A scientific research indicates that psychological stress has a positive impact on the human immune system, and studies demonstrating elevated levels of immune system proteins in depressive patients, including interleukin-1β (IL-1β), IL-6, soluble IL-2 receptors, and tumour necrosis factor-alpha (TNF-alpha), suggest a close relationship between the immune system and depression. Immune cytokine peripheral inducers can cause depressive symptoms, and they can lower the monoamine levels that most modern antidepressants are designed to raise in the brain. Immune mediators, such as cytokines, have an impact on a variety of central nervous system (CNS) processes associated with depression, including cognition, sleep, and reward.
IL-1β, which is produced by microglia, astrocytes, and neurons and is primarily expressed in the hypothalamus, hippocampus, cerebral cortex, and thalamus, interacts with its receptor, IL-1R1, which is also present throughout the brain but is more strongly expressed in the hippocampus. Nuclear factor (NF)-κB, MAPK, and JNK are three signalling pathways that are activated by the binding of IL-1β to IL-1R1 to act as host defences. When under psychological stress, the hypothalamus and hippocampus produce more IL-1β, and when IL-1β is administered, the HPA axis is activated, hippocampal long-term potentiation is suppressed, and BDNF production is downregulated. These effects are similar to those of a stress response. At both the cellular and behavioural levels, blocking IL-1β signalling by administering IL-1 receptor antagonists alleviated stress-like symptoms brought on by IL-1β. The serotonin transporter gene, which is important for treating depression, can also be controlled by IL-1β. This suggests that IL-1 antagonists could be a fresh option for treating depression.
Although IL-1β exerts a cytostatic impact on hippocampus progenitor cells in response to stress, IL-6 may also contribute to the reduction of proliferation. The idea that hippocampus neurogenesis is essential for the treatment of depression may be supported by this. Additionally, mice with the IL-6 gene removed demonstrated resistance to the onset of depressive symptoms brought on by stress, which might be used as a tool to investigate the patho-physiology of depression and test new antidepressant medications.
TNF- may stimulate the HPA axis, directly stimulate indoleamine-2,3-dioxygenase, which is found in brain macrophages and dendritic cells, and catabolize tryptophan, the building block for serotonin synthesis. Successive investigations found that TNF-α and IL-1β enhance serotonin absorption in mice midbrain and striatal synaptosomes by activating serotonin transporters via p38 MAPK activation. This type of TNF-α serotonin-decreasing impact may suggest that inhibiting TNF-α signalling may help to alleviate depressive symptoms, which have the same goal as SSRIs: to limit the re-uptake of serotonin. The idea above is supported by studies demonstrating that genetic deletion of either TNFα- receptor 1 (TNFR1) or TNFR2 causes a series of antidepressant-like behaviors in a variety of animal models, while administration of TNFα causes depression-like behaviors that can be prevented by antidepressant medications like fluoxetine.
The simultaneous occurrence of mental and physical symptoms in depressive patients can be explained, minimum by the presence of those cytokines in the peripheral and central nervous systems. Future studies on the association between cytokines and depression may concentrate on the still mostly unidentified neuronal circuits underpinning the physical and behavioral impacts, as well as the more intricate interactions between brain cells.