Depression is one of the most common and harmful mental disorders, affecting about 15–20% of the general population (1, 2). The number of depression cases reported worldwide increased by 49.9% from 1990 to 2017 (3). Generally, depression causes unhealthy behaviors, such as smoking, reduced physical activity, and excessive calorie intake (4, 5) and has been shown to be associated with increased inflammation, metabolic dysregulation, increased obesity, and worsening chronic diseases (6–8). Though several potential psychophysiological mechanisms explain this association, the inflammatory hypothesis of immune hyper-activation and dysregulated cytokine production has been widely supported (6, 9–11).

In a meta-analysis of inflammatory markers of depression, inflammatory cytokines have been shown to be representative biomarkers (12, 13). Cytokines are typically pro- and anti-inflammatory, and their balance determines the outcome of the inflammatory response (14). In a systematic review and meta-analysis of 82 studies measuring cytokine levels in healthy controls and participants with major depressive disorder (MDD), the latter had elevated peripheral levels of chemokine ligand 2, interleukin (IL)-1 receptor antagonist, 2, 6, 10, 12, 18, and tumor necrosis factor-alpha (TNF-α) and lower interferon-gamma (IFN-γ) levels (12). However, the direction of association between cytokine levels and severity of depression is ambiguous (9, 12, 15, 16). In patients with MDD, a linear correlation was observed between IL-1β, IL-8, and TNF-α and the severity of depression, whereas the transforming growth factor-beta (TGF-β) was significantly decreased in patients with chronic hepatitis B infection who had mild depression compared to those without depression and with moderate to severe depression (15, 16). Further evidence of the role of inflammation in psychiatric disorders has shown that anti-inflammatory agents influence changes in cytokine levels in MDD in a meta-analysis of clinical trials, indicating antidepressant effects (13, 17).

Neurobiological pathways involved in depression include inflammatory cytokine signals that initiate an inflammatory response in the brain and interfere with the activity of important behavioral regulatory neurotransmitters, including norepinephrine, dopamine, and serotonin (6, 18). Inflammatory cytokines can affect hypothalamic–pituitary–adrenal (HPA) regulation (18), causing the early onset of physical symptoms, such as pain, fatigue, loss of appetite, reduced exercise, sleep disorders, and reduced work performance and productivity (19). Prolonged activation of inflammation is detrimental to physical and mental well-being (19, 20). In recent years, nurses’ awareness of the importance of depression has increased because it can increase the risk of missed nursing care as well as threaten their own health (21–23).

The prevalence of depression is about twice as high among nurses as the general population (22, 24, 25). Nurses experience greater work stress than other healthcare professionals (21) and are at an increased risk of depression owing to shift work (26) and exhaustion owing to consistently caring for patients (27). Recently, researchers have identified a close association between depressive symptoms in nurses and abnormal eating habits (5, 28), increased risk of autoimmune diseases (29), and ovarian cancer (30). However, evidence for the role of inflammation in depression in the nurse population is limited. Therefore, understanding how depression is associated with inflammatory biomarkers among nurses and signaling the need for prevention and intervention are important.

The present study aimed to use a comprehensive immune-profiling approach to determine whether an abnormal profile of circulating cytokines could be identified in nurses with self-reported depression and whether this profile is associated with the severity of depression.

This study investigated the association between depression severity and inflammatory cytokine profiles among female nurses of childbearing age. We found that self-reported depressive symptoms were associated with pro-inflammatory cytokines. Serum IL-6, IL-8, IL-18, and IFN-γ levels are estimated biomarkers for depression severity in nurses, showing that they may increase the risk of inflammatory dysregulation when nurses have high depressive symptoms. Recent changes in peripheral cytokines and chemokines in depression have shown that patients with MDD have increased average levels of pro-inflammatory immune markers and decreased levels of anti-inflammatory immune markers (12, 13). In our study, moderately severe depressive symptoms in nurses were associated with elevated levels of IL-6, IL-8, and IL-18, whereas IFN-γ showed the opposite profile. Participants with severe depressive symptoms showed decreased levels of IL-6, IL-8, IL-18, and IFN-γ. These results suggest a state of immune system dysregulation.

Increased levels of pro-inflammatory cytokines IL-6, IL-8, and IL-18 in nurses with moderately-severe depressive symptoms support a meta-analysis of inflammatory markers in depression studies that identify depression as a pro-inflammatory state (12). During acute infection, dendritic cells and macrophages produce IL-6, which is secreted in response to acute inflammatory stimulation (12). IL-8, which plays a pro-inflammatory role, mediates the movement of neutrophils to the inflammatory site as chemokines and influences the immune response in the acute inflammatory stage (40). IL-18 may have a significant effect on the pathophysiology of the CNS and contribute to neuro-inflammation (41). Higher levels of depression symptoms were associated with increased levels of pro-inflammatory biomarker IL-6 in caregivers caring for an older person in the community (42). Pregnant women with severe anxiety and accompanying depressive symptoms showed a significant increase in serum levels of IL-6 and TNF-α (43). Similar to our results, this suggests that nurses with high depressive symptoms are at risk of increased inflammation, and that changes in cytokine concentrations may be affected by the intensity of depressive symptoms.

Contrastingly, the blood samples of nurses with severe depression in our study showed a decrease in pro-inflammatory cytokine levels. Regarding the severity of depression, some studies did not find a relationship between cytokines and disease severity (44, 45) or showed a negative correlation between serum cytokine levels and depression severity in patients with major depression (46), pregnant women with depressive symptoms (47), and patients with breast cancer (48). In the present study, IL-6, IL-8, and IL-18 levels increased with moderately severe depressive symptoms but decreased with severe depressive symptoms. This finding suggests the dysregulation of the HPA axis. The hypothalamus is the central site for regulating autonomous body functions and adapting behavior to environmental stimuli and is involved in depression pathology (49). The interaction between cytokines and HPA activity has been observed to be dependent on depression (50). Adaptation of the HPA response was maximized when faced with a severe stressor, and the HPA response to a stressor repeated daily was shown to decrease gradually (51). In other words, a state of reduced immune response is considered to result from a blunt HPA axis response. However, the validation of these results requires further research with broader sample profiles.

In our study, the level of IFN-γ decreased in both depressive and non-depressive symptom groups. This was consistent with the meta-analysis results of 17 studies showing that patients with MDD had decreased IFN-γ levels compared with healthy controls (13). However, another meta-analysis that considered smoking status reported increased IFN-γ levels (12). The nurses in the study were in a controlled, tobacco-free state, and the results of IFN-γ were more controversial. Given that it has not previously been consistent in a smaller meta-analysis (52) related to IFN-γ, we believe that more studies on IFN-γ in relation to depression are needed.

Both TNF-α and IL-2 are well known pro-inflammatory cytokines that play a central role in the early stages of the immune response, highlighting the systemic nature of inflammatory conditions (53). Higher levels of depression symptoms were associated with increased levels of pro-inflammatory biomarkers CRP and TNF-α in older nurses working in the United States (54). In this study, no significant results were observed for TNF-α and IL-2 levels; however, there exists an inverted U-shape relationship between the severity of depressive symptoms and TNF-α and IL-2 levels. These results may support the notion that chronic stress does not control immune function but may lead to the suppression of the immune response (53). However, further studies using longitudinal samples that can reflect acute and chronic stress are needed to confirm these findings.

Notably, the participants in this study were nurses with self-reported depressive symptoms, not diagnosed with depression. Because of their healthcare knowledge, nurses are more likely to engage in healthy lifestyle habits such as no smoking and regular exercise; however, because of work shifts, most of the time, they are involved in physically demanding tasks, such as standing for long. The nature of labor-intensive work can affect systemic inflammation and depression. Screening nurses for depression and providing early intervention may be ways to improve health before symptoms worsen, leading to physiological dysregulation.

This result should be considered in light of several limitations. First, although the Korean Nurses’ Health Study is a large cohort study, participants who provided blood were conveniently extracted and the sample size was relatively small. Additionally, the samples were all female, with a limited ability to investigate potential gender differences. Previous studies have shown sex differences in both depression and inflammation, and women are more likely to experience a more detrimental effect of depression on inflammation. Second, causality could not be inferred by considering the cross-sectional characteristics of the current study. Future longitudinal studies are needed to address whether nurses who self-reported depressive symptoms are within, or fluctuate between, cytokine signatures and disease severity categories over time. Finally, various cytokines have been studied; however, the results do not reflect changes in the overall immune network response, such as immune cell abnormalities. Further studies of other immune cells, such as the ratio of T-helper type-1 (Th1) cells to type-2 (Th2) cells are needed, which can provide a comprehensive understanding of changes in overall immune network responses.

Our study showed inflammatory cytokine profiles in female nurses with depressive symptoms. Serum IL-6, IL-8, IL-18, and IFN-γ are estimated biomarkers for depression and can identify the physiopathology of inflammatory regulation abnormalities in depression. Current research also suggests that more attention should be paid to depression among nurses, given that most nurses do not seek mental health services for depression. We propose early detection and intervention, considering the mechanisms linking depression to physical illness and disease.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the institutional review board of the Ewha Womans University (No. 117-4). The patients/participants provided their written informed consent to participate in this study.

YK, YP, OK, and HL designed the study, collected the data, and interpreted the results. YK and HL interpreted data, wrote the manuscript, interpreted the results, and discussed and revised the manuscript. HP collected and organized the biological samples and performed and interpreted the cytokine assay. YP and OK organized the survey, collected data, and discussed and revised the manuscript. All authors contributed to the article and approved the submitted version.

The Korean Nurses’ Health Study received financial support to conduct research from the Korea Disease Control and Prevention Agency of the Korea National Institute of Health. This research was supported by a grant from the Korea Disease Control and Prevention Agency (2016ER630500, 2016ER630501 and 2022ER0602-01).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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