“Depression (−)”: HCV patients without depression, “Depression (+)”: HCV patients with depression following IFN-α therapy . HCV, hepatitis C virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase.
Hepatitis C virus (HCV) infection affects approximately 170 million people worldwide. Interferon-alpha (IFN-α) is a cytokine that is related to early viral infection and has both antiviral and antiproliferative properties. The current standard treatment for long-term chronic hepatitis C (CHC) consists of combination therapy with IFN-α and ribavirin, which has a broad spectrum antiviral effect. Despite the potential therapeutic benefits of IFN-α, its administration often causes many side effects, such as somatic and neuropsychiatric symptoms. Depression is a serious and frequently occurring side effect of IFN-α therapy, and this is one of the major reasons for cessation of the therapy. Therefore, in order to avoid the discontinuation of INF-α therapy owing to depressive symptoms, it is important to identify the risk factor(s) leading to the onset of associated depressive symptoms. In this chapter, we introduce our novel findings on the association between IFN treatment and the onset of depression in CHC patients as well as the potential neurobiological mechanisms by which depression may arise. We also highlight a potential approach for predicting the onset risk of depression as a side effect in these patients.
- hepatitis C
- tryptophan catabolism
- indoleamine 2
- 3-dioxygenase 1
Hepatitis C virus (HCV) infection is a global health problem. Up to 85% of HCV-infected patients may develop long-term chronic hepatitis C (CHC), a disease state associated with serious clinical sequela, including liver cirrhosis, hepatic fibrosis, and hepatocellular carcinoma [1, 2, 3, 4]. It has been estimated that up to 20% of CHC patients will develop hepatic cirrhosis over a 20–25-year period, and these individuals are at an increased risk for developing end-stage hepatic diseases or hepatocellular carcinoma . Therefore, aggressive antiviral treatments to successfully induce viral remission constitute a major strategy for reducing the morbidity and mortality associated with CHC.
Immunotherapy with interferon-alpha (IFN-α) is commonly used to treat CHC and several types of malignancies owing to its antiviral, antiproliferative, and immunoregulatory effects . In clinical trials, more than 50% of CHC patients treated with combination therapy using IFN-α and ribavirin achieved a sustained viral response, defined as undetectable HCV in the blood 6 months following the end of treatment . Despite the efficacy of IFN-α in CHC treatment, IFN-α therapy causes serious side effects; early signs include somatic symptoms (anorexia, pain, insomnia, fever, and fatigue). Prolonged therapy causes neuropsychiatric symptoms including depressive states, anhedonia, anxiety, and cognitive impairment. In particular, depression is a serious and frequently occurring side effect of IFN-α therapy, and this leads to discontinuation of the therapy in up to 45% of patients [6, 7]. Therefore, in order to avoid the discontinuation of IFN-α therapy owing to depressive symptoms induced by the cytokine, it is important to identify the risk factor(s) leading to the associated depressive symptoms.
A number of findings suggest that the neuropsychiatric side effects observed during IFN-α therapy may be linked to aberrations in the tryptophan (TRP)-kynurenine (KYN) pathway [8, 9]. Clinical studies have found that IFN-α therapy reduces plasma TRP and serotonin (5-hydroxythrptamine; 5-HT) levels  and increases KYN levels in plasma and cerebrospinal fluid (CSF). In addition, the KYN/TRP ratio, an index of indoleamine 2,3-dioxygenase 1 (IDO1) activity, is increased in patients receiving IFN-α therapy .
IDO1 is an extrahepatic enzyme that catalyzes the conversion of TRP to KYN, which can produce many neuroactive metabolites such as 3-hydroxykynurenine (3-HK), kynurenic acid (KA), and quinolinic acid (QUIN). Intriguingly, QUIN levels in CSF have been found to correlate with the severity of depressive pathology , and post-mortem studies have shown increased microglia QUIN levels in the frontal cortex of severely depressed patients .
In the current chapter, we present the findings of our latest study, which demonstrates the association between IFN treatment and changes in the TRP-KYN pathway in the blood of HCV patients. To do so, we investigated the effect of chronic
2. Molecular characteristics and antiviral mechanisms of interferons (IFNs)
2.1. Classification of IFNs
IFNs were first introduced in 1957 as antiviral molecules. Based on their receptor types on the cell membrane surface, IFNs are classified into type I and type II. IFN type I mainly consists of IFN-α/β, while IFN type II consists of IFN-γ. IFN type I is a family of cytokines in which their amino acid sequence similarity reaches 30–80%. They are produced by a wide variety of cells, including fibroblasts, epithelial cells, and hepatocytes [12, 13]. However, in most viral infections, plasmacytoid dendritic cells (pDCs) are probably the major source of these cytokines. In contrast, IFN type II (IFN-γ) is a single gene cytokine unrelated in structure to IFN-α/β, which is produced largely by macrophages, natural killer (NK) cells, and T lymphocytes .
2.2. Immune response for HCV infection and IFN induction
The host response against HCV infection is first triggered when a pathogen-associated molecular pattern (PAMP), presented by an infecting virus, is recognized and engaged by specific PAMP receptors expressed on the host cells. This leads to the activation of signals that ultimately induce the expression of antiviral effector genes [14, 15] (Figure 1). For RNA viruses, protein, and nucleic acid products of infection or replication have been identified as viral PAMPs. These are engaged by specific toll-like receptors (TLRs) or nucleic acid-binding proteins that serve as PAMP receptors [15, 16, 17]. The viral RNA of HCV contains each of these PAMP signatures, and is adequate to trigger the host response when introduced into naïve cells [18, 19]. In hepatocytes, which is the target cell of HCV infection, independent pathways of retinoic acid-inducible gene I (RIG-I) and TLR3 signaling construct two major pathways of host defense triggered by double-stranded (ds) RNA [19, 20, 21]. Viral PAMP binding to RIG-I or TLR3 results in the phosphorylation and activation of interferon regulatory factor 3 (IRF-3) by TANK-binding kinase 1 (TBK-1) and I kappa B kinase ε (IKK-ε) [14, 22]. The dimer of phospho-IRF-3 translocates to the cell nucleus, interacts with its transcription partners, including CREB-binding protein (CBP)/p300, and binds to the cognate-DNA positive regulatory domain (PRD) in the promoter region of IRF-3 target genes, such as IFN-β [14, 23]. The engagement of PAMP receptors also leads to the synthesis of IFN-α/β, tumor necrosis factor (TNF), and a variety of other cytokines, which are largely produced by mainly pDCs that express TLRs in abundance. IFN-α/β produced by pDCs activates NK cells, thereby enhancing their cytotoxic potential and stimulating their production of IFN-γ. IFN-α/β produced by pDCs also modulates the activation of CD8+ T cells, which produce additional IFN-γ and represent the central players in the pathogen-specific adaptive immune response .
2.3. The antiviral effect of IFNs on HCV
IFN-α mediates a wide range of biological activities including antiproliferation, immunomodulation, and antiviral responses. IFN-α/β acts to induce the antiviral response in cells. These cells can be far from IFN-α/β production site and IFN-α/β interacts with specific cell surface receptors, type I IFN receptors (interferon-alpha receptor 1 (IFNΑR1) and IFNΑR2; Figure 1). IFNARs signal to the nucleus via Janus kinase-1 (Jak1) and tyrosine kinase 2 (Tyk2) phosphorylation of the signal transducers and activators of transcription (STATs) . The classic IFN-α/β signaling pathways activate STAT1/STAT2 heterodimers and the trimeric IFN-stimulated gene factor (ISGF) complex containing IRF-9, which activate the expression of specific subsets of genes controlled by promoters containing interferon-stimulated response elements (ISRE; Figure 1) . Interferon-stimulated genes (ISGs) are the genetic effectors of the host response, although the details of the signaling mechanisms by which IFN-α/β and IFN-γ induce the transcription of ISGs are still being defined . IRF-7 is a transcription factor and an ISG. It is expressed in many tissue types, including complex liver tissue, in response to IFN. IRF-7 is activated after expression via viral PAMP signaling pathways that overlie with the IRF-3 activation pathway. IRF-7 phosphorylation, dimerization, and heterodimerization with IRF-3 lead to bind its cognate virus-responsive element (VRE) in the promotor region of IFN-α genes. Then, this binding results in the production of various IFN-α subtypes. The transcription effector action of IRF-7 also promotes diversification of the ISG response, establishing a positive-feedback loop that amplifies IFN production, and antiviral action . This increases the plenty of RIG-I and viral PAMP signaling modules whose continued signaling acts to amplify IFN production and the host response. The medicinal administration of IFN-α promotes an antiviral reaction against HCV infection by stimulating ISG expression via the IFN-α/β receptor and the JAK-STAT pathway. In addition to stimulating ISG expression, IFN-α induces or promotes the maturation of immune effector cells, and enhances the production of other cytokines by resident hepatic cells to indirectly modulate the cell-mediated defenses and adaptive immunity to HCV . Viral trigger and control of the host response may elucidate cellular tolerance for HCV RNA replication and influence the outcome of infection.
3. Side effect: IFN-induced depression and tryptophan metabolism
IFN-α has been shown to develop depression in many diseases, not only CHC, but also in melanoma, chronic myelogenous leukemia, and renal cell carcinoma . However, CHC patients may be more susceptible to developing IFN-induced depression than patients with other disorders, possibly due to a baseline 5-HT system dysfunction. Depression in CHC patients may result from changes in platelet 5-HT function, with decreased 5-HT concentrations during CHC infection compensated for by a decrease in reuptake and metabolism . Immune activation, particularly by IFN-γ, affects the catabolism of TRP, a precursor of 5-HT, by inducing expression of IDO1. IDO1 is the first and rate-limiting enzyme that converts TRP to N-formyl-L-kynurenine, which is further metabolized to QUIN (Figure 2). IFN treatment of CHC patients results in a decrease in plasma TRP and an increase in plasma KYN . Another clinical study with cancer patients has shown that immunotherapy with IFN-α significantly increases the severity of depressive symptoms, which is related to a depletion of serum 5-HT and induction of the catabolism of TRP to KYN . Thus, TRP catabolism switches from the 5-HT pathway to the KYN pathway, resulting in a decrease in 5-HT levels.
IDO1 is induced by several pro-inflammatory cytokines including IFNs (IFN-α/β, γ), TNF-α, and interleukin 6 (IL-6). It is also widely accepted that IFNs, especially IFN-γ, are essential factors for IDO1 induction since two ISREs and IFN-γ-activated site (GAS) element sequences are found in the 5′-flanking region of the IDO1 gene . Recent preclinical studies in mice have demonstrated that pharmacological inhibition of IDO1 enzymatic activity or genetic deletion of IDO1 abrogates acute and chronic inflammation-dependent behavioral changes induced by peripheral or central administration of lipopolysaccharide (LPS) [29, 30, 31, 32, 33]. Additionally, it has been reported that peripheral administration of KYN alone can induce depression-like behavior in rats . In a clinical study, patients receiving IFN-α therapy showed increases in the total Montgomery-Asberg Depression Rating Score (MADRS), an index of depressive symptoms similar to the KYN/TRP ratio; this indicates IDO1 activity and the KYN/KA ratio, which reflects a neurotoxic challenge . These findings suggest that only TRP depletion itself may not be required for the induction of behavioral changes as a result of IDO1 activation; and that KYN and its neuroactive metabolites are more related to cytokine-induced depression-like behaviors than TRP depletion. However, it is still unclear whether direct activation of IDO1 and KYN metabolites plays a definitive role in the induction of depressive symptoms by IFN-α treatment.
4. The association between IFN treatment and changes in the TRP-KYN pathway on depression as a side effect in humans and mice
4.1. Changes in the levels of serum TRP and its metabolites in HCV patients with IFN-α therapy
In order to further clarify the relationship between the IDO1-induced KYN pathway and the development of depressive symptoms during IFN-α therapy, we conducted a study in which we measured TRP metabolites of the KYN pathway in the serum of HCV patients undergoing IFN-α therapy.
A total of 49 patients (32 males and 17 females; mean age 54.0 ± 2.3 years) suffering from CHC were recruited. Table 1 shows the clinical characteristics of patients with HCV. In this study, most of patients were treated with recombinant (r) IFN-α 2b or pegylated (PEG)-IFN-α 2b (21 patients (42.9%) received each medicine, respectively). Five patients (10.2%) were treated with natural (n) IFN-α, and others received PEG-IFN-α 2a (2.0%) and rIFN-α 2a (2.0%), individually. All interferons have almost the same efficiency and induce about the same activation of the KYN pathway . No patient had a past record of psychiatric treatment, and all were off from depressive symptoms prior to IFN-α treatment. They did not take any antidepressant medications during the study period. At an average of 104.2 ± 15.8 days after the IFN-α administration, some patients presented with apathy, social isolation tendencies, melancholy, depressed mood, and an intention to stop IFN administration. Patients who felt depressed mood were referred for psychiatric evaluation and identified as major depressive disorder (MDD) by a psychiatrist. Nineteen of the HCV patients were diagnosed with depressive symptoms [depression (+)], while 30 of them did not present depressive symptoms [depression (−)]. The diagnosis to verify the incidence of depressive symptoms associated to MDD was made according to the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders fourth edition) and ICD-10 (International Statistical Classification of Disease and Related Health problems-10) base on clinical interviews.
|(a) Clinical characteristics of HCV patients|
|Depression (−)||Depression (+)|
|All subjects||30 (male: 20; female:10)||19 (male: 12; female: 7)|
|Age||54.33 ± 2.06||54.0 ± 2.29|
|HCV genotype 1b||24 (80%)||15 (78.9%)|
|HCV genotype 2a||4 (13.3%)||3 (15.8%)|
|HCV genotype 2b||2 (6.7%)||1 (5.3%)|
|AST||59.43 ± 5.09||57.47 ± 6.45|
|ALT||82.68 ± 11.36||69.56 ± 8.65|
|(b) The time points of blood sampling|
|Time points||Depression (||Depression (+) (mean ± SEM)||df||p value|
|(a) Before the onset of therapy||1–35 d (6.3 ± 1.8 d)||0–22 d (6.7 ± 1.3 d)||0.230||48||0.819|
|(b) 2 w after the onset of therapy||13–15 d (13.8 ± 0.1 d)||12–15 d (13.6 ± 0.2 d)||0.513||61||0.610|
|(c) 4 w after the onset of therapy||25–30 d (27.9 ± 0.1 d)||25–29 d (27.6 ± 0.3 d)||0.952||40||0.347|
|(d) The period of therapy||167–343 d (252.0 ± 15.7 d)||54–337 d (183.4 ± 22.0 d*)||2.592||46||0.013|
For all HCV patients, blood was collected before the onset of IFN-α therapy as well as 2 and 4 weeks after initiation of treatment. There was a no significant time difference for blood sampling between depression (−) and (+) patients (Table 1b and Figure 3).
Previous studies suggested that IDO1-mediated TRP metabolism could be implicated in the development of depression, as a side effect of IFN-α therapy in HCV patients. We also found that HCV patients showed decreased TRP and increased KYN concentrations without any changes in KA, AA, and 3-HAA concentrations during IFN-α therapy (Figure 3b and Table 2a). Furthermore, depression (+) patients presented a higher increase in 3-HK concentration compared to depression (−) patients during treatment (Table 2a). Ogawa et al. recently showed that plasma TRP concentration was significantly decreased in MDD patients compared to healthy controls . Teraishi et al. also demonstrated increased KYN metabolites along the TRP-KYN-QUIN pathway, but not the KYN-KA pathway, in MDD patients . Our results showed that the level of 3-HK in the serum significantly increased in depression (+) patients are consistent with these findings. We also investigated the ratios of 3-HK/KA (reflecting neurotoxic indices) [39, 40] and KYN/TRP (reflecting IDO1 activity) in depression (−) and depression (+) HCV patients during IFN-α treatment (Figure 3c and Table 2b). The ratios of KYN/TRP and 3-HK/KA in both groups increased during treatment. However, in depression (+) patients, the ratios of KYN/TRP and 3-HK/KA increased much larger in depression (−) patients during treatment (Table 2b). In these patients, the serum KYN/TRP and 3-HK/KA ratios increased more at the diagnosis of depression, but at 70.3 ± 9.1 days post therapy, they returned to the same levels as before onset of the therapy (data not shown). The severity of depression was not assessed during treatment, using neither the MADRS nor Hamilton Depressing Rating Scale. Therefore, we could not clearly show the direct association between the aggravation of depressive symptoms and changes in TRP metabolites. However, our results suggest that HCV patients with a high sensitivity for IDO1 activation by IFNs are highly susceptible to the depression-related side effects of IFN-α treatment.
|(a) Changes in the levels of serum TRP and its metabolites|
|% of value before IFN-α therapy||df|
|Depression (−)||Depression (+)|
|2 w after onset of therapy|
|TRP||95.4 ± 2.93||100.5 ± 3.98||0.965||40||0.340|
|KYN||108.6 ± 4.77||118.1 ± 4.24*||1.200||39||0.237|
|3-HK||117.0 ± 7.13||152.6 ± 10.4***, ##||2.886||38||0.006|
|KA||97.4 ± 5.51||95.9 ± 7.13||0.136||38||0.892|
|AA||119.9 ± 7.42||115.5 ± 7.11||0.381||41||0.706|
|3-HAA||102.9 ± 6.53||121.8 ± 12.6||1.452||37||0.155|
|4 w after onset of therapy|
|TRP||92.0 ± 2.55||93.3 ± 6.49||0.213||39||0.833|
|KYN||104.8 ± 4.38||114.4 ± 6.38||1.204||39||0.236|
|3-HK||123.0 ± 9.01||155.0 ± 11.5***||2.005||36||0.053|
|KA||91.9 ± 5.12||88.8 ± 6.98||0.341||40||0.735|
|AA||107.5 ± 5.32||103.6 ± 11.3||0.361||40||0.720|
|3-HAA||101.9 ± 6.52||104.5 ± 14.8||0.182||36||0.857|
|(b) Changes in serum KYN/TRP and 3-HK/KA ratios|
|% of value before IFN-α therapy||df|
|Depression (−)||Depression (+)|
|2 w after onset of therapy|
|KYN/TRP||115.6 ± 4.55||114.1 ± 5.95||0.198||42||0.844|
|3-HK/KA||129.1 ± 9.52||144.0±9.06*||1.036||39||0.308|
|4 w after onset of therapy|
|KYN/TRP||115.7 ± 5.69||138.3±8.84*,#||2.094||35||0.044|
|3-HK/KA||129.6 ± 8.67||171.1 ± 18.6***,#||2.325||35||0.026|
4.2. The effects of chronic
Ifn-γ gene expression on depression-like behavior in mice
We hypothesized that the high induction of IDO1 and the imbalance of TRP metabolites induced by IFNs in humans may be related to psychiatric side effects, such as depression. Previous studies have shown that all three IFNs (IFN-α, -β, and -γ) induce strong IDO1 activity in human peripheral blood mononuclear cells [41, 42]. In contrast, in mouse, IDO1 is induced more markedly by IFN-γ than IFN-α, which has only a weak direct IDO1-stimulatory effect. Therefore, we investigated whether IDO1 activity induced by
To conduct this experiment, for murine
In order to clarify whether the activation of IDO1 by IFN-γ-affected behaviors, three tests, open-field test (OFT), the Y-maze test, and forced swimming test (FST), were performed in mice. Mice were transfected with either a pCpG-mcs plasmid (control vector) that did not contain the
4.3. Changes in the levels of TRP and its metabolites in the serum and frontal cortex of mice following chronic Ifn-γ gene expression
In order to further elucidate the relationship between the IDO1-induced KYN pathway and the development of depression-like behavior in mice transfected with the pCpG-Muγ plasmid, we measured TRP metabolites in the serum and frontal cortex of these mice.
The serum and the frontal cortex were corrected from mice immediately following behavioral testing to determine the levels of TRP, KYN, KA, 3-HK, 3-HAA, and AA (Figure 5b and c). The concentration of serum TRP was significantly decreased in IFN-γ transfected (+) mice compared to IFN-γ-transfected (−) mice. In contrast, the levels of serum KYN and 3-HK were significantly increased in the IFN-γ-transfected (+) mice (Figure 5b). In the frontal cortex, IFN-γ transfected (+) mice had significantly higher KYN and 3-HK levels than the IFN-γ-transfected (−) mice. The TRP and KA levels in the frontal cortex tended to be lower in the IFN-γ-transfected (+) mice (Figure 5c). The activation of IDO1 by
4.4. The effects of Ido1 gene-deficiency on depression-like behavior, changes in TRP metabolism, 5-HT, and its turnover in the frontal cortex of mice following chronic Ifn-γ gene expression
Additionally, we evaluated the role of IDO1 in the development of depression-like behavior after
The increase in time spent in an immobile posture in the
Other studies have emphasized that the 5-HT pathway is also relevant to depression. In a clinical study, it has been shown that levels of TRP and 5-hydroxytryptophan, a precursor of 5-HT, were significantly decreased from their baseline levels in the serum of HCV patients during IFN-α therapy . Thus, we speculate that biological mechanisms underlying the IFN-α treatment induced-depressive symptoms are linked not only to the activated IDO1 and KYN pathway but also to a dysfunction of the 5-HT system. To clarify on the basis of the neurotransmitter changes in depression-like behavior after
Taken together, an alternative interpretation for the involvement of IDO1 in IFN-γ-induced depression-like behavior may be that depression is related to not only the generation of neuroactive TRP metabolites but also to the alteration of serotoninergic neurotransmission.
The levels of TRP metabolites in the serum of HCV patients changed significantly. In particular, the increase in serum 3-HK concentration in depressive HCV patients was much larger than that in HCV patients without depressive symptoms. The ratios of serum KYN/TRP, reflecting IDO1 activity, and 3-HK/KA were increased in depressive and non-depressed HCV patients with therapy. However, the increase in serum KYN/TRP and 3-HK/KA ratios in depressive patients was much higher than that of non-depressive HCV patients. When the
This work was supported by Grant-in Aid for Scientific Research of YM (26860368 and 16K08948).
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