The Role of Cytokine Network in the Pathophysiology of Schizophrenia

Current Psychiatry Reviews, 2005, 1, ???-???

1

The Role of Cytokine Network in the Pathophysiology of Schizophrenia Yong-Ku Kim* Department of Psychiatry, Korea University College of Medicine, Seoul, Korea Abstract: A growing body of evidence suggests that cytokines have a role in schizophrenia. Cytokines are involved in neurodevelopment, schizophrenic psychopathology, and neurodegeneration, and these processes are all part of the pathophysiology of schizophrenia. Cytokines modulate neuronal action, differentiation, and survival during neurodevelopment and are important factors in the processes of neurotoxicity and neurodegeneration. Cytokines also play a role in the activity and survival of neurons that utilize certain neurotransmitters, particularly dopamine, serotonin, and glutamate. This paper addresses the potential role of the cytokine network in the pathophysiology of schizophrenia.

Keywords: Cytokine, antipsychotics, neurotransmitter, neurodegeneration, neurodevelopment, schizophrenia. INTRODUCTION The immune hypothesis of schizophrenia proposes that schizophrenia is accompanied by the dysregulation of cytokines in both the peripheral and the central nervous systems, and furthermore, that cytokine dysregulation plays a causative role in the etiology of the disease. The macrophage–T lymphocyte theory of schizophrenia [1,2] proposes that chronically activated macrophages and T lymphocytes, along with excessive interleukin-2 and other cytokine secretions, are a cause of some cases of schizophrenia. There is now increasing evidence that schizophrenia is characterized by increased nonspecific innate immunity, decreased type I helper cell cellular immunity, and a Th1-Th2 imbalance with a shift to the Th2 system [3] or the activation of the inflammatory response system [4,5]. Cytokines are multifunctional proteins that are released by a variety of cells both in the brain (e.g., neurons and glia) and elsewhere in the body (e.g., macrophages and lymphocytes). These proteins play a crucial role in cell-tocell communication in the immune system and in the interaction between the immune system and the CNS [6]. The activities of cytokines are mediated through specific receptors expressed on the cell surface or through soluble receptors shed from cells [7]. Cytokines are involved in the regulation of sleep, appetite, mood, and also in cognition, learning, neurodevelopment, and neurodegeneration [8,9]. Cytokines modulate the activity, differentiation, and survival of neuronal cells in the neurodevelopmental stage of brain [10]. In addition, cytokine overexpression in the brain is an important factor in neurotoxicity and neurodegeneration [11]. Cytokines interact with neuroendocrine system, e.g., the hypothalamic-pituitary-adrenocortical system, the autonomic system (epinephrine, norepinephrine), and the neurotransmitter system (dopamine, serotonin, glutamine) [12-15].

psychological deterioration in adulthood[16]. The pathophysiology of the disease involves both genes and environment[17]. The etiology of the disease is attributed to the failure of normal neuronal development due to environmental factors (e.g., obstetric complications or maternal viral infections) or a genetic defect manifesting itself during gestation or the perinatal period. Such defects alter the development of the CNS in some way. The resulting developmental deficit accounts for the premorbid cognitive and psychosocial dysfunction in schizophrenia [18]. The onset of psychotic symptoms in adolescence or early adulthood may be related to an excess in the normal synaptic pruning that occurs in certain brain regions, such as the prefrontal cortex [19]. Specifically, psychological stress during this period can stimulate perturbations in neuronal activity that could otherwise be endured without long-term psychological consequences [20]. The neurotransmitter alterations including phasic and tonic dopamine transmission [21], serotonin receptor dysfunction[22] and NMDA receptor hypofunction[23] can also contribute to the positive, negative and cognitive symptoms of schizophrenia that emerge during the adolescence. In some schizophrenic patients, persistent, recurrent sensitization of the dopamine system over time [24] or oxidative stress by glutamate induced neurotoxicity [25] can leads to a degenerative phase manifested by persistent morbidity, treatment resistance, and clinical deterioration. Cytokines may have a role in the pathophysiology of schizophrenia (Fig. 1). In this paper, we first analyze current research on cytokines in schizophrenia, focusing on each class of cytokine. Next, we address the potential role of the cytokine network in the pathophysiology of the disease, focusing on neurodevelopment, neurotransmitters, and neurodegeneration. Finally, we discuss the present limitations and future perspectives in cytokine research in schizophrenia.

Schizophrenia is characterized by premorbid intellectual deficits, onset of psychosis in late adolescence, and

THE CYTOKINE NETWORK IN SCHIZOPHRENIA

*Address correspondence to this author at the Department of Psychiatry, Korea University College of Medicine, Ansan Hospital, 516, Go-Jan Dong, Ansan City, Kyunggi Province, 425-070, Korea; Tel: +82-31-4125140; Fax: +82-31-412-5144; E-mail: [email protected]

Cytokines have been classified as monocytic, Th1, Th2, or Th3 cytokines depending on the cell types that release them [26]. The monocytic or pro-inflammatory cytokines (e.g., IL-1, IL-6, IL-12, IL-18, TNF-α) are released mainly

1573-4005/05 $50.00+.00

© 2005 Bentham Science Publishers Ltd.

2

Current Psychiatry Reviews, 2005, Vol. 1, No. 2

Yong-Ku Kim

Fig. (1). The potential role of cytokines in the pathophysiology of schizophrenia. Cytokines are involved in neurodevelopment, schizophrenic psychopathology, and neurodegeneration. Maternal infection or brain injury induces a failure of normal development through dysregulation of the cytokine network. The interaction of cytokine genes and the environmental factors may determine the risk for schizophrenia. Cytokines influence central monoamine activity in a cytokinespecific manner and modulate psychotic symptoms. Cytokines are also important factors in the processes of neurotoxicity and neurodegeneration.

from monocytes and macrophages and are involved in nonspecific innate immunity. Th1 cytokines (e.g., IL-2, IFN-γ ) are secreted by type-1 T helper cells and play a role in cellmediated immunity (CMI) and activate cytotoxic and inflammatory functions. Th2 cytokines (e.g., IL-4, IL-5, IL9, IL-10, IL-13, LIF) are released by type-2 T helper cells and stimulate humoral immune response and exert antiinflammatory effects. It is now proposed that there are populations of regulatory T cells, some designated Th3, that exert their action primarily by secreting transforming growth factor-beta-1 (TGF-β1). TGF-β1 has more demonstrable immunosuppressive effects than any other cytokine. It suppresses the production of pro-inflammatory or Th1 cytokines such as IFN-γ , TNF-α, and IL-12 [27]. Th2 cytokines, particularly IL-4 and IL-10, promote differentiation of TGF-β1 producing cells from naive T cells. Thus, TGF-β1 is one of the molecules that terminates immune responses [28]. The balance between proinflammatory cytokines (e.g., IL-1β, IL-6, TNF-α) and antiinflammatory cytokines (e.g., IL-1 receptor antagonist, IL-4, IL-10, TGF-β) can play a pivotal role in the magnitude of neurological and psychiatric manifestations, as well as neuroimmunological and neuroinflammatory responses [29]. 1. Monocytic Cytokines Proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, are proteins created and released by monocytes and other immune cells in response to infection, inflammation, tissue damage, or physical or psychological stress. These

cytokines have long been recognized as key mediators of immune-to-brain communication and have an important role in responses in fever, such as decreased food intake, increased sleep, and increased pain sensitivity. There are many research studies that indicate that the monocytic arm of CMI may be activated in schizophrenia. These studies include the following findings on patients with schizophrenia: (1) more monocytes in peripheral blood [30] and more macrophages in CSF [31] during acute psychotic episodes; (2) higher plasma levels of IL-6 [32-37], and higher levels of soluble IL-6 receptor (sIL-6R) in plasma and CSF [36,38,39]; (3) higher levels of IL-1β in plasma [40-42] and in PBMC [41,43]; (4) higher levels of TNF-α in PBMC [41] and in serum [42,44]; (5) higher serum levels of IL-18 [45]; (6) higher IL-1 receptor antagonist IL-1RA [46,47] ; (7) higher plasma levels of IL-8, a chemokine cytokine produced by monocytes, macrophages, endothelial cells, and activated T cells [48,49]; and (8) higher plasma concentrations of acute phase proteins or reactants, such as haptoglobin, alpha-1-acid glycoprotein, and alpha-1antitrypsin, fibrinogen, C3 and C4 complement proteins, and hemopexin [50,51]. It should be stressed, however, that some studies have detected no alteration of IL-1β, IL-6, and TNF-α in blood [52,53] or in CSF [54,55] of patients with schizophrenia. 2. Th1 Cytokines Schizophrenia is accompanied by signs of suppression or activation of the Th1 arm of CMI. Evidence supporting a

Cytokines and Schizophrenia

decrease of Th1 function in schizophrenia includes the following findings in patients with schizophrenia: (1) lower mitogen-stimulated IL-2 production [56-61] and lower IL-2 serum level [42]; (2) less production of IFN-γ [60]; (3) less mitogen-induced lymphocyte proliferation [62]; (4) fewer total T and T helper cells [63]; and (5) fewer IL-2 secreting cells and CD4+ cells [61]. In contrast, there are some studies that indicate that Th1 function is activated in schizophrenia. Studies supporting this view have made the following findings in patients with schizophrenia: (1) higher production of IL-2 and IFN-γ [6467]; (2) higher concentrations of IL-2 in plasma [5,48,59] and in CSF [68,69]; (3) higher serum concentrations of soluble IL-2 receptor(sIL-2R) [46,70,71]; (4) more activated lymphocytes in CSF [72]; and (5) more CD4+ T cells in blood [42]. However, some studies did not find any significant changes in IL-2, IFN-γ and IL-2 receptor [66,73,74]. Some of the contradictory findings regarding Th1 cytokines may be explained by other findings. (1) Increased serum sIL-2R levels may compete with IL-2 for binding to cellular IL-2Rs [75]. (2) Intrinsic differences in schizophrenic patients’ T cells or their decreased number of T cells decrease IL-2 production in vitro [56,61]. (3) The exhaustion theory holds that the hyporesponsiveness of peripheral blood mononuclear cells and decreased in vitro production of Th1 cytokines are caused by an overproduction of cytokines such as IL-2, in vivo. The overproduction of cytokines renders the immune cells refractory to antigenic stimulation. In this regard, Kim et al. [59] found, in the same group of schizophrenic patients, a significant increase in IL-2 serum concentrations and a significant decrease in the stimulated in vitro production of IL-2. 3. Th2 Cytokines Some studies suggest that Th2 functions may be increased in schizophrenia. These findings include the following: (1) an increase in IL-4 in CSF in juvenile schizophrenia [76]; (2) increased IL-10 plasma levels in treatment-resistant schizophrenia [49]; (3) increased mitogenstimulated IL-10 production in chronic schizophrenia [77]. However, two studies found no differences in IL-10 between patients and controls [64,65]. 4. Th3 Cytokines Regarding the Th3 cytokines in schizophrenia, no data are available yet. In a recent unpublished study, we found that the plasma levels of TGF-β1 in schizophrenic patients were higher than normal controls [78]. Moreover, antipsychotic treatment normalized TGF-β1 levels in the schizophrenic patients [78]. 5. Effects of Antipsychotic Drugs on Cytokines Typical antipsychotic drugs such as haloperidol or perazine decrease monocytic cytokines (IL-1β, IL-6, or TNFα) in schizophrenic patients [33,38,41,79]. An animal experiment revealed that haloperidol significantly inhibits the stimulated production of IL-1β and TNF-α in a dosedependent manner [80]. In contrast, repeated administration


3

in vivo of atypical antipsychotics (i.e., clozapine or risperidone), significantly increases the plasma concentrations of IL-6 and TNF-α [33,79,81]. Short-term treatment with clozapine (median=12 days) increases the plasma concentrations of IL-6 [79], whereas prolonged treatment with antipsychotic agents significantly decreases IL-6R concentrations [38,82]. In vitro, clozapine and haloperidol significantly increase the production of IL-1RA, which may antagonize the activities of IL-1 [83]. In vivo, repeated administration of atypical antipsychotics (clozapine or risperidone) significantly increases the plasma concentrations of IL-2R [33,79,81,82]. Since one biological function of sIL-2R is to inhibit the effects of IL-2 by binding this cytokine [84] and since sIL-6R forms an immunostimulating complex with IL-6, the net result of the increase of sIL-2R and the decrease of sIL-6R by antipsychotic treatments may reflect a functional downregulation of these activating cytokines. Clozapine and haloperidol significantly suppress the production of IL-2 and IFN-γ in vitro [83,85] and of IL-2 in vivo [5]. Risperidone is associated with decreased IFN-γ production in schizophrenia [67]. However, Song et al. [83] found that clozapine significantly increases the stimulated production of IFN-γ . In contrast, chlorpromazine upregulates the secretion of IL-10 in mice [86,87]. Risperidone is associated with augmented IL-10 in schizophrenia [67]. Atypical antipsychotics enhance the production of leukemia inhibitory factor receptor (LIF-R), which increases anti-inflammatory capacity in treatment-resistant schizophrenia [49]. Taken together, these findings support the following conclusions: (1) Typical antipsychotic agents have immunosuppressive activities through stimulation of the production of the IL-1RA and IL-10 and suppression of the production of pro-inflammatory cytokines, such as IL-6 and TNF-α. (2) Repeated administration of atypical antipsychotics has immunosuppressive effects by stimulating production of the IL-1RA and IL-2R. (3) Shortterm treatment with clozapine induces the production of proinflammatory cytokines such as IL-6, IFN-γ and TNF-α, an effect that disappears upon prolonged treatment. In this context, anti-inflammatory drugs and cytokine antagonists may have a potential therapeutic effect on schizophrenia [88,89]. CYTOKINES, NEURODEVELOPMENT, GENES IN SCHIZOPHRENIA

AND

Schizophrenia may be related to a defect in brain development, perhaps during the second half of gestation [90]. This view has been supported by brain imaging and post-mortem neuropathological findings indicating a failure of normal neuronal development such as neurogenesis, neuronal proliferation, neural differentiation, migration, and synaptogenesis in schizophrenia [91,92]. Moreover, such defects predispose to a characteristic pattern of brain malfunction in early adult life and to symptoms in response to antidopaminergic drugs [18]. Although the reasons for the neurodevelopmental error in schizophrenia are not readily apparent, epidemiological studies suggest that environmental factors such as prenatal viral infections or birth trauma are significant risk factors for schizophrenia [93].

4


Yong-Ku Kim

Cytokines also regulate synaptic proteins and structural molecules in the schizophrenic brain [10]. A recent animal study demonstrated that pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α produce dose-dependent decreases in the number of neurons immunoreactive for MAP2, which influences dendrite morphology [94]. This finding suggests that cytokines have a role in the modulation of neuronal survival during neurodevelopment. In addition, it was reported that IL-1β, IL-6, and TNF-α affect developing monoamine neurons such as tyrosine hydroxylase and 5-HT neurons [15]. Moreover, a recent study showed that the spatial learning and memory impairment in IL-2 knockout mice was accompanied by reductions in hippocampal infrapyramidal mossy neuronal fiber length, a factor that correlates positively with spatial learning ability, suggesting that IL-2 also plays a role in the development and regulation of brain neurons involved in spatial learning and memory [95]. Maternal viral infection is one of the ways that cytokines could perturb brain development. Maternal infection can alter pro-inflammatory cytokine levels in the fetal environment, which may have a significant impact on the developing brain [96]. Maternal infection with human influenza virus alters expression of reelin in the developing mouse brain, an important secretory protein responsible for normal lamination of the brain [97]. Such observations indicate the potential contribution of cytokines to neurodevelopmental etiology of schizophrenia. Genetic factors have also been implicated in the pathogenesis of schizophrenia and a multifocal, polygenetic etiology is considered most likely [98]. Since the majority of individuals exposed to neurodevelopmental insults such as infections or brain injury do not develop schizophrenia in adulthood, it is possible that a genetic vulnerability to neuronal injury contributes to the expression of schizophrenia. Interestingly, specific cytokine polymorphisms differentially modulate cytokine-mediated neuronal injury, and may represent susceptibility genes for development of schizophrenia following viral infection or brain injury during neurodevelopment [94]. The TNF-α gene is located on the short arm of chromosome 6, a locus associated with susceptibility to schizophrenia. A recent study indicated that a TNF-α polymorphism (-G308A) was significantly more frequent in schizophrenia patients as compared with controls [99]. Moreover, TNF-α receptor II can modify phenotypic aspects of the disease such as brain morphology and the age of onset of the illness [100]. The number of carriers of certain alleles of IL-1β (-511; allele 1), IL-1α (-889; allele 2), and IL-1RA (allele 1) is significantly higher among schizophrenia patients than among controls [101]. Given the fact that genetic mutations could predispose a fetus to a higher risk from environmental factors such as infection or anoxia [102], the interaction of cytokine genes and environmental factors may largely determine the risk for schizophrenia. CYTOKINES AND NEUROTRANSMITTERS SCHIZOPHRENIC PSYCHOPATHOLOGY

IN

Abnormal brain dopamine activity has been suggested to be the main neurotransmitter abnormality causing schizophrenia, but there has been much criticism and

qualification of this idea [103]. Recently, another neurotransmitter, serotonin, has generated much interest in schizophrenia research. Many atypical antipsychotic drugs such as clozapine have been shown to exert potent serotoninrelated activity [104]. Moreover, dopamine and serotonin play a major role in mediating the psychotic symptoms of schizophrenia [105]. There is some evidence that a functional link exists between IL-2, central dopaminergic transmission, and positive symptoms such as delusion or hallucination. Zalcman et al. (1994) demonstrated in mice that dopamine turnover in the prefrontal cortex is altered following an intraperitoneal injection of IL-2. Also, IL-2 induces behavioral changes that are associated with alterations in central dopaminergic processes. In a recent animal study, IL2 treatment increased climbing behavior related to an increase of dopaminergic activity, and this activity could be blocked by selective dopamine D1 and D2 receptor antagonists [106]. Furthermore, IL-2 appears play a role in the pathogenesis of schizophrenia since levels are elevated in CSF and plasma in neuroleptic-free patients [5,68]. Increased CSF levels of IL-2 predict the expression of psychotic symptoms [69]. Moreover, there is further evidence that plasma levels of IL-2 as well as the dopaminergic metabolite homovanillic acid are increased coincident with the positive symptoms, and significantly decreased following treatment with haloperidol [5]. Conversely, IL-6 levels are associated with both negative symptoms [5] and duration of illness [5,34,107]. These reports raise the question of whether the elevated plasma IL-6 in schizophrenia might occur in response to the development of cerebral atrophy, which has been reported to be related to the duration of illness [108]. Moreover, structural brain abnormalities have been considered as a possible pathogenesis of negative symptoms [109]. Therefore, IL-6 may be associated with negative symptoms. Cytokines are known to influence central monoamine activity in a cytokine-specific manner [110,111]. In other words, IL-2 increases hypothalamic and hippocampal norepinephrine utilization and dopamine turnover in the prefrontal cortex, whereas IL-6 induces profound elevation of serotonin and mesocortical dopamine activity in the hippocampus and prefrontal cortex. IL-1, in contrast, induces a wide range of central monoamine alterations. Hence, it will be of great interest to determine which cytokines could be related to specific schizophrenic symptoms and neurotransmitters. CYTOKINES AND SCHIZOPHRENIA

NEURODEGENERATION

IN

The view that schizophrenia is a neurodegenerative disorder is supported by several pieces of clinical evidence: the progressive deteriorating course of the disease, the long latency period, and the apparent ability of treatment to modify the course of the illness [16]. However, casting doubt on this hypothesis is the lack of progressive structural alteration and the absence of astrogliosis in the brains of schizophrenic patients; these traits would be expected for a severe and chronic neurodegenerative process [112,113]. Nonetheless, it was recently demonstrated that activated microglial cells are observed in a subset of schizophrenia patients [114,115]. Microglial activation is a key factor in



5

defending the neural parenchyma against infectious diseases, inflammation, and neurodegeneration [116].

PRESENT LIMITATIONS AND PERSPECTIVES IN CYTOKINE RESEARCH IN SCHIZOPHRENIA

Cytokines can be mediators or inhibitors of neurodegeneration. For example, TGF-β seems to exert primarily neuroprotective actions, while TNF-α contributes to neuronal injury and exerts protective effects [117]. Recently, the link between cytokines and serotonergic turnover has been explored. It was reported that cytokines such as IL-1β, IL-2 and IFN-„ reduce the production of 5-HT by stimulating the activity of indoleamine 2,3 dioxygenase (IDO), an enzyme which converts tryptophan, the precursor of 5-HT, to kynurenine [118,119]. The kynurenine is again metabolized [120] into quinolinic acid and kynurenic acid. Quinolinic acid is the excitotoxic NMDA receptor agonist [121], and kynurenine is the antagonist of all three ionotropic excitatory amino acid receptors [122]. Therefore, it has been proposed that overexpression of IDO leads to the depletion of plasma tryptophan and reduced synthesis of 5HT in the brain of depressive patients [123]. The cytokineserotonin interaction that leads to a challenge between neurodegenerative quinolinate and neuroprotective kynurenate in the brain may also explain the neurodegeneration in schizophrenia (Fig. 2). In agreement with these ideas, recent studies have shown elevated levels of kynurenic acid in the CSF [124] and in the cortical brain tissue of schizophrenic patients [125]. More recently, an animal study demonstrated that the increase in endogenous kynurenic acid levels produces significant actions on the tonic afferent control of the firing pattern of rat ventral tegmental dopamine neurons. This result suggests that the elevated levels of kynurenic acid in schizophrenia may induce hyperactivity of the mesocorticolimbic dopamine system [126]. Therefore, the involvement of the interactions between cytokines, the tryptophan degradation pathway, and neurodegeneration in schizophrenia need further exploration.

The first limitation in current cytokine research in schizophrenia is inconsistent replications of laboratory findings, particularly measurements of cytokines. The results in this field are heterogeneous and often contradictory. The inconsistency of the results is due to several important factors: (1) variability of methodology such as differences in the assay or stimulation procedure, (2) heterogeneity of experimental parameters such as the number of patients, diagnostic characterizations, or treatment status, (3) insufficient control of putative confounding factors such as age, gender, body mass index, smoking, and ongoing or recent infectious disease [5,74,127-130], and (4) lack of definition, at the biochemical level, of subgroups within patients diagnosed with schizophrenia. It is worthwhile to note that not all schizophrenic patients have cytokine abnormalities. It is obvious that such immune abnormalities occur only in a subgroup of schizophrenic patients. Previously, we found that there is a subgroup of schizophrenic patients who have markedly elevated IL-2 and IL-12 levels while others have normal levels, indicating a considerable heterogeneity in cytokine abnormalities [5,131]. There is some evidence that the alterations in cytokines or cytokine abnormalities are more pronounced in treatmentresistant schizophrenic patients. Lin et al. [36] found that serum IL-6 was significantly higher in schizophrenic patients suffering from treatment-resistant schizophrenia than in normal volunteers, whereas no significant differences were detected in treatment-responsive patients and normal controls. In this regard, it will be of great interest to further explore the subgroup of schizophrenia patients showing the immune alterations. In addition, considering the fact that most studies are concerned with a single measurement or cross sectional measure, a longitudinal study is necessary to

Fig. (2). The role of cytokines in neurodegeneration in schizophrenia in relation to the serotonin degradation pathway. Cytokines activate trpytophan degradation pathway by the stimulating the activity of indoleamine 2,3 dioxygenase (IDO) enzyme which convert tryptophan to kynurenine. The balance between neurodegenerative quinolinate and neuroprotective kynurenate can lead to the neurodegeneration in schizophrenia.

6


confirm whether cytokine levels would be altered depending on the patient’s clinical status such as acute, subacute, or remission. The second limitation is a lack of specificity in cytokine changes. For instance, elevated levels of IL-6 and its soluble receptors have been observed in patients with schizophrenia, major depression, mania, and post-traumatic stress disorder. These findings call into question the usefulness of correlating biological variables with disease entities that are exclusively defined by clinical criteria. Third, our knowledge about the role of cytokines in human brain activity in schizophrenia is still in its infancy. So far, cytokine studies in schizophrenia have mainly focused on peripheral cytokines. However, it has been postulated that the central cytokine system and peripheral cytokine systems are differently regulated [6]. In addition, an impairment of the blood-brain barrier in schizophrenia has been reported [132]. Thus, further studies of the brain cytokine network in schizophrenia will be very important in understanding further immunological mechanisms in the etiology and pathogenesis of schizophrenia. Fourth, the role of cytokines in psychological stress should be investigated. In schizophrenia, the impact of stressful life events or expressed emotions on psychotic decompensation and relapse frequency has been well established [20]. Although the assumption that stress is involved in the acute onset of schizophrenia is far less clear, schizophrenic patients are impaired in their biological response to stress by showing blunted cortisol responses to psychological stress [133]. This finding supports the notion that schizophrenic patients have an impaired ability to adapt, both psychologically and biologically, to their environment. Stress influences many aspects of the central nervous system, the immune system, and the endocrine system. In fact, these three systems are so closely linked that they can be considered as a single network [134,135]. The relationship between cytokine alterations and psychological stress in schizophrenia should be explored in more detail. CONCLUSIONS Cytokines may play a role in the pathophysiology of schizophrenia, especially in the stages of neurodevelopment, psychotic decompensation, and neurodegeneration. Maternal viral infection or birth trauma induces a failure of normal neuronal development through dysregulation of the cytokine network. Specific cytokine polymorphisms may represent susceptibility genes for development of schizophrenia following the insult during neurodevelopment. Cytokines also influence central monoamine activity in a cytokinespecific manner, and this activity modulates psychotic symptoms in schizophrenia. Cytokines are mediators and inhibitors of neurodegeneration. It has been proposed that the interaction between cytokines and the tryptophan degradation pathway through IDO is involved in neurodegeneration in schizophrenia. Current cytokine studies in schizophrenia have several limitations including inconsistent results, lack of specificity, and insufficient data on brain cytokines and the effect of stress on cytokines. Therefore, more studies using appropriate designs should be undertaken.

Yong-Ku Kim

ACKNOWLEDGEMENTS This study was supported by a grant of the Korea Health 21 R&D Project, Minister of Health & Welfare, Republic of Korea. (0405-NS01-0704-0001) ABBREVIATIONS CMI

= Cell-mediated immunity

CNS

= Central nervous system

CSF

= Cerebrospinal fluid

IDO

= Indoleamine 2,3 dioxygenase

IFN

= Interferon

IL

= Interleukin

PBMC

= Peripheral blood mononuclear cells

IL-1RA = IL-1 receptor antagonist LIF

= Leukemia inhibitory factor

PNS

= Peripheral nervous system

sIL-2R

= Soluble interleukin-2 receptor

sIL-6R

= Soluble interleukin-6 receptor

TGF

= Transforming growth factor

TNF

= Tumor necrosis factor

Th1

= T helper 1 cell

Th2

= T helper 2 cell

REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]

Smith RS. Is schizophrenia caused by excessive production of interleukin-2 and interleukin-2 receptors by gastrointestinal lymphocytes? Med Hypotheses 1991; 34: 225-9. Smith RS. A comprehensive macrophage-T-lymphocyte theory of schizophrenia. Med Hypotheses 1992; 39: 248-57. Muller N, Riedel M, Ackenheil M, et al. The role of immune function in schizophrenia: an overview. Eur Arch Psychiatry Clin Neurosci 1999; 249 Suppl 4: 62-8. Maes M. Cytokines in schizophrenia. Biol Psychiatry 1997; 42: 308-9. Kim YK, Kim L and Lee MS. Relationships between interleukins, neurotransmitters and psychopathology in drug-free male schizophrenics. Schizophr Res 2000; 44: 165-75. Szelenyi J. Cytokines and the central nervous system. Brain Res Bull 2001; 54: 329-38. Fernandez-Botran R. Soluble cytokine receptors: basic immunology and clinical applications. Crit Rev Clin Lab Sci 1999; 36: 165-224. Allan SM. The role of pro- and antiinflammatory cytokines in neurodegeneration. Ann N Y Acad Sci 2000; 917: 84-93. Rothwell NJ, Luheshi G and Toulmond S. Cytokines and their receptors in the central nervous system: physiology, pharmacology, and pathology. Pharmacol Ther 1996; 69: 85-95. Nawa H, Takahashi M and Patterson PH. Cytokine and growth factor involvement in schizophrenia--support for the developmental model. Mol Psychiatry 2000; 5: 594-603. Rothwell NJ and Strijbos PJ. Cytokines in neurodegeneration and repair. Int J Dev Neurosci 1995; 13: 179-85. Gaillard RC, Spinedi E, Chautard T, et al. Cytokines, leptin, and the hypothalamo-pituitary-adrenal axis. Ann N Y Acad Sci 2000; 917: 647-57. Barkhudaryan N and Dunn AJ. Molecular mechanisms of actions of interleukin-6 on the brain, with special reference to serotonin


[14]

[15] [16] [17] [18] [19] [20] [21]

[22] [23] [24] [25] [26] [27]

[28] [29] [30]

[31] [32] [33] [34] [35] [36] [37] [38]

and the hypothalamo-pituitary-adrenocortical axis. Neurochem Res 1999; 24: 1169-80. Ignatowski TA, Noble BK, Wright JR, et al. Neuronal-associated tumor necrosis factor (TNF alpha): its role in noradrenergic functioning and modification of its expression following antidepressant drug administration. J Neuroimmunol 1997; 79: 8490. Jarskog LF, Xiao H, Wilkie MB, et al. Cytokine regulation of embryonic rat dopamine and serotonin neuronal survival in vitro. Int J Dev Neurosci 1997; 15: 711-6. Keshavan MS. Development, disease and degeneration in schizophrenia: a unitary pathophysiological model. J Psychiatr Res 1999; 33: 513-21. Bayer TA, Falkai P and Maier W. Genetic and non-genetic vulnerability factors in schizophrenia: the basis of the "two hit hypothesis". J Psychiatr Res 1999; 33: 543-8. Weinberger DR. On the plausibility of "the neurodevelopmental hypothesis" of schizophrenia. Neuropsychopharmacology 1996; 14: 1S-11S. Mirnics K, Middleton FA, Lewis DA, et al. Analysis of complex brain disorders with gene expression microarrays: schizophrenia as a disease of the synapse. Trends Neurosci 2001; 24: 479-86. Gispen-de Wied CC. Stress in schizophrenia: an integrative view. Eur J Pharmacol 2000; 405: 375-84. Moore H, West AR and Grace AA. The regulation of forebrain dopamine transmission: relevance to the pathophysiology and psychopathology of schizophrenia. Biol Psychiatry 1999; 46: 4055. Iqbal N and van Praag HM. The role of serotonin in schizophrenia. Eur Neuropsychopharmacol 1995; 5 Suppl: 11-23. Olney JW, Newcomer JW and Farber NB. NMDA receptor hypofunction model of schizophrenia. J Psychiatr Res 1999; 33: 523-33. Duncan GE, Sheitman BB and Lieberman JA. An integrated view of pathophysiological models of schizophrenia. Brain Res Brain Res Rev 1999; 29: 250-64. Coyle JT. The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 1996; 3: 241-53. Mosmann TR and Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today 1996; 17: 138-46. Schmitt E, Hoehn P, Huels C, et al. T helper type 1 development of naive CD4+ T cells requires the coordinate action of interleukin-12 and interferon-gamma and is inhibited by transforming growth factor-beta. Eur J Immunol 1994; 24: 793-8. Prud'homme GJ and Piccirillo CA. The inhibitory effects of transforming growth factor-beta-1 (TGF-beta1) in autoimmune diseases. J Autoimmun 2000; 14: 23-42. Plata-Salaman C and Turrin N. Cytokine interactions and cytokine balance in the brain: relevance to neurology and psychiatry. Mol Psychiatry 1999; 4: 302-6. Wilke I, Arolt V, Rothermundt M, et al. Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients. Eur Arch Psychiatry Clin Neurosci 1996; 246: 279-84. Nikkila HV, Muller K, Ahokas A, et al. Accumulation of macrophages in the CSF of schizophrenic patients during acute psychotic episodes. Am J Psychiatry 1999; 156: 1725-9. Shintani F, Kanba S, Maruo N, et al. Serum interleukin-6 in schizophrenic patients. Life Sci 1991; 49: 661-4. Maes M, Meltzer HY and Bosmans E. Immune-inflammatory markers in schizophrenia: comparison to normal controls and effects of clozapine. Acta Psychiatr Scand 1994; 89: 346-51. Ganguli R, Yang Z, Shurin G, et al. Serum interleukin-6 concentration in schizophrenia: elevation associated with duration of illness. Psychiatry Res 1994; 51: 1-10. Naudin J, Mege JL, Azorin JM, et al. Elevated circulating levels of IL-6 in schizophrenia. Schizophr Res 1996; 20: 269-73. Lin A, Kenis G, Bignotti S, et al. The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6. Schizophr Res 1998; 32: 9-15. van Kammen DP, McAllister-Sistilli CG, Kelley ME, et al. Elevated interleukin-6 in schizophrenia. Psychiatry Res 1999; 87: 129-36. Maes M, Bosmans E, Calabrese J, et al. Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. J Psychiatr Res 1995; 29: 141-52.

Current Psychiatry Reviews, 2005, Vol. 1, No. 2 [39]

[40]

[41]

[42]

[43] [44]

[45] [46] [47]

[48]

[49]

[50] [51] [52]

[53] [54] [55]

[56] [57]

[58] [59] [60]

7

Muller N, Dobmeier P, Empel M, Riedel M, Schwarz M, Ackenheil M. soluble IL-6 receptors in the serum and cerebrospinal fluid of paranoid schizophrenic patients. Eur Psychiatry 1997; 12: 294-99. Katila H, Appelberg B, Hurme M, et al. Plasma levels of interleukin-1 beta and interleukin-6 in schizophrenia, other psychoses, and affective disorders. Schizophr Res 1994; 12: 2934. Kowalski J, Blada P, Kucia K, et al. Neuroleptics normalize increased release of interleukin- 1 beta and tumor necrosis factor-alpha from monocytes in schizophrenia. Schizophr Res 2001; 50: 169-75. Theodoropoulou S, Spanakos G, Baxevanis CN, et al. Cytokine serum levels, autologous mixed lymphocyte reaction and surface marker analysis in never medicated and chronically medicated schizophrenic patients. Schizophr Res 2001; 47: 13-25. Sirota P, Schild K, Elizur A, et al. Increased interleukin-1 and interleukin-3 like activity in schizophrenic patients. Prog Neuropsychopharmacol Biol Psychiatry 1995; 19: 75-83. Monteleone P, Fabrazzo M, Tortorella A, et al. Plasma levels of interleukin-6 and tumor necrosis factor alpha in chronic schizophrenia: effects of clozapine treatment. Psychiatry Res 1997; 71: 11-7. Tanaka KF, Shintani F, Fujii Y, et al. Serum interleukin-18 levels are elevated in schizophrenia. Psychiatry Res 2000; 96: 75-80. Akiyama K. Serum levels of soluble IL-2 receptor alpha, IL-6 and IL-1 receptor antagonist in schizophrenia before and during neuroleptic administration. Schizophr Res 1999; 37: 97-106. Maes M, Bosmans E, Ranjan R, et al. Lower plasma CC16, a natural anti-inflammatory protein, and increased plasma interleukin-1 receptor antagonist in schizophrenia: effects of antipsychotic drugs. Schizophr Res 1996; 21: 39-50. Zhang XY, Zhou DF, Zhang PY, et al. Elevated interleukin-2, interleukin-6 and interleukin-8 serum levels in neuroleptic-free schizophrenia: association with psychopathology. Schizophr Res 2002; 57: 247-58. Maes M, Bocchio Chiavetto L, Bignotti S, et al. Increased serum interleukin-8 and interleukin-10 in schizophrenic patients resistant to treatment with neuroleptics and the stimulatory effects of clozapine on serum leukemia inhibitory factor receptor. Schizophr Res 2002; 54: 281-91. Kim YK, Lee MS, Hahm W, et al. Relationships between acute phase proteins and activities of interleukin-1beta, interleukin-6 in schizophrenic patients. Seoul J Psychiatry 1994; 19: 179-86. Maes M, Delange J, Ranjan R, et al. Acute phase proteins in schizophrenia, mania and major depression: modulation by psychotropic drugs. Psychiatry Res 1997; 66: 1-11. Xu HM, Wei J and Hemmings GP. Changes of plasma concentrations of interleukin-1 alpha and interleukin-6 with neuroleptic treatment for schizophrenia. Br J Psychiatry 1994; 164: 251-3. Baker I, Masserano J and Wyatt RJ. Serum cytokine concentrations in patients with schizophrenia. Schizophr Res 1996; 20: 199-203. Katila H, Hurme M, Wahlbeck K, et al. Plasma and cerebrospinal fluid interleukin-1 beta and interleukin-6 in hospitalized schizophrenic patients. Neuropsychobiology 1994; 30: 20-3. Barak V, Barak Y, Levine J, et al. Changes in interleukin-1 beta and soluble interleukin-2 receptor levels in CSF and serum of schizophrenic patients. J Basic Clin Physiol Pharmacol 1995; 6: 61-9. Villemain F, Chatenoud L, Galinowski A, et al. Aberrant T cellmediated immunity in untreated schizophrenic patients: deficient interleukin-2 production. Am J Psychiatry 1989; 146: 609-16. Ganguli R, Brar JS, Chengappa KR, et al. Mitogen-stimulated interleukin-2 production in never-medicated, first-episode schizophrenic patients. The influence of age at onset and negative symptoms. Arch Gen Psychiatry 1995; 52: 668-72. Hornberg M, Arolt V, Wilke I, et al. Production of interferons and lymphokines in leukocyte cultures of patients with schizophrenia. Schizophr Res 1995; 15: 237-42. Kim YK, Lee MS and Suh KY. Decreased interleukin-2 production in Korean schizophrenic patients. Biol Psychiatry 1998; 43: 701-4. Arolt V, Rothermundt M, Wandinger KP, et al. Decreased in vitro production of interferon-gamma and interleukin-2 in whole blood

8


[61]

[62]

[63] [64] [65] [66]

[67]

[68] [69]

[70] [71] [72] [73]

[74]

[75] [76] [77]

[78] [79] [80] [81] [82]

of patients with schizophrenia during treatment. Mol Psychiatry 2000; 5: 150-8. Zhang XY, Zhou DF, Cao LY, et al. Decreased production of interleukin-2 (IL-2), IL-2 secreting cells and CD4+ cells in medication-free patients with schizophrenia. J Psychiatr Res 2002; 36: 331-6. Chengappa KN, Ganguli R, Yang ZW, et al. Impaired mitogen (PHA) responsiveness and increased autoantibodies in Caucasian schizophrenic patients with the HLA B8/DR3 phenotype. Biol Psychiatry 1995; 37: 546-9. Muller N, Hofschuster E, Ackenheil M, et al. T-cells and psychopathology in schizophrenia: relationship to the outcome of neuroleptic therapy. Acta Psychiatr Scand 1993; 87: 66-71. Rothermundt M, Arolt V, Weitzsch C, et al. Immunological dysfunction in schizophrenia: a systematic approach. Neuropsychobiology 1998; 37: 186-93. Cazzullo CL, Sacchetti E, Galluzzo A, et al. Cytokine profiles in drug-naive schizophrenic patients. Schizophr Res 2001; 47: 293-8. O'Donnell MC, Catts SV, Ward PB, et al. Increased production of interleukin-2 (IL-2) but not soluble interleukin-2 receptors (sIL2R) in unmedicated patients with schizophrenia and schizophreniform disorder. Psychiatry Res 1996; 65: 171-8. Cazzullo CL, Sacchetti E, Galluzzo A, et al. Cytokine profiles in schizophrenic patients treated with risperidone: a 3-month followup study. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 33-9. Licinio J, Seibyl JP, Altemus M, et al. Elevated CSF levels of interleukin-2 in neuroleptic-free schizophrenic patients. Am J Psychiatry 1993; 150: 1408-10. McAllister CG, van Kammen DP, Rehn TJ, et al. Increases in CSF levels of interleukin-2 in schizophrenia: effects of recurrence of psychosis and medication status. Am J Psychiatry 1995; 152: 12917. Maes M, Meltzer HY, Buckley P, et al. Plasma-soluble interleukin-2 and transferrin receptor in schizophrenia and major depression. Eur Arch Psychiatry Clin Neurosci 1995; 244: 325-9. Gaughran F, O'Neill E, Cole M, et al. Increased soluble interleukin 2 receptor levels in schizophrenia. Schizophr Res 1998; 29: 263-7. Nikkila HV, Muller K, Ahokas A, et al. Increased frequency of activated lymphocytes in the cerebrospinal fluid of patients with acute schizophrenia. Schizophr Res 2001; 49: 99-105. Gattaz WF, Dalgalarrondo P and Schroder HC. Abnormalities in serum concentrations of interleukin-2, interferon-alpha and interferon-gamma in schizophrenia not detected. Schizophr Res 1992; 6: 237-41. Haack M, Hinze-Selch D, Fenzel T, et al. Plasma levels of cytokines and soluble cytokine receptors in psychiatric patients upon hospital admission: effects of confounding factors and diagnosis. J Psychiatr Res 1999; 33: 407-18. Caruso C, Candore G, Cigna D, et al. Biological significance of soluble IL-2 receptor. Med Inflamm 1993; 2: 3-21. Mittleman BB, Castellanos FX, Jacobsen LK, et al. Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. J Immunol 1997; 159: 2994-9. Cazzullo CL, Scarone S, Grassi B, et al. Cytokines production in chronic schizophrenia patients with or without paranoid behaviour. Prog Neuropsychopharmacol Biol Psychiatry 1998; 22: 947-57. Kim YK, Myint AM, Lee BH et al. Th1, Th2, and Th3 cytokine alterations in schizophrenia. Prog Psychopharmacol Biol Psychiatry 2004 (in press). Maes M, Bosmans E, Kenis G, et al. In vivo immunomodulatory effects of clozapine in schizophrenia. Schizophr Res 1997; 26: 221-5. Moots RJ, Al-Saffar Z, Hutchinson D, et al. Old drug, new tricks: haloperidol inhibits secretion of proinflammatory cytokines. Ann Rheum Dis 1999; 58: 585-7. Pollmacher T, Hinze-Selch D and Mullington J. Effects of clozapine on plasma cytokine and soluble cytokine receptor levels. J Clin Psychopharmacol 1996; 16: 403-9. Muller N, Empl M, Riedel M, et al. Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia. Eur Arch Psychiatry Clin Neurosci 1997; 247: 308-13.

Yong-Ku Kim [83] [84] [85] [86]

[87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97]

[98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108]

Song C, Lin A, Kenis G, et al. Immunosuppressive effects of clozapine and haloperidol: enhanced production of the interleukin-1 receptor antagonist. Schizophr Res 2000; 42: 157-64. Damle RN, Advani SH and Gangal SG. Analysis of regulation of T-cell responses by soluble inhibitory factors from the sera of patients with Hodgkin's disease. Int J Cancer 1992; 50: 192-6. Leykin I, Mayer R and Shinitzky M. Short and long-term immunosuppressive effects of clozapine and haloperidol. Immunopharmacology 1997; 37: 75-86. Mengozzi M, Fantuzzi G, Faggioni R, et al. Chlorpromazine specifically inhibits peripheral and brain TNF production, and upregulates IL-10 production, in mice. Immunology 1994; 82: 20710. Tarazona R, Gonzalez-Garcia A, Zamzami N, et al. Chlorpromazine amplifies macrophage-dependent IL-10 production in vivo. J Immunol 1995; 154: 861-70. Muller N, Riedel M, Scheppach C, et al. Beneficial antipsychotic effects of celecoxib add-on therapy compared to risperidone alone in schizophrenia. Am J Psychiatry 2002; 159: 1029-34. Desta M, Tadesse A, Gebre N, et al. Controlled trial of hydroxychloroquine in schizophrenia. J Clin Psychopharmacol 2002; 22: 507-10. Weinberger DR. Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry 1987; 44: 660-9. Harrison PJ. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 1999; 122 ( Pt 4): 593-624. Waddington JL. Schizophrenia: developmental neuroscience and pathobiology. Lancet 1993; 341: 531-6. Gilmore JH and Jarskog LF. Exposure to infection and brain development: cytokines in the pathogenesis of schizophrenia. Schizophr Res 1997; 24: 365-7. Marx CE, Jarskog LF, Lauder JM, et al. Cytokine effects on cortical neuron MAP-2 immunoreactivity: implications for schizophrenia. Biol Psychiatry 2001; 50: 743-9. Petitto JM, McNamara RK, Gendreau PL, et al. Impaired learning and memory and altered hippocampal neurodevelopment resulting from interleukin-2 gene deletion. J Neurosci Res 1999; 56: 441-6. Urakubo A, Jarskog LF, Lieberman JA, et al. Prenatal exposure to maternal infection alters cytokine expression in the placenta, amniotic fluid, and fetal brain. Schizophr Res 2001; 47: 27-36. Fatemi SH, Emamian ES, Kist D, et al. Defective corticogenesis and reduction in Reelin immunoreactivity in cortex and hippocampus of prenatally infected neonatal mice. Mol Psychiatry 1999; 4: 145-54. Prasad S, Semwal P, Deshpande S, et al. Molecular genetics of schizophrenia: past, present and future. J Biosci 2002; 27: 35-52. Boin F, Zanardini R, Pioli R, et al. Association between -G308A tumor necrosis factor alpha gene polymorphism and schizophrenia. Mol Psychiatry 2001; 6: 79-82. Wassink TH, Crowe RR and Andreasen NC. Tumor necrosis factor receptor-II: heritability and effect on brain morphology in schizophrenia. Mol Psychiatry 2000; 5: 678-82. Katila H, Hanninen K and Hurme M. Polymorphisms of the interleukin-1 gene complex in schizophrenia. Mol Psychiatry 1999; 4: 179-81. Jones P and Murray RM. The genetics of schizophrenia is the genetics of neurodevelopment. Br J Psychiatry 1991; 158: 615-23. Davis KL, Kahn RS, Ko G, et al. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148: 1474-86. Schmidt CJ, Sorensen SM, Kehne JH, et al. The role of 5-HT2A receptors in antipsychotic activity. Life Sci 1995; 56: 2209-22. Lieberman JA and Koreen AR. Neurochemistry and neuroendocrinology of schizophrenia: a selective review. Schizophr Bull 1993; 19: 371-429. Zalcman SS. Interleukin-2-induced increases in climbing behavior: inhibition by dopamine D-1 and D-2 receptor antagonists. Brain Res 2002; 944: 157-64. Naudin J, Capo C, Giusano B, et al. A differential role for interleukin-6 and tumor necrosis factor-alpha in schizophrenia? Schizophr Res 1997; 26: 227-33. Waddington JL. Neurodynamics of abnormalities in cerebral metabolism and structure in schizophrenia. Schizophr Bull 1993; 19: 55-69.

Cytokines and Schizophrenia [109] [110] [111] [112]

[113] [114] [115]

[116] [117] [118]

[119]

[120]

[121]

Crow TJ. Molecular pathology of schizophrenia:more than one disease process. Br. Med. J. 1980; 280, 66-80. Zalcman S, Green-Johnson JM, Murray L, et al. Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6. Brain Res 1994; 643: 40-9. Zalcman S, Murray L, Dyck DG, et al. Interleukin-2 and -6 induce behavioral-activating effects in mice. Brain Res 1998; 811: 111-21. Arnold SE, Trojanowski JQ, Gur RE, et al. Absence of neurodegeneration and neural injury in the cerebral cortex in a sample of elderly patients with schizophrenia. Arch Gen Psychiatry 1998; 55: 225-32. Falkai P, Honer WG, David S, et al. No evidence for astrogliosis in brains of schizophrenic patients. A post-mortem study. Neuropathol Appl Neurobiol 1999; 25: 48-53. Bayer TA, Buslei R, Havas L, et al. Evidence for activation of microglia in patients with psychiatric illnesses. Neurosci Lett 1999; 271: 126-8. Radewicz K, Garey LJ, Gentleman SM, et al. Increase in HLADR immunoreactive microglia in frontal and temporal cortex of chronic schizophrenics. J Neuropathol Exp Neurol 2000; 59: 13750. Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci 1996; 19: 312-8. Allan SM and Rothwell NJ. Cytokines and acute neurodegeneration. Nat Rev Neurosci 2001; 2: 734-44. Guillemin GJ, Kerr SJ, Pemberton LA, et al. IFN-beta1b induces kynurenine pathway metabolism in human macrophages: potential implications for multiple sclerosis treatment. J Interferon Cytokine Res 2001; 21: 1097-101. Sakash JB, Byrne GI, Lichtman A, et al. Cytokines induce indoleamine 2,3-dioxygenase expression in human atheromaasociated cells: implications for persistent Chlamydophila pneumoniae infection. Infect Immun 2002; 70: 3959-61. Dang Y, Dale WE and Brown OR. Comparative effects of oxygen on indoleamine 2,3-dioxygenase and tryptophan 2,3dioxygenase of the kynurenine pathway. Free Radic Biol Med 2000; 28: 615-24. Schwarcz R, Whetsell WO, Jr. and Mangano RM. Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science 1983; 219: 316-8.

Current Psychiatry Reviews, 2005, Vol. 1, No. 2 [122] [123] [124] [125] [126]

[127]

[128] [129] [130]

[131] [132] [133] [134] [135]

9

Perkins MN and Stone TW. An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinolinic acid. Brain Res 1982; 247: 184-7. Myint AM, Kim YK. Cytokine-serotonin interaction through IDO: A neurodegeneration hypothesis of depression. Med Hypotheses 2004; 61: 519-25. Erhardt S, Blennow K, Nordin C, et al. Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett 2001; 313: 96-8. Schwarcz R, Rassoulpour A, Wu HQ, et al. Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 2001; 50: 521-30. Erhardt S and Engberg G. Increased phasic activity of dopaminergic neurones in the rat ventral tegmental area following pharmacologically elevated levels of endogenous kynurenic acid. Acta Physiol Scand 2002; 175: 45-53. De Groote D, Zangerle PF, Gevaert Y, et al. Direct stimulation of cytokines (IL-1 beta, TNF-alpha, IL-6, IL-2, IFN-gamma and GM-CSF) in whole blood. I. Comparison with isolated PBMC stimulation. Cytokine 1992; 4: 239-48. Whicher J and Ingham E. Cytokine measurements in body fluids. Eur Cytokine Netw 1990; 1: 239-43. De Jongh R, Vranken J, Vundelinckx G, et al. The effects of anticoagulation and processing on assays of IL-6, sIL-6R, sIL-2R and soluble transferrin receptor. Cytokine 1997; 9: 696-701. Hinze-Selch D and Pollmacher T. In vitro cytokine secretion in individuals with schizophrenia: results, confounding factors, and implications for further research. Brain Behav Immun 2001; 15: 282-318. Kim YK, Suh IB, Kim H, et al. The plasma levels of interleukin12 in schizophrenia, major depression, and bipolar mania: effects of psychotropic drugs. Mol Psychiatry 2002; 7: 1107-14. Schwarz MJ, Ackenheil M, Riedel M, et al. Blood-cerebrospinal fluid barrier impairment as indicator for an immune process in schizophrenia. Neurosci Lett 1998; 253: 201-3. Jansen LM, Gispen-de Wied CC, Gademan PJ, et al. Blunted cortisol response to a psychosocial stressor in schizophrenia. Schizophr Res 1998; 33: 87-94. Espinosa E and Bermudez-Rattoni F. [Behavior-immunity relationship: the role of cytokines]. Rev Invest Clin 2001; 53: 24053. Kim YK, Maes M. The role of cytokine network in psychological stress. Acta Neuropsychiatrica 2003; 15: 148-55.