Pro-Inflammatory Cytokines: Potential Links between the Endocannabinoid System and the Kynurenine Pathway in Depression

Abstract

Substance use/abuse is one of the main causes of depressive symptoms. Cannabis and synthetic cannabinoids in particular gained significant popularity in the past years. There is an increasing amount of clinical data associating such compounds with the inflammatory component of depression, indicated by the up-regulation of pro-inflammatory cytokines. Pro-inflammatory cytokines are also well-known to regulate the enzymes of the kynurenine pathway (KP), which is responsible for metabolizing tryptophan, a precursor in serotonin synthesis. Enhanced pro-inflammatory cytokine levels may over-activate the KP, leading to tryptophan depletion and reduced serotonin levels, which can subsequently precipitate depressive symptoms. Therefore, such mechanism might represent a possible link between the endocannabinoid system (ECS) and the KP in depression, via the inflammatory and dysregulated serotonergic component of the disorder. This review will summarize the data regarding those natural and synthetic cannabinoids that increase pro-inflammatory cytokines. Furthermore, the data on such cytokines associated with KP activation will be further reviewed accordingly. The interaction of the ECS and the KP has been postulated and demonstrated in some studies previously. This review will further contribute to this yet less explored connection and propose the KP to be the missing link between cannabinoid-induced inflammation and depressive symptoms.

The potency of common proinflammatory cytokines measurement for revealing the risk and severity of anxiety and depression in psoriasis patients

“… 15 This study exhibited that IL‐17A and TNF‐α were positively linked to anxiety, while TNF‐α, IL‐17A, along with IL‐23 were positively linked to depression in psoriasis patients. The possible reason might be that: proinflammatory cytokines might trigger anxiety and depression in various ways, for example, enhanced proinflammatory cytokines might activate the kynurenine pathway, leading to tryptophan depletion and reduced serotonin levels, which further causes depressive symptoms 13 , 31 ; meanwhile, proinflammatory cytokines might also activate the HPA axis or affect the neurotransmitter metabolism, thereby causing anxiety or depression. 32 Therefore, TNF‐α, IL‐17A, and IL‐23 increments were linked with aggravated depression and anxiety in psoriasis patients.…”

“…Proinflammatory cytokines are reported to participate in the progression and pathogenesis of anxiety and depression. 12 , 13 For example, tumor necrosis factor‐α (TNF‐α) activates the hypothalamic–pituitary–adrenal (HPA) axis and indoleamine 2,3‐dioxygenase, which leads to the tryptophan depletion and thereby causes depression. 12 Meanwhile, interleukin (IL)‐1, IL‐6, IL‐8, etc., would activate the kynurenine pathway, which reduces the level of serotonin; thereby inducing anxiety and depression.…”

“… 12 Meanwhile, interleukin (IL)‐1, IL‐6, IL‐8, etc., would activate the kynurenine pathway, which reduces the level of serotonin; thereby inducing anxiety and depression. 13 Clinically, proinflammatory cytokines are linked with anxiety or depression in some autoimmune disease patients, such as multiple sclerosis and rheumatoid arthritis (RA) patients. 14 , 15 For example, IL‐2 is correlated with anxiety; while TNF‐α and IL‐1β are linked to depression in multiple sclerosis patients.…”

“…Proinflammatory cytokines are reported to participate in the progression and pathogenesis of anxiety and depression 12,13 . For example, tumor necrosis factor‐α (TNF‐α) activates the hypothalamic–pituitary–adrenal (HPA) axis and indoleamine 2,3‐dioxygenase, which leads to the tryptophan depletion and thereby causes depression 12 .…”

“…For example, tumor necrosis factor‐α (TNF‐α) activates the hypothalamic–pituitary–adrenal (HPA) axis and indoleamine 2,3‐dioxygenase, which leads to the tryptophan depletion and thereby causes depression 12 . Meanwhile, interleukin (IL)‐1, IL‐6, IL‐8, etc., would activate the kynurenine pathway, which reduces the level of serotonin; thereby inducing anxiety and depression 13 . Clinically, proinflammatory cytokines are linked with anxiety or depression in some autoimmune disease patients, such as multiple sclerosis and rheumatoid arthritis (RA) patients 14,15 .…”