Hobad Huy Nguyen

Background: Depression is a mental health disorder that affects 300 million people worldwide¹ and is characterized by persistent impaired motivation, decreased mood, and in severe cases suicidality.² According to the Diagnostic and Statistical Manual Version 5, Major Depressive Disorder (MDD) lasts for at least two weeks and interferes with social and occupational functioning, causing a burden on society.³ Chronically stressful events such as divorce, isolation, and chronic health conditions have been known to cause MDD. Current treatment guidelines include selective serotonin reuptake inhibitors and tricyclic antidepressants combined with psychotherapy for a synergistic treatment.¹ Unfortunately up to ⅓ of patients are resistant to this treatment, and medications cannot alieve the physical side effects of depression.¹ Interleukin 6 (IL-6) is a pro-inflammatory exerkine that normally plays a role in immune defense and hematopoiesis.⁴ High Interleukin 6 levels have been measured in patients with MDD and an increase in IL-6 positively correlates with severity of symptoms.⁴ Aerobic exercise has been known for years to have a beneficial effect on psychological symptoms of depression in addition to physical symptoms such as restlessness, difficulty sleeping, and loss of appetite.

Purpose: The purpose of this review was to explore the mechanisms by which interleukin-6 causes symptoms of depression and how the interplay of exercise is able to improve depressive symptoms

Search Methods: Using the pubmed database search function in addition to the Texas A&M Medical Sciences Library online database to identify relevant articles in the years of 2018-2024 using the search terms “Interleukin-6”, “Exercise”, “Major Depressive Disorder”, “Kynurenine” and “Depression”.

Results: Stress causes a rise of stress hormones, Epinephrine and Cortisol which increase levels of interleukin 6 in the blood.⁵ Interleukin 6 causes trans-signaling in neuronal cells in the brain. SOCS3, a tumor suppressor protein, which normally inhibits IL-6 signaling fails to function properly.⁶ The failure of the feedback inhibition by SOCS3 leads to the expression of Indoleamine-2,3-Dioxygenase which is the first enzyme of the Kynurenine Pathway.⁷ In one study that looked at plasma kynurenine levels in MDD patients, it was found that plasma kynurenine was significantly elevated in individuals that attempted suicide versus healthy volunteers.⁸ In another study, a specific product of the Kynurenine pathway, Quinolinic acid was found to be elevated. Individuals with Major depressive disorder displayed higher numbers of quinolinic acid immunopositive cell densities in the subgenual anterior cingulate cortex with increased microglial formations in Quinolinic acid reactive cells.⁹ Several papers have demonstrated evidence of exercise decreasing interleukin-6 and improving depression. In one study, Individuals with depressive symptoms while on hemodialysis were put on a bicycle exercise regiment and IL-6 levels and scores for depression were measured before and after. In the individuals which had the exercise treatment, IL-6 had the strongest decline while also having a strong improvement in depressive symptoms.¹⁰ In another study, previously sedentary older adults that exercised over an 11-week period had lower scores on the Perceived Stress Levels in addition to decreased IL-6 serum levels, additionally mood and quality of life scores were increased in adults that exercised.¹¹

Conclusion: The overexpression of interleukin-6 in stressed conditions leads to increased signaling which is not inhibited by SOCS3 function. The product of this signaling is Indoleamine-2,3-Dioxygenase which activates the kynurenine pathway and creates toxic products in the brain, leading to pathogenesis of Major Depressive Disorder. Exercise has a dampening effect on serum levels of interleukin-6 in blood and improves symptoms.

Works Cited:

1. Kandola A, Ashdown-Franks G, Hendrikse J, Sabiston CM, Stubbs B. Physical activity and depression: Towards understanding the antidepressant mechanisms of physical activity. Neurosci Biobehav Rev. 2019 Dec;107:525-539. doi: 10.1016/j.neubiorev.2019.09.040. Epub 2019 Oct 2. PMID: 31586447.
2. Yang L, Zhao Y, Wang Y, Liu L, Zhang X, Li B, Cui R. The Effects of Psychological Stress on Depression. Curr Neuropharmacol. 2015;13(4):494-504. doi: 10.2174/1570159×1304150831150507. PMID: 26412069; PMCID: PMC4790405.
3. The Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5; American Psychiatric Association [APA], 2013)
4. Kang Y, Shin D, Kim A, You SH, Kim B, Han KM, Ham BJ. The effect of inflammation markers on cortical thinning in major depressive disorder: A possible mediator of depression and cortical changes. J Affect Disord. 2024 Mar 1;348:229-237.   doi: 10.1016/j.jad.2023.12.071. Epub 2023 Dec 30. PMID: 38160887.
5. Yeager MP, Guyre CA, Sites BD, Collins JE, Pioli PA, Guyre PM. The Stress Hormone Cortisol Enhances Interferon-υ-Mediated Proinflammatory Responses of Human Immune Cells. Anesth Analg. 2018 Aug;127(2):556-563. doi: 10.1213/ANE.0000000000003481. PMID: 30028389.
6. Kalkman HO. Novel Treatment Targets Based on Insights in the Etiology of Depression: Role of IL-6 Trans-Signaling and Stress-Induced Elevation of Glutamate and ATP. Pharmaceuticals. 2019; 12(3):113. https://doi.org/10.3390/ph12030113
7. Jeon SW, Kim YK. Kynurenine and serotonin pathways of tryptophan metabolism: The etiology and pathogenesis of depression. In: Hayes V, editor. New Developments in Tryp-tophan Research. New York: Nova Science Publishers; 2015. p.29–48.
8. Sublette ME, Galfalvy HC, Fuchs D, Lapidus M, Grunebaum MF, Oquendo MA, Mann JJ, Postolache TT. Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behav Immun. 2011 Aug;25(6):1272-8. doi: 10.1016/j.bbi.2011.05.002. Epub 2011 May 14. PMID: 21605657; PMCID: PMC3468945.
9. Steiner, J., Walter, M., Gos, T. et al. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: Evidence for an immune-modulated glutamatergic neurotransmission?. J Neuroinflammation 8, 94 (2011). https://doi.org/10.1186/1742-2094-8-94
10. Zhao, C., Ma, H., Yang, L., & Xiao, Y. (2017). Long-term bicycle riding ameliorates the depression of the patients undergoing hemodialysis by affecting the levels of interleukin-6 and interleukin-18. Neuropsychiatric Disease and Treatment, 13, 91–100.
11. Starkweather AR. The effects of exercise on perceived stress and IL-6 levels among older adults. Biol Res Nurs. 2007 Jan;8(3):186-94. doi: 10.1177/1099800406295990. PMID: 17172317.