Cytokines and Pathogenesis of Depressive Disorders During Chronic Illness

Sharon Edamala

What are Cytokines? Table 1. Psychological effects of cytokine immunotherapy. Behavioral side effects
Mechanisms Underlying Cytokine-Induced Depression associated with the administration of proinflammatory cytokines during the length
Inflammation is mediated by proteins called cytokines. of an illness are listed. Abbreviations: IFN, interferon; IL, interleukin; TNF, tumor
Serotonin hypothesis of depression suggests major depressive disorder (MDD) is characterized by
necrosis factor. Adapted from Schiepers et al. (2005).
• Synthesized by nucleated cells, secreted as a response to cell stress serotonin neurotransmission disorders which can be induced by chronic inflammation.
Immunotherapy Neuropsychiatric Effects Clinical Condition Treated
• Proinflammatory cytokines induce inflammation to activate an immune • Alters serotonin turnover in brain regions associated with MDD, lowers activity of presynaptic
response; anti-inflammatory cytokines reduce inflammation post-infection serotonergic neurons, and creates changes in serotonin reuptake from the synaptic cleft and to IFN- Fatigue Cancer
postsynaptic serotonin receptors Psychomotor slowing Multiple sclerosis

Tryptophan (TRP) is the precursor for serotonin synthesis. Depressed mood Chronic hepatitis C, other viral
infections
• High level of proinflammatory cytokines in the blood results in lower tryptophan levels and less
Anxiety
serotonin synthesized Social withdrawal
• Activation of Trp 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) results in tryptophan Irritability
Anorexia
degradation
Cognitive disturbances (mental
slowing, lack of concentration,
memory impairment)
IFN- Fatigue Multiple sclerosis
Figure 3. TRP can be Depressed mood
metabolized through the Cognitive impairment (Metastatic) cancer
serotonergic or kynurenic IL-1 Cognitive impairment (mental (Metastatic) cancer
Figure 1. A) Cytokines stimulate specific cells. Different cell types can secrete the pathway. When the immune slowing)
same cytokine, and one cytokine can act on multiple cells. B) Cytokines can be system is activated, IL-2 Fatigue
used to communicate over a variety of distances. Adapted from Creative tryptophan is pushed from Anhedonia
Diagnostics (n.d) the serotonergic pathway to Dysphoria
the kynurenic pathway, Cognitive impairment
resulting in quinolinic acid TNF- Fatigue Cancer
Proinflammatory cytokines also mediate sickness behavior. (which is neurotoxic) instead Anorexia
• Characteristics of sickness that accompany an infection: fever, decreased of serotonin. Adapted from
appetite, weight loss, lower levels of physical activity, loss of interest in social Anderson and Maes (2017).
Conclusions and Future Directions
environments, etc.
• Helps sick individuals temporarily cope with the infection There are barriers to understanding depression through an immunological lens.
• Various types of depressive disorders influence the immune system differently
By activating the kynurenine pathway, proinflammatory cytokines cause the synthesis of quinolinic • Lack of generalizability of depression studies
The Problem acid (QUIN) and 3-hydroxykynurenine (3OH-KYN). • Role of genetics in increasing chances of developing depression during illness
Dysregulation of proinflammatory and anti-inflammatory cytokine levels can • Linked to Parkinson’s disease, anxiety, and depression
cause endocrine and behavioral changes. • 3OH-KYN may lead to overproduction of reactive oxygen species and increased monoamine oxidase There is a large comorbidity of depression with the presence of proinflammatory
• Long-term exposure to a pathogen can lead to high sustained levels of activity, both associated with depressive disorders. cytokines.
proinflammatory cytokines resulting in chronic inflammation • MDD more prevalent in those with chronic inflammatory conditions e.g.,
• Psychological stressors contribute to a greater risk for infection, prolonged Depression is also associated with hypothalamic pituitary adrenal (HPA) axis hyperactivity caused rheumatoid arthritis, cardiovascular disease, Type 2 diabetes
length of infection, and slower wound healing by increased levels of cortisol in serum. • Major depressive disorder develops in 1/3 of patients that are treated with IL-2
• Proinflammatory cytokines activate HPA axis and induce corticosteroid receptor resistance in the • IFN- immunotherapies can increase mortality rates by 39%
hypothalamus and pituitary gland
• QUIN may cause hippocampal degeneration and loss of corticosteroid receptors Future research has potential to mitigate or stop development of depression
during chronic illness.
Figure 2. Interactions
between the central • Drugs that target the immune, endocrine, and neurotransmitter pathways
nervous system (top), Figure 4. The HPA axis is responsible for • Studies with consistent methods; cytokine levels can vary depending on the
endocrine system (right), the neuroendocrine response to stress kind of body fluid they were extracted from
immune system and is tightly regulated. With repeated • Investigate the relationship between poor behavioral coping strategies and the
(bottom), and autonomic exposure to a stressor, a person can body’s perception of stress, and how levels of proinflammatory cytokines may
nervous system (left). habituate to the stressor with continuous change as a result
Adapted from Schiepers, HPA activation.
Wichers, and Maes
(2005). Acknowledgements
I would like to thank Dr. Nancy Wall and Dr. Judith Humphries for their advising and
support during this project.

Literature Cited
This project explores the relationship between elevated levels of
Anderson, G., & Maes, M. (2017). Interactions of tryptophan and its catabolites with melatonin and the alpha 7 nicotinic receptor in central nervous system and
proinflammatory cytokines and the development of depressive psychiatric disorders: Role of the aryl hydrocarbon receptor and direct mitochondria regulation. International Journal of Tryptophan Research, 10,
117864691769173. doi: 10.1177/1178646917691738
symptoms or disorders in individuals with chronic illnesses from a Creative Diagnostics. (n.d.). Cytokines and cytokine receptors ELISA Kits. Retrieved from https://www.creative-diagnostics.com/cytokines-and-cytokine-receptors-
elisa-kits.htm
neuroimmunological perspective. Schiepers, O. J., Wichers, M. C., & Maes, M. (2005). Cytokines and major depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 29(2), 201–
217. doi: 10.1016/j.pnpbp.2004.11.003