Abstract
The endocannabinoid (eCB) system is one of the key players in immunoregulation, and reduced activity of the eCB system has been linked with depressive-like behaviours in animal studies and depression in clinical samples. There is a well-established link between immune activation and depression, such as following the administration of the pro-inflammatory cytokine, interferon-α (IFN-α), used to treat hepatitis C viral (HCV) infection. However, the role of peripheral endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), following immunotherapy with IFN-α and in IFN-α -induced depression, have not been examined yet.In this study, we investigated whether circulating AEA and 2-AG were modified by treatment with IFN-α and whether they were involved in the development of IFN-α-induced depression. We also explored whether circulating eCBs were associated with peripheral cytokines during and after IFN-α treatment. We measured serum concentrations of AEA and 2-AG using High Performance Liquid Chromatography with Tandem Mass Spectrometry, and serum concentrations of cytokines using Meso Scale Discovery electrochemiluminescence V-PLEX assay, in 70 patients with HCV infection and 41 healthy subjects. We assessed HCV patients at baseline, IFN-α-treatment weeks (TW) 4 and 24, end of treatment (END) and at six months follow-up (FU). We assessed depression using M.I.N.I. International Neuropsychiatric Interview.We found a different pattern of change in peripheral AEA and 2-AG during and after IFN-α treatment. Whilst 2-AG increased earlier in immunotherapy (TW4), remained elevated throughout treatment, and reduced at six months follow-up (FU), AEA increased later in treatment (TW24) and remained elevated six months post-treatment. We also found that baseline levels of AEA were lower in HCV patients compared with healthy controls, whereas there were no differences in 2-AG levels. Interestingly, AEA, but not 2-AG, was significantly, negatively correlated with interleukin (IL)-2 and IL-17a at six months follow-up. We did not find any difference in both eCBs between patients with and without IFN-α-induced depression, at any time point.Our findings suggest that AEA and 2-AG are involved in different stages of immunoregulation following IFN-α treatment, where AEA might be involved in chronic inflammation. Lack of association between peripheral eCBs and IFN-α-induced depression suggests that different biological mechanisms may underpin inflammation-induced depression compared with classic “psychiatric” depression, or that any changes in the eCB system in depression may not be captured by peripheral AEA and 2-AG.
Highlights
Considerable research suggests a bi-directional interaction between the endocannabinoid and immune systems, with the eCB system being involved mainly in attenuation of inflammation through the regulation of both, the innate and adaptive immune systems (Boorman et al, 2016)
This is the first study to use a prospective cohort design in order to explore the role of peripheral eCBs, in both, patients with hepatitis C viral (HCV) receiving IFN-α treatment, and IFN-α induced depression
At six months post-treatment, HCV patients showed a significant decrease in serum IL-2, IL-6, IL-10, IL-17a and tumor necrosis factor (TNF)-α compared with end of treatment, and all cytokines at this time point were no longer different from their baseline levels, except for IL-10, which was lower than its baseline levels
Summary
Considerable research suggests a bi-directional interaction between the endocannabinoid (eCB) and immune systems, with the eCB system being involved mainly in attenuation of inflammation through the regulation of both, the innate and adaptive immune systems (Boorman et al, 2016). We focused on the role of peripheral eCBs, AEA and 2AG, in patients with chronic HCV infection receiving peg-IFN-α treatment, the aforementioned immune challenge and established model to investigate inflammation-induced depression using a longitudinal design. The comparison in eCB levels between patients with HCV and healthy controls was examined, since one previous study found that plasma AEA and 2-AG were elevated in HCV patients compared with the control group (Patsenker et al, 2015) To our knowledge, this is the first study to use a prospective cohort design in order to explore the role of peripheral eCBs, in both, patients with HCV receiving IFN-α treatment, and IFN-α induced depression
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