Suicidality Linked to High Levels of the Pro-Inflammatory Cytokines IL-1β and IL-6

Suicidality High Levels Cytokines IL-1 IL-6
Suicidality and Pro-Inflammatory Cytokines IL-1β and IL-6

A recent  study published in the journal Biological Psychiatry indicates the presence of aberrant cytokine levels in patients with suicidality, and identifies a link between pro-inflammatory cytokines, and specifically, interleukin (IL)-1β and IL-6 with suicidal behavior.

Death by suicide is the second leading cause of mortality among the 15–29 age group worldwide (WHO, 2012). It is estimated that 40 000 people die of suicide every year in the United States, and the global death toll is estimated to be at ~800 000 (WHO, 2014).

Mechanistically, it is known that inflammation can trigger depressive symptoms and is associated with suicidality based on studies involving patients who receive interferon (IFN)-based or interleukin-2 (IL-2) immuno-therapy.

Previous research has shown that major depression is associated with an immune response with an increased production of pro-inflammatory cytokines including IL-1 and IL-6.

More recent data indicate that pre-existing individual differences in the sensitivity of the peripheral immune system may predict the vulnerability to social stress, and that an “IL-6 hyper-responsiveness” is an preexisting trait that may associate with a greater risk of stress-related disorder development such as depression.

It is known that certain cytokines (the ‘immune hormones’ or the chemical messengers between immune cells) contribute to the development of autoimmune diseases and arthritis, atherosclerosis, or allergy and asthma. Some of these cytokines have also been associated with major depression.

There is growing evidence that inflammatory mediators play a critical role in the pathophysiology of both major depression and suicidal behavior. Immunological differences have been reported in both major affective disorders and suicidal behavior.

Specifically, increased levels of pro-inflammatory cytokines have been shown to correlate with the severity of depression and various cytokines have been identified as potentially important in understanding the pathophysiology of major affective disorders/suicidality.

In a systematic review Gianluca Serafini et al. outlined the association between suicidality and IL2, IL-6, IL-8, TNF-α and VEGF levels that have been found altered in suicidal behavior.

In the Biological Psychiatry meta-analysis study, based on 18 studies and including 583 patients with suicidality, Carmen Black and Brian Miller of Georgia Regents University demonstrate that suicidal patients had significantly increased levels of the pro-inflammatory cytokines, IL-1β and IL-6, both in their blood and postmortem brain.

Interestingly, cerebrospinal fluid levels of IL-8 were significantly decreased in patients with suicidality, as compared to control subjects. Levels of IL-1β and IL-6 were most robustly associated with suicidality, and these cytokines may help distinguish suicidal from nonsuicidal patients.

Further studies are needed to evaluate whether these cytokines or other biomarkers may help distinguish patients at risk of suicide or associated self-destructive behaviors.

An Update

In 2016, Licínia Ganança et al. reviewing 22 studies concerning cytokines and suicidal ideation, suicide attempts or suicide completion, found that the most consistent finding was elevated IL-6, found in 8 out of 14 studies, in CSF, blood, and postmortem brain. These authors concluded that suicide risk has been associated with chronic stress, HPA hyperactivity, serotonergic abnormalities, and in some studies, persistently elevated inflammatory markers, especially elevation of IL-6.

In 2017, L. Brundin, E. Bryleva 1 and K. T. Rajamani highlighted the role of inflammation and the dysregulation of the immune system in pathophysiology of suicidality.

Suicidality contributing factors
Contributing factors to suicidal behavior etiology. Genetic factors can predispose individuals to behavioral traits that predispose them to exhibit suicidal behavior. Proximal factors with an underlying immune component can induce a sustained immune response, which, then, is known to modulate a variety of downstream effectors including modifying monoamine metabolism, increasing tryptophan metabolism via the kynurenine pathway, and dysregulating the hypothalamic–pituitary axis. KYN, kynurenine; KYNA, kynurenic acid; MS, multiple sclerosis; NE, norepinephrine; QUIN, quinolinic acid; SLE, systemic lupus erythematosus; 5-HT, serotonin. From: ‘Role of Inflammation in Suicide: From Mechanisms to Treatment‘ L. Brundin, E.Y. Bryleva & K. T. Rajamani, Neuropsychopharmacology, 42pages 271–283 (2017). Public domain.

According to these authors the potential upstream triggers of suicidal behavior include various inflammatory conditions (TBI, vitamin deficiency, autoimmune disorders, and infections).

These conditions, through raised levels of inflammatory mediators, can cause dysregulation of the kynurenine pathway of tryptophan catabolism, hyperactivation of the Hypothalamic-Pituitary-Adrenal (HPA) axis, and alterations in monoamine metabolism in the patients. These neurobiological effects might cause profound changes in emotion and behavior, which could ultimately lead to suicide in vulnerable individuals.

A recent 2020 review indicates a link between abnormally higher IL-1β, IL-6, TNF-α, transforming growth factor (TGF)-β1, VEGF, kynurenic acid (KYN), and lower IL-2, IL-4, and interferon (IFN)-γ levels in specific brain regions and suicidal behavior.

Unfortunately, most studies are not able to exclude the exact contribution of major depressive disorder (MDD) as a mediator/moderator of the link between inflammatory cytokines abnormalities and suicidal behavior.

In 2022, Mao-HsuanHuang et al. studied the association of Suicidal behavior (SB) and different mood states of bipolar I disorder (BD) in 77 patients with BD versus 61 healthy controls. Patients were divided into two groups: with suicidal ideation (SI; n = 21) and no SI.

These authors found that patients with SI had higher levels of soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1) than those without SI and the controls. BD patients with or without a history of suicide attempt had higher levels of CRP than the controls. SI was associated with serum levels of sTNF-αR1 and IL-6sR.

Source: Biol Psychiatry, 2015, 78:28. doi: 10.1016/j.biopsych.2014.10.014. Epub 2014 Oct 30
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Cover Image and Credit: Stress. By Ekaterina Zakharova. Via