the IL-6 signal transducing protein), as well as other pro-inflammatory cytokines. The researchers recruited 45 individuals, PTSD patients (n=13) who were victims of two types of traumatic events (fire event and motor vehicle accidents events), and control healthy individuals (n=32) with negative history of psychiatric disorders.
This study was based on previous findings of elevated increased serum IL-1????and the presence of inflammatory response system activation, which is associated with increased serum IL-6 because both cytokines can induce the production of one another (Durum & Oppenheim, 1989). A major contribution of this study is the inclusion of male and female accident survivors with PTSD, with MMD, because MMD demonstrate high degree of co-morbidity with PTSD, and is also characterized by activation of the IRS with increased serum level of IL-6 (Maes et al., 1999).
Results from this study revealed that Serum IL-6 and sIL-6R concentrations were significantly higher in PTSD patients in comparison with normal participants. Additionally, serum sIL-6R concentrations were significantly higher in PTSD patients with co-morbid MMD than in PTSD patients without MMD and normal participants. The researchers concluded that PTSD is associated with increased IL-6 signaling. They also hypothesized that stress-induced secretion of pro-inflammatory cytokines (IL-6) is involved in the catecholaminergic pathophysiology of PTSD, which represents a positive relationship between indicators of IRS activation and HPA axis activity in PTSD.
These results are in agreement with those of naother study conducted by Baker et al. (2001), who found elevated cerebrospinal spinal IL-6 levels in PTSD patients with a past diagnosis of MDD. Although Baker et al. (2001) reported conflicting results of unchanged blood plasma IL-6 levels they also made an important revelation that cerebrospinal fluid (CSF) levels of IL-6 were higher in PTSD patients compared with control subjects. Their study examined the relation of IL-6 levels and hypothalamic-pituitary-adrenal and noradrenergic activity in PTSD patients. The finding from this study reveals that plasma IL-6 was not different between the two groups; however, PTSD patients have increased CSF concentrations of IL-6. They explained that the low cortisol secretion as a result of lowered glucocorticoid suppression of IL-6 secretion contributed to their findings. The researchers concluded that the higher levels of CSF IL-6 could be possibly a sign of neurological deterioration or compensatory protection (Baker et al., 2001),
In another prospective study, Pervanidou et al. (2007) investigated the hypothalamic-pituitary-adrenal axis activity, the sympathetic nervous system and inflammatory factors in children and adolescent following motor vehicle accidents related to later PTSD development. They concluded that high levels of IL-6 are associated with PTSD development in children and adolescents following a motor vehicle accident (Pervanidou et al., 2007).
Collectively, these findings reveal that immune dysfunction is present in PTSD patients with MDD. Furthermore, a good number of studies confirm that increased IL-6 levels in PTSD civilians (Maes et al., 1999; Gill, Vythilingam, & Page, 2008), Bosnian refugees with PTSD (Rohelder et al., 2004), and in the cerebrospinal fluid of Vietnam combat veterans with PTSD (Baker et al. 2001). However IL-6 findings are inconsistent. These inconsistencies are related to the timing of blood sample collection. In particular, it is well established that IL-6 demonstrates a unique circadian rhythm (Vgontzas et al, 2005). Given this fact, it is thus clear that the discrepancies in the timing of the sampling may contribute to the inconsistencies of previous studies.
Consequently, Gill, Luckenbaugh, Charney & Vythilingam (2010), conducted the first unique study by comparing serial overnight serum levels of IL-6 in a well-distinguished sample of PTSD participants (with and without MDD) and non-traumatized healthy control participants as well. This study attends to the identified methodological limitations of prior reports and will help to clarify the incoherent results. They also investigated serum IL-6, plasma ACTH and cortisol, along with their response to hydrocortisone. The researchers hypothesized that patients with PTSD with MDD will have higher serum IL-6 levels compared with those with PTSD without MDD and healthy control subjects. The research findings demonstrated sustained, basal, overnight elevations of serum IL-6 levels in patients with PTSD with co-morbid MDD but not in subjects with PTSD without co-morbid MDD.
The results are in line with the findings of a previous study by Gill, Vythilingam, & Page (2008), who compared hypothalamic-pituitary-adrenal axis and immune function in women with PTSD (n=26, with and without MMD) with traumatized controls (n =24) and non-traumatized healthy controls (n=21). Findings from this study revealed higher IL-6 levels in women with PTSD with MDD compared with PTSD without MDD. However, this study is limited by its cross sectional design in regards to the use of non-stimulated basal samples for cortisol and DHEA which hindered how these alterations resulted and how best to address them with an intervention. In addition, this study is not generalizable due to its limited sample size and the inclusion of only African Americans. On the contrary, this study is unique in the sense that it recruited African Americans only and the inclusion of healthy controls as well as traumatized controls without PTSD, which reflected a vigorous comparison. A final critique of the study is the limited two time points for saliva collection, which hindered understanding the biological differences that could have been detected better by serial time points.
However, in Gill, Luckenbaugh, Charney & Vythilingam (2010) the overnight elevation led to a more comprehensive conclusion, in addition to helping clarify the inconsistent results obtained from previous single time point studies of IL-6 in PTSD (Maes et al., 1999; Gill, Vythilingam, & Page, 2008; Rohelder et al., 2004; Baker et al. 2001). These results confirm that increased IL-6 levels are only observed in patients with PTSD with MDD. The most interesting contribution of this study is that the researchers were able to differentiate between PTSD with and without co-morbid MDD by investigating overnight levels of IL-6 and their sensitivity to the glucocorticoid hydrocortisone. These distinctions are useful in clarifying the differences in symptoms presentation, treatment responses, and the medical co-morbidity, which are more pronounced in patients with PTSD with MDD.
Nevertheless, several critiques were identified in this study; a major critique is the limited sample size of both PTSD participants (n=18; with MDD n=9 and without MDD n=9) and healthy control individuals with negative previous trauma (n=14) that resulted in some discrepancies in the ACTH findings. Another limitation of the study is that the PTSD with MDD participants had more females than the PTSD with MDD participants; researchers should have attempted to reduce variability attributaed to gender as confounding factors. A final critique is that the study did not elucidate if IL-6 insensitivity to hydrocortisone in patients with PTSD and MDD could be resolved with an alteration in the dose or duration of hydrocortisone treatment. This study delineated an important distinction that should be investigated further.
Cortisol
Traumatic events result in physiologic responses that stimulate the hypothamic pituitary adrenal axis and the sympathetic nervous system. These activations cause immune dysregulations. Hypothamic pituitary adrenal axis controls inflammation by releasing cortisol, which then reduces inflammation (Gill & Szanton, 2011). The immune system also interacts with the HPA axis in order to adjust its activities; for example interleukin-6 (IL-6) activates the HPA axis, resulting in higher cortisol levels, which decreases IL-6, thereby reducing or preventing further inflammation (Bauer, Wieck, Lopes, Teixeira, & Grassi-Oliveira, 2010).
Empirical evidence also indicates dysregulation of inflammatory activities by low levels of circulating cortisol could increase IL-6 levels. It is well established in psychoneuroimmunology that in normal healthy individuals, a bidirectional relationship exist between the immune and endocrine systems. This bidirectional communication can be interrupted by frequent and sustained stress states, leading to biological changes that likely underlie the risk for psychological and physical health declines. Prolonged activation of hypothalamic-pituitary-adrenal axis along with immune dysregulation and inflammation lead to undesirable consequences such as the development of physical and psychological disorders (Gill & Szanton, 2011). Traumatic events can interferes with this relationship, causing an alteration in both systems because of the chronic or acute stress it exerts on human bodies (Gill, Saliga, Woods, & Page, 2009).
In support of this assertion, as previously mentioned, Gill et al. (2008) found decreased levels of cortisol and increased levels ofIL-6 in PTSD patients. Together, these findings extend those of Gill et al. (2010), which further supported this relationship and investigated glucocorticoid sensitivity in PTSD patients. Their results revealed that PTSD patients were more sensitive and responsive as evidenced by an immense decrease in IL-6 levels; nevertheless PTSD patients with co-morbid MDD were less responsive. Hence, endocrine alteration will possibly contribute to increased levels of IL-6, for example increased cortisol levels in PTSD subjects without co-morbid MDD may decrease IL-6 production, while decreased or inadequate cortisol levels in PTSD subjects with co-morbid MDD may increase IL-6 production (Gill, Luckenbaugh, Charney & Vythilingam, 2010). In line with this, Fries, Hesse, Hellhammer and Hellhammer (2005) investigated Low cortisol levels in patients with PTSD and other psychological co-morbid disorders. They anticipated that the occurrence of lower levels of cortisol is a result of sustained hypothalamic-pituitary-adrenal axis activation. Further evidence suggested that low levels of circulating cortisol might lead to the development of PTSD in women due to the immune alteration as a result of sustained inflammation.
In summary, there is evidence suggesting that PTSD is associated with elevations of IL-6, which is more prevalent in co-morbid MDD patients. These studies suggest that chronic inflammation is likely present in PTSD and that additional studies are needed in larger samples to determine the role of IL-6 in PTSD-associated health declines.
Epigenetic
Segman et al. (2005) found that traumatic events may induce epigenetic modifications for genes that encode immuno-regulatory proteins in individuals with PTSD. Patients are known to have heightened stress reactivity, in addition to exhibiting a distinct expression profile for genes that influence immune function (Kerlinger & Lee, 2000: Li, 2002). Epigenetic modifications may possibly induce gene activity, and this could result in an increase in inflammatory cytokine levels (Dulac, 2010). Recent evidence reveal that for PTSD patients, the experience of a traumatic event triggers downstream alterations in immune function by decreasing methylation of immune-related genes (Uddin et al., 2010). The study by Uddin et al. (2010) identified a set of uniquely unmethylated genes that encode for immune function in individuals with PTSD. Their findings demonstrate the capacity of a traumatic event to trigger long-lasting epigenetic-induced alterations in immune function, possibly through brain-immune interactions, which could contribute to high levels of peripheral inflammation (Uddin et al, 2010). This study suggests that higher levels of pro-inflammatory cytokines in PTSD patients are associated with gene function deregulations. In spite of this, the study is limited by its cross-sectional design, which prevents determining whether the PTSD methylation pattern was present prior to the traumatic exposure representing a pre-existing biologic vulnerability. However, the results reveal the possibility of a traumatic life event inducing long-lasting alterations in immune function through epigenetic modification.
Although currently there is little evaluation of stress-related epigenetic modifications in humans, the findings in individuals with PTSD provides preliminary evidence suggesting that the experience of a traumatic event results in epigenetic imprinting of genes that encode for immune function (Uddin et al, 2010). In support of this study, Yehuda et al. (2009) reported that altered gene activity lead to increased levels of inflammation in PTSD patients. These preliminary evidences also suggest that the experience of a traumatic event results in epigenetic imprinting of genes that encode for immune function (Uddin et al, 2010). Collectively, these findings provide an impetus for further exploration in epigenetic and PNI paradigm that could lead to innovative interventions for PTSD patients.
Summary
In conclusion, this critical literature review examined the association between PTSD and the value of the pro-inflammatory marker IL-6 as a potential biomarker for predicting the development of PTSD symptoms, as well as co-morbid MDD as a medical burden related to PTSD. Collectively, the studies mentioned in this review indicate that PTSD is associated with increased blood and plasma levels of IL-6. High levels of IL-6 following a trauma have also been linked to PTSD development. In addition, low cortisol levels are indicative of higher levels of IL-6, demonstrating inflammatory actions dysregulation.
As for the state of science, based on the literature review it is clear that the association between IL-6 and the development of PTSD is extremely multifaceted. It is doubtful that a simple blood assay will provide significant predictive biomarker for the development of PTSD. Since most of the findings from previous studies have not yet replicated consistently, rigorous studies are still needed in order for these comparisons to hold. This review links PTSD to depression and suggests that chronic inflammation underlies this association. However, it is still unclear whether immune dysregulation are fundamental or marginal to the development of PTSD. Nonetheless, it has been established that inadequate regulation of IL-6 production flowing traumatic events may increase the risk for developing PTSD. The implications of dysregulated immunity in PTSD are significant and remain to be an area of vigorous research that may eventually lead to the development of novel immune-related -interventions.
Nursing research has proved crucial in studies aimed at examining the effects of traumatic events on the person as a whole. It is emphasized that developing a better understanding of immune dysregulation and its impact to physical and psychological health in trauma patients, this will lead to the development of novel interventions. With the combination of both pharmacological and psychological interventions, nurses can provide greater benefits and better outcomes to the physical and psychological health of trauma patients in the hope of preventing the development of PTSD and other associated co-morbidities resulting from immune dysregulation (Gill, Saligan, Woods, & Page, 2009).
Existing research reveal that sustained inflammatory alterations of the immune system are associated with inadequate regulation of the cortisol. However, results are inconsistent and further research is necessary in order to enhance the knowledge to better understand the mechanisms that will inform the development of future interventions. Further research is also needed to better understand intrinsic confounding variables of trauma patients and its role in immune alterations, which enhance the risk of PTSD development (Gill, Saligan, Woods, & Page, 2009).
Recommendations and Future Research
In conclusion, most studies were not generalizable and there is insufficient evidence in literature to support a clear recommendation for the utilization of IL-6 as a potential biomarker for predicting the development of PTSD. Although these findings indicate that PTSD is associated with excessive inflammation, prospective studies are warranted to investigate the timing of immune dysregulation occurrence in patients experiencing traumatic events, and how the link between immune system and the endocrine system in regards to the development of PTSD and health outcomes.
There are many confounding factors that might account for the lack of inconsistent and significant results, hence larger vigorous cross-sectional studies of PTSD individuals that reduce variability attributable to confounding factors such as, types, timing, and duration of traumatic events experienced, as well as gender and other co-morbid psychiatric disorders.
Furthermore, it is still unclear how immune dysregulation relate to the development PTSD. Future studies should investigate the effect of psychological and pharmacological interventions on the inflammatory processes in PTSD. These studies could investigate immune function before and after introducing pharmacological and psychological interventions, which will aid in understanding how immune dysregulation contribute to the development PTSD.
In addition, although there is little evaluation of stress-related epigenetic in regards to epigenetic, findings provide impetus for further exploration in epigenetic and PNI paradigm that could lead to innovative interventions for PTSD patients. Furthermore, it is fundamentally important to understand epigenetic modifications that could contribute to the excessive inflammation and higher levels of IL-6 observed in PTSD patients. These types of studies may provide a greater insight into the mechanisms of excessive inflammation in PTSD and possibly to the development of unique interventions to both prevent and treat PTSD.
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