MEMBRANE PHOSPHOLIPIDS ANDCYTOKINE INTERACTION IN SCHIZOPHRENIA

Jeffrey K. Yao

VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania 15206Department of Psychiatry, University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania 15213Department of Pharmaceutical Sciences, School of Pharmacy

University of Pittsburgh, Pittsburgh, PA 15213

Daniel P. van Kammen

Aventis, Inc., Bridgewater, New Jersey 08807Department of Psychiatry, University of Pennsylvania

Philadelphia, Pennsylvania 19104Department of Psychiatry, Columbia University

New York, New York 10032

I. Abnormal Membrane Phospholipids

A. Evidence for Membrane Phospholipid Defects

B. Increased Phospholipase Activities

C. Increased Oxidative Stress

D. Physiological Significance of Arachidonic Acid Signaling

II. Disturbed Immune Function

A. An Overactive ‘‘Innate’’ Immune System?

B. The Blunted Th1 System

C. The Activated Th2 System

D. Conflicting Findings

III. Polyunsaturated Fatty Acids and Cytokines

IV. Stress and Immune Response

A. Oxidative Stress

B. Psychological Stress

V. Conclusion

References

Although the potential key role that lipids may have in schizophrenia is

not fully understood, multiple lines of evidence to date implicate the lipid envir-

onment in the behavior of neurotransmitter systems. Decreased phospholipid

polyunsaturated fatty acids (PUFAs) have been demonstrated in both brain

and peripheral membranes in schizophrenia, which is consistent with the hypoth-

esis of myelin-related dysfunction in schizophrenia. Membrane defects, such as

those induced by decreased PUFAs in phospholipids, can significantly alter a

broad range of membrane functions and ipso facto behavior through multiple

‘‘downstream’’ eVects. A number of putative mechanisms have been identified

INTERNATIONAL REVIEW OF 297NEUROBIOLOGY, VOL. 59

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to explain the decreased PUFAs in schizophrenia, notably the increased turnover

of phospholipids and decreased incorporation of arachidonic acid (AA) in mem-

branes. In addition to increased oxidative stress, altered immune function may

also be responsible for increased phospholipase activities. This association is par-

ticularly relevant in relation to phospholipids/PUFA, as AA can be converted to

a variety of biologically active compounds, such as eicosanoids, which serve as

potentmessengers in regulating the inflammatory response, as well as endocannab-

inoids, which may aVect schizophrenic psychopathology. Direct evidence of

immune changes in some patients with schizophrenia have come to light, particu-

larly in the activities of several cytokines known to be altered in autoimmune dys-

function. Given the diverse physiological function of AA, the specific behavioral

symptomatology of schizophrenia is related mostly to the eVect of AA changes that

regulates neurodevelopment, neurotransmitter homeostasis, phosphatidylinositol

signaling, and neuromodulatory actions of endocannabinoids in schizophrenia.

Hence, in the current conceptualization, AA may be at a nexus point in the

cascade leading to the syndrome of schizophrenia and represents a common

biochemical pathway leading to the varied symptomatology of this disorder.

I. Abnormal Membrane Phospholipids

Schizophrenia is a major mental disorder without a clearly identified

pathophysiology. Numerous hypotheses have been proposed over the years to

conceptualize the pathophysiology of schizophrenia, focusing primarily on

neurotransmitter systems. However, one avenue of research that is gaining cur-

rency is the study of membrane composition and function. The membrane is a

complex structure, composed primarily of phospholipids and their constituent

fatty acids, that provides scaVolding for many key functional systems, including

neurotransmitter receptor binding, signal transduction, transmembrane ion

channels, prostanoid synthesis, and mitochondrial electron transport systems.

Thus, the dynamic state of all membranes, including those of neurons and glia,

is dependent on their composition, such that small changes in key phospholipids

or the polyunsaturated fatty acids (PUFAs) that make up phospholipids can lead

to a broad range of membrane dysfunctions. Key PUFAs in phospholipids are the

n-3 (or !3) and n-6 (or !6) series, of which docosahexaenoic acid (DHA, 22:6n-3)

and arachidonic acid (AA, 20:4n-6) are the most abundant in the brain.

A. Evidence for Membrane Phospholipid Defects

A variety of data suggest defects in phospholipid metabolism and cell signal-

ing in schizophrenia. Those findings include (1) decreased PUFAs and altered

phospholipids in plasma (Horrobin et al., 1989), red blood cells (RBC) (Assies

298 YAO AND VAN KAMMEN

et al., 2001; Glen et al., 1994; Keshavan et al., 1993; Peet et al., 1996; Ponizovsky

et al., 2001; Yao et al., 1994a), platelets (Pangterl et al., 1991; Schmitt et al., 2001;

Steudle et al., 1994), skin fibroblasts (Mahadik et al., 1996), and postmortem brain

tissues (Horrobin et al., 1991; Yao et al., 2000); (2) an increased turnover of in vivo

brain phospholipid metabolites detected using 31P magnetic resonance spectros-

copy (MRS) (Fukuzako, 1996; Pettegrew et al., 1991, 1993; Williamson et al.,

1991); (3) a significant correlation between RBC phospholipid PUFAs and31P MRS measures of phospholipid metabolites in the brain (Richardson et al.,

2001; Yao et al., 2002a); (4) increased turnover of inositol phospholipids (Das

et al., 1992; Essali et al., 1990; Yao et al., 1992; Zilberman-Kaufman et al., 1992)

and production of second messengers (Kaiya et al., 1989; Yao et al., 1996); and (5)

increased lipid peroxidation (Akyol et al., 2002; Khan et al., 2002; Mahadik et al.,

1998).

Reduced membrane PUFAs have been linked to the symptom

severity (Glen et al., 1994; Peet et al., 1995; Ponizovsky et al., 2001; Yao et al.,

1994b), development of tardive dyskinesia (Nilsson et al., 1996; Vaddadi et al.,

1989), and reduced niacin-induced cutaneous flushing (Glen et al., 1996;

Horrobin, 1980; Hudson et al., 1995; Messamore et al., 2003; Rybakowski and

Weterle, 1991). Moreover, studies have further demonstrated decreased AA

and DHA levels in the RBC of first-episode, never-medicated patients

(Arvindakshan et al., 2003b; Reddy et al., in press). Taken together, these data sup-

port the notion that molecular changes in membrane phospholipids may be pre-

sent prior to both clinical and biological manifestations of the disorder (Pettegrew

et al., 1993).

B. Increased Phospholipase Activities

A number of putative mechanisms have been identified to explain the de-

creased PUFA levels in schizophrenia (Yao, 2003), notably the increased break-

down of phospholipids and decreased incorporation of AA. Both oxidative

stress and altered immune function may play a role in an induction of phospho-

lipase activities. Phospholipase A2 (PLA2) is a rate-limiting enzyme responsible

for the breakdown of membrane phospholipids (Dawson, 1985). In addition to

being the required step for eicosanoid biosynthesis, PLA2 also plays a pivotal role

in inflammation (Chakraborti, 2003).

1. Phospholipase A2

Increased cytoplasmic PLA2 activity has been found in serum of drug-free

schizophrenic patients (Gattaz et al., 1987, 1990; Noponen et al., 1993). Such

increases in serum PLA2 activity, however, were also found in patients with

other psychiatric disorders (Noponen et al., 1993), raising a question about the

MEMBRANCE PHOSPHOLIPIDS AND CYTOKINE INTERACTION 299

specificity of this finding to schizophrenia. Subsequently, Gattaz et al. (1995)

showed that intracellular membrane-bound PLA2 activity was significantly

higher in platelets of schizophrenia patients than in normal and psychiatric con-

trols, with no significant diVerences between normal and psychiatric controls. It

is thus unlikely that the increased platelet PLA2 activity in schizophrenia results

from nonspecific stressors. However, an attempt to replicate increased PLA2

activity in schizophrenia has led to a conflicting finding (Albers et al., 1993).

Those discrepancies may be due to diVerences in the assay procedure and the

heterogeneous class of extracellular PLA2.

The superfamily of PLA2 is divided into three types of enzymes: Ca2þ-

dependent cytosolic PLA2 (cPLA2), Ca2þ-dependent secretory PLA2 (sPLA2),

and Ca2þ-independent PLA2 (iPLA2) (Capper and Marshall, 2001; Chakraborti,

2003). Ross et al. (1997) showed that increased iPLA2, not Ca2þ-dependent PLA2,

was found in serum of patients with schizophrenia. A variety of antipsychotic

drugs also inhibit PLA2 activity (Aarsman et al., 1985; Schroder et al., 1981;

Taniguchi et al., 1988).

The potential clinical significance of PLA2 alterations in schizophrenia has

been examined less systematically. Previously, Ross et al. (1997) found positive re-

lationships between calcium-independent PLA2 and general psychopathology

scores and positive symptoms, but not with negative symptoms. They examined

PLA2 activity in chronic schizophrenic patients who were receiving long-term

antipsychotic treatment and exhibiting significant positive symptoms. Although

they were not characterized as poor outcome patients, the clinical characteristics

of these patients are suggestive of an unfavorable outcome. Gattaz’s laboratory

has replicated their earlier findings of increased PLA2 activities in drug-free

patients with schizophrenia (Tavares et al., 2003). Moreover, they demonstrated

that those patients without a response to niacin had the highest PLA2 activities

as compared to those with a positive response. Whether the relations between

PLA2 and AA in first-episode patients with schizophrenia will be the same or

diVerent than that observed in those with severe chronic schizophrenia remains

to be determined.

2. Phospholipase C

In addition to PLA2, other pathways, including the phospholipase C (PLC)–

diacylglycerol (DAG) lipase pathway, as well as the phospholipase D–phosphatidic

acid phosphohydrolase pathway, are also involved in the release of AA from

membrane phospholipids. The receptor-stimulated hydrolysis of inositol phos-

pholipids, particularly phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2), is initi-

ated by a specific PLC (Berridge and Irvine, 1984; Nishizuka, 1984). The

resulting DAG and inositol 1,4,5-triphosphate (1,4,5-IP3) led to the activation

of protein kinase C (PKC) and elevation of cytosolic Ca2þ, which provides mo-

lecular links between extracellular signals and intracellular events (Kishimoto

300 YAO AND VAN KAMMEN

et al., 1980; Nishizuka, 1984). Quantitative determination of inositol phosphates

provides direct evidence for PI hydrolysis by PLC in intact cells (Siess, 1989). An

increased turnover of platelet PI was found in both drug-treated and drug-free

patients (Das et al., 1992; Essali et al., 1990; Yao et al., 1992) but not in drug-naive

patients (Essali et al., 1990). The increased production of IP3 may be due to an

increase in the precursor, PI-4,5-P2, associated with a desensitization of the intra-

cellular IP3 receptor by neuroleptics (Das et al., 1992). However, Zilberman-

Kaufman et al. (1992) reported an increased inositol-1-phosphatase in RBC of

chronic schizophrenia patients. They interpreted that the increased enzyme activ-

ity might compensate physiologically for a deficiency of inositol in these patients.

Furthermore, the hyperactivity of the PI signaling system in schizophrenia has

also been demonstrated in the postmortem human brain ( Jope et al., 1994;

O’Neill et al., 1991; Pacheco and Jope, 1996; Wallace and Claro, 1993), which

is markedly diVerent from diseases with major depression and bipolar mood

disorder showing a decreased activity of G-protein-mediated PI hydrolysis

( Jope et al., 1996; Pacheco and Jope, 1996).

C. Increased Oxidative Stress

Much of the biochemical research focus in schizophrenia has been on

neurotransmitter systems. Although the role of dopamine in the pathophysiology

of schizophrenia remains preeminent, recent findings suggest instead that

multiple neurotransmitter systems may be altered. In many ways, schizophrenia

can be conceptualized as having a ‘‘multineurotransmitter’’ pathology. Whether

these are primary or secondary to other pathological processes, such as oxidative

stress and membrane dysfunction, will need to be determined. We emphasize,

however, that alterations in the activity of several neurotransmitter systems

can both contribute to and be modified by oxidative stress (or membrane

dysfunction).

1. Activation of Phospholipase by Reactive Oxygen Species (ROS)

PUFAs are highly susceptible to free radical insult and autoxidation to form

peroxy radicals and lipid peroxide intermediates, the existence of which within

cell membranes results in unstable membrane structure, altered membrane fluid-

ity and permeability, and impaired signal transduction. The brain, which is rich

in PUFAs, is particularly vulnerable to free radical-mediated damage.

Goldman et al. (1992) provided evidence that the formation of ROS is im-

portant for the activation of cellular PLA2. Later they showed that the epidermal

growth factor signaling of PLA2 activation and AA release are aVected by the

antioxidants, suggesting that PLA2 may be targeted by ROS (Goldman et al.,

1997). However, Takekoshi et al. (1995) demonstrated that oxidized DAG are

MEMBRANCE PHOSPHOLIPIDS AND CYTOKINE INTERACTION 301

more eVective in activating PKC than its nonoxidized forms. The oxidized

DAG is formed by the PLC-dependent hydrolysis of phosphatidylcholine

hydroperoxides (Kambayashi et al., 2002). In addition, both PKC activation

and protein tyrosine phosphorylation are required for the hydrogen peroxide-

induced activation of phospholipase D (Min et al., 1998; Natarajan et al., 1996).

Together, these findings support a role of ROS in phospholipase-mediated cell

signaling (Thannickal and Fanburg, 2000).

In schizophrenia, decreased levels of RBC-PUFAs (AA in particular) were

associated significantly with increased levels of plasma lipid peroxides in never-

medicated, first-episode schizophrenia patients (Arvindakshan et al., 2003b;

Khan et al., 2002). It is thus reasonable to hypothesize that increased oxidative stress

may be one of the mechanisms responsible for the reduction of membrane PUFAs.

2. Multineurotransmitter Defects and Free Radical Pathology

Numerous studies have shown that dopamine (DA) metabolism yields free

radicals under normal physiological conditions (e.g., Cohen, 1994). A number

of DA metabolic pathways exist that lead to the generation of hydroxyl radicals.

DA is susceptible to autoxidation when the antioxidant defense system (AODS) is

weak (Zhang and Dryhurst, 1994). Interestingly, it has been recognized that

DA-mediated toxicity is also mediated through DA actions on N-methyl-

d-aspartate (NMDA) glutamate receptors (Ben-Shachar et al., 1995; Cadet and

Kahler, 1994; Michel and Hefti, 1990). There is accumulating evidence that

NMDA-mediated excitotoxicity involves free radicals, such as superoxide and

nitric oxide (Coyle and Puttfarcken, 1993; Patel et al., 1996). In fact, antioxidants

(e.g., ascorbate and vitamin E) protect neurons against glutamate neurotoxicity

(Ciani et al., 1996; MacGregor et al., 1996).

Other neurotransmitters, particularly glutamate, can also induce metabolic

processes that increase free radical production. Activation of NMDA receptors

by glutamate stimulates PLA2 activity to release AA to act as a second messenger,

which in turn can lead to the formation of free radicals (Iuliano et al., 1994).

A decreased availability of AA, due either to increased PLA2 activity or to lipid

peroxidation, can lead to impaired glutamatergic neurotransmission (Olney and

Farber, 1995), which has been proposed as a pathogenetic mechanism in schizo-

phrenia. A dopamine–glutamate imbalance has also been implicated in

schizophrenia (Carlsson and Carlsson, 1990). Antipsychotic drugs that block

dopamine receptors may also enhance glutamatergic neurotransmission.

3. Impaired Antioxidant Defense System

Biological systems have evolved complex protective strategies against free

radical toxicity. There are multiple pathways leading to excess free radical

generation and subsequent oxidative stress. Under physiological conditions, the

302 YAO AND VAN KAMMEN

potential for free radical-mediated damage is kept in check by the antioxidant de-

fense system, comprising a series of enzymatic and nonenzymatic components.

The critical antioxidant enzymes include superoxide dismutase (SOD), catalase

(CAT), and glutathione peroxidase (GSH-Px). These enzymes act cooperatively

at diVerent sites in the metabolic pathway of free radicals. In addition to the

superoxide and hydroxyl radicals, another pathway is the formation of peroxyni-

trite by a reaction of a nitric oxide (NO) radical and a superoxide radical. Nitric

oxide can also produce hydroxyl radicals as well as nitrogen dioxide radicals.

Nitric oxide is a free radical by its unpaired electron. Because NO radicals cannot

produce initiation or propagation reactions, they do not generate free radical

chain reactions. Elevated NO production has been linked to various neuro-

degenerative disorders, including Alzheimer’s disease (Norris et al., 1996; Thorns

et al., 1998), multiple sclerosis (Heales et al., 1999), and Parkinson’s disease

(Bockelmann et al., 1994; Gerlach et al., 1999; Hunot et al., 1996).

There is increasing evidence of antioxidant defense system (AODS) deficits

in schizophrenia (Yao et al., 2001). The AODS is a complex, interrelated

system to dampen oxidative stress and protect tissue components from free

radical-mediated damage. A significant contribution to the body’s total antioxi-

dant capacity comes from antioxidant molecules in plasma, such as albumin,

uric acid, and bilirubin. Thus, plasma is an important but complex vehicle

that serves as a protective factor against oxidative damage to diVerent blood

components and also distributes dietary antioxidants to the rest of the body.

Significant reductions of plasma antioxidants (e.g., albumin, bilirubin, and uric

acid) are seen early in the course of schizophrenia (Reddy et al., 2003), consistent

with previous findings in patients with chronic schizophrenia (Yao et al., 1998a,b,

2000b). More importantly, these reductions are observed independently of

treatment, as patients were antipsychotic drug naive at entry into the study.

Furthermore, these patients were physically healthy, with no evidence of liver

or kidney disease or significant calorie restrictions, suggesting that the lowered

levels of plasma antioxidants are not indicative of ongoing disease processes or

malnutrition. Rather, the lowered levels may be indicative of subtle changes

reflecting either the acute-phase response (APR) (Maes et al., 1997, 2000a,b)

or oxidative stress (Mahadik and Evans, 2003; Yao et al., 2001). The APR is

increased in schizophrenia and is associated with a reduction in albumin

(Wong et al., 1996).

In addition, we have demonstrated a significantly higher level of NO in

schizophrenia brains than in those of normal and nonschizophrenia psychiatric

controls (Yao et al., in press). These findings were independent of age, brain

weight, postmortem interval, sample storage time, alcohol use, or cigarette

smoking. Thus, elevated NO levels in schizophrenia brains lend further support

for the possibility of free radical pathology in schizophrenia.

MEMBRANCE PHOSPHOLIPIDS AND CYTOKINE INTERACTION 303

D. Physiological Significance of Arachidonic Acid Signaling

Although much of the attention by early investigators has been on the n-3

fatty acids (e.g., DHA), increasing attention is being paid to the potentially

important role that AA may play in the pathophysiology of schizophrenia.

In brain, AA and its metabolites are considered to be intracellular second mes-

sengers. Many neurotransmitters can potentiate AA release through a receptor-

dependent hydrolysis of membrane phospholipids (e.g., inositol phospholipids),

which suggests that the receptor-mediated AA release may participate in

neuronal signal transduction (Vial and Piomelli, 1995). Therefore, the depleted

AA resulting from an increased phospholipid breakdown could be a common

factor that regulates prostaglandin biosynthesis, neurotransmission, and neuronal

deficits in schizophrenia (Peet et al., 1994).

1. Serotonin Receptor Activation

There is abundant evidence that serotonin (5-HT2) receptors in the brain

play a regulatory role in behavior (Leysen and Pauwels, 1990). 5-HT2 receptors

stimulate the release of AA in hippocampal neurons through the activation of

PLA2 that is independent of inositol phospholipid hydrolysis (Felder et al.,

1990). Thus, serotonin may potentially mediate some pathophysiological pro-

cesses through receptor-stimulated AA or eicosanoids. We have demonstrated

that drug-free schizophrenia patients exhibit reduced physiologic responsivity

mediated through the platelet 5-HT2 receptor complex, which can be modified

by haloperidol treatment (Yao et al., 1996).

2. The Endocannabinoid System

Another candidate neurobiological system that has received increased atten-

tion in recent years is the endocannabinoid system. �9-Tetrahydrocannabinol

(THC), the psychoactive ingredient from Cannabis saliva or marijuana, has been

known for centuries to cause acute euphoria, altered time perception, dissociation

of ideas, paranoia, motor impairment, enhanced appetite, cognitive impairment,

and occasionally hallucinations. Because of the similarities between THC-

induced psychosis and many symptoms of acute schizophrenia, a possible

relationship between THC use and the development of psychosis has been

proposed. Two endogenous THC ligands, anandamide (Devane et al., 1992)

and 2-arachidonoylglycerol (2-AG) (Sugiura et al., 1997; Stella et al., 1997),

have been discovered in the brain areas known to be implicated in schizophrenic

brain pathology. Both anandamide and 2-AG are derivatives of arachidonic

acid. Anandamide is synthesized from phosphatidylethanolamine (PE) by

the ‘‘transacylase-phosphodiesterase pathway’’ (Schmid, 2000). However, 2-AG

is converted from diacylglycerols by sn-1-DAG lipase, which is mainly

304 YAO AND VAN KAMMEN

followed by the phospholipase C-mediated degradation of phosphatidylinositol.

Anandamide has been shown to induce AA release and its product, prostaglandin

F2� (Someya et al., 2002).

Given the localization of the endogenous cannabinoid receptor (CB1) system

in brain areas (i.e., cortical and limbic structures) known to be implicated in

schizophrenic brain pathology (Herkenham et al., 1990, 1991), it is plausible that

dysfunction of the CB1 system with endogenous ligands may be associated with

the pathophysiology of schizophrenia. Moreover, there is a close interaction

between CB1 and dopaminergic systems. Cannabinoid agonists such as THC

and the endogenous ligands, anandamide and 2-AG, can modulate the dopami-

nergic system (French, 1997; Gardner and Lowinson, 1991; Sanudo-Pena et al.,

1996). Indeed, initial evidence suggests elevated anandamide levels in schizo-

phrenia patients (Leweke et al., 1999; Yao et al., 2002b), higher densities of CB1

receptors in the schizophrenia dorsolateral prefrontal cortex (Dean et al., 2001),

and linkages between CB1 receptor genes and schizophrenia (Leroy et al.,

2001; Ujike et al., 2002). Hence, a missing link in the PUFA/phospholipid

theory of schizophrenia may have been the presence of hallucinogenic endogen-

ous cannabinoids, a fact that can now be integrated with current hypotheses

and may go a long way in relating AA activity and the clinical outcome of

schizophrenia.

3. Eicosanoids

The notion of altered immune function in schizophrenia has been postulated

and examined for a number of years (see later). This association is particularly

relevant in relation to phospholipids/PUFA, as AA can be converted into a

variety of biologically active metabolites, which are collectively referred to as ei-

cosanoids, through the concerted reactions of cyclooxygenase (COX) and

lipoxygenases. Interestingly, Muller et al. (2002) reported a double-blind, add-

on study that the COX-2 inhibitor celecoxib decreased significantly the total

score on the positive and negative syndrome scale (PANSS) as compared to

placebo. Thus, it is conceivable that immune dysfunction in schizophrenia is

not just an epiphenomenon but may play a role in the pathogenetic mechanism

of the disorder (Muller et al., 2002).

Eicosanoids are potent messengers that modulate the inflammatory res-

ponse of the immune system (Calder, 2001). More recently, direct evidence of

immune changes in schizophrenia has come to light, particularly in the activities

of several cytokines known to be abnormal in autoimmune dysfunction, even

though there is no evidence of an acute brain inflammation or autoimmune

changes in schizophrenia. Presumably, the aforementioned altered processes may

induce changes in the immune system with behavioral and cellular consequences,

without evidence of chronic inflammation.

MEMBRANCE PHOSPHOLIPIDS AND CYTOKINE INTERACTION 305

4. Arachidonic Acid, GAP-43, and Neurodevelopment

Arachidonic acid is highly involved in the developmental process, particularly

in relation to the growth-associated protein-43 (GAP-43), a key protein that

contributes to dendrite growth and synaptogenesis (Benowitz and Ruttenberg,

1997). AA phosphorylates GAP-43 via protein kinase C, thus converting it

to its active state, which can then modulate such processes as long-term potentia-

tion (LTP) and axonal growth through the action of neural cell adhesion

molecules (Luo and Vallano, 1995; Meiri et al., 1998; Schaechter and Benowitz,

1993). Interestingly, AA-induced GAP-43 activity is also involved in the

mechanism of DA release (Ivins et al., 1993), and levels of GAP-43 itself have

been shown to be elevated in schizophrenia brain (Blennow et al., 1999; Per-

rone-Bizzozero et al., 1996; Sower et al., 1995). Initial evidence also suggests that

transgenic mice overexpressing GAP-43 display hyperlocomotive behaviors

reminiscent of amphetamine psychotic animals, an eVect that is reversed by anti-

psychotic halperidol treatment (Routtenberg et al., 2001). Taken together, these

data illustrate the fact that the AA cascade is at the core of many processes

(LTP, neurite growth, glutamatergic, and DA release), which could lead to the di-

verse collection of symptoms observed in schizophrenia. Thus, AA dysregulation

is a strong candidate for the biochemical substrate of faulty neurodevelopment in

schizophrenia.

II. Disturbed Immune Function

Advances in immunology suggest that two functionally diVerent yet balanced

immune systems are present in the human (Muller et al., 2000). The unspecific,

‘‘innate’’ immune system represents the first line of defense, which consists of

monocytes/macrophages, granulocytes, and natural killer cells in its cellular

arm and acute-phase proteins and the complement system in its humoral arm.

A person is born with an ‘‘innate’’ immune system. However, the specific, ‘‘adap-

tive’’ immune system consists of the cellular arm of Tand B cells and the humoral

arm of the specific antibodies, which is developed through the lifelong contact

with pathogens. Moreover, the adaptive immune system appears to discriminate

the cell-mediated cytotoxic responses from those antibody-mediated immune

responses (Mosmann and Sad, 1996). Upon immune activation, native T-helper

(Th0) cells are converted into either Th1 cells that mediate cytotoxic function or

Th2 cells that induce an antibody-dependent immune response. Characteristic-

ally, the Th1 system produces interleukin-2 (IL-2), interferon-� (IFN-�), and

tumor necrosis factor-� (TNF-�), whereas the Th2 system produces IL-4, IL-6,

and IL-10.

306 YAO AND VAN KAMMEN

Cytokines are small, nonenzymatic glycoproteins that are secreted by one

cell for the purpose of changing either its own functions (autocrine eVect) or those

of adjacent cells (paracrine eVect) (Haddad, 2002). Administration of cytokines

can lead to various psychiatric symptoms, including apathy, depression, delu-

sions, hallucinations, paranoia, and fatigue (DenicoV et al., 1987; McDonald

et al., 1987; Niiranen et al., 1988; Spath-Schwalbe et al., 1998; Walker et al.,

1997). Therefore, it is possible that the altered immune system is involved in

the pathophysiology of psychiatric disorders. Previously, epidemiological

(Brown et al., 2000; Mednick et al., 1988; O’Callaghan et al., 1991) and genetic

(Badenhoop et al., 1996; Lindholm et al., 1999; Schwab et al., 1995) studies have

linked immune dysfunction to schizophrenia.

A. An Overactive ‘‘Innate’’ Immune System?

Although there are no cellular and/or tissue damages resulting from abnor-

mal immune reactions, there is a distinct humoral immune reactivity in schizo-

phrenia (Muller et al., 2000; Schwarz et al., 2001). The unspecific, ‘‘innate’’

immune system appears to be overactivated in some patients with schizophrenia,

as evident by an increase of monocytes (Wilke et al., 1996) and gamma/delta cells

(Muller et al., 1998).

In addition, several studies have shown increased levels of IL-6 in schizophre-

nia (Frommberger et al., 1997; Ganguli et al., 1994; Lin et al., 1998; Maes et al.,

1995; van Kammen et al., 1999a), which might be related to the duration

(Ganguli et al., 1994) and treatment resistance (Lin et al., 1998) of the disease. More-

over, high levels of the soluble IL-6 receptor (sIL-6R) were found selectively in a

subgroup of schizophrenic patients with more pronounced paranoid-hallucinatory

syndrome (Muller et al., 1997a,b). Following antipsychotic treatment, levels of

both IL-6 and sIL-6R were reduced (Maes et al., 1995; Muller et al., 1997a,b). Thus,

antipsychotic drugs may inhibit IL-6 production (Lin et al., 1998).

Because the activation of monocytes and macrophages, as well as astrocytes

and microglia, leads to the production and release of IL-6, increased levels of

IL-6 in schizophrenia (see later) may be the consequence of activation of the

‘‘innate’’ immune system.

B. The Blunted Th1 System

In contrast, the specific, ‘‘adaptive’’ immune system appears to be imbal-

anced in schizophrenia. There is a decreased in vitro production of IL-2 (Bessler

et al., 1995; Cazzullo et al., 1998; Ganguli et al., 1989, 1995; Villemain et al., 1989;

Zhang et al., 2002a), as well as a decreased production of interferon-� (Arolt et al.,

MEMBRANCE PHOSPHOLIPIDS AND CYTOKINE INTERACTION 307

2000; Rothermund et al., 1998; Wilke et al., 1996). Both findings suggested that

the Th-1 system is underactivated in schizophrenia. In normal physiological

conditions, IL-2 is maintained at relatively low levels in peripheral blood. In

schizophrenia, however, increased levels of IL-2 (Kim et al., 2000; Zhang et al.,

2002b) and IL-2 receptors (Rapaport et al., 1993, 1994; Rapaport and Lohr,

1994) are present in serum as well as increased IL-2 levels in cerebrospinal fluid

(CSF) (Licinio et al., 1993; McAllister et al., 1995). In addition, McAllister et al.

(1995) further demonstrated that CSF IL-2 levels were associated with a recur-

rence of psychotic symptoms. Relapse-prone patients had significantly higher

levels of CSF IL-2 than those patients who did not relapse, suggesting a role of

CSF IL-2 than those patients who did not relapse, suggesting a role of CSF IL-2

in relapse in schizophrenia. Thus, it is possible that a decreased in vitro production

of IL-2 is a consequence of overproduction of IL-2 in vivo (Ganguli et al., 1992).

C. The Activated Th2 System

Several studies report increased levels of IL-6 in schizophrenia. Because the

Th2 system can produce IL-6, the increased production of IL-6 can thus result

from activation of either the Th2 system or the monocytes/macrophage cells

(see Section II,A). Other studies demonstrating increased levels of IL-4 (Mittle-

man et al., 1997), IL-10 (Cazzullo et al., 1998; van Kammen et al., 1997), and

IgE (Ramchand et al., 1994) further support an activation of the Th2 system in

schizophrenia. Moreover, CSF IL-10 levels were significantly correlated with

negative symptoms in unmedicated patients with schizophrenia (van Kammen

et al., 1997). In patients treated with haloperidol, however, a significant correl-

ation was found between CSF IL-10 levels and the severity of psychosis measured

by the Bunney–Hamburg psychosis rating scale (van Kammen et al., 1997).

Taken together, Muller et al. (2000) suggested an imbalance of the ‘‘adaptive’’

immune system with a shift to Th2-like immune reactivity in a subgroup of

patients with schizophrenia. This subgroup is further characterized by more

pronounced negative symptoms and poor outcome (Schwarz et al., 2001).

D. Conflicting Findings

Despite the aforementioned data that support an imbalance of the ‘‘adaptive’’

immune system in schizophrenia, the respective evidence is not always conclu-

sive. Contrary to blunted Th1 production, increased in vitro productions of IL-2

and interferon-� and decreased levels of serum IL-2 were found in schizophrenia

patients (Cazzullo et al., 2001; O’Donnell et al., 1996; Theodoropoulou et al.,

2001). Others have reported no significant diVerences between schizophrenia

308 YAO AND VAN KAMMEN

patients and control subjects (Baker et al., 1996; Haack et al., 1999; Wilke et al.,

1996). Furthermore, several studies have failed to replicate increased circulating

levels of IL-6 in schizophrenia (Baker et al., 1996; Haack et al., 1999; Monteleone

et al., 1997; Shintani et al., 1991; Wei et al., 1992; Xu et al., 1994). These

inconsistencies may be the result of diVerences in assay methodology, sample

size, sample handling, diagnostic criteria, and comparison groups. In addition,

several confounding factors, including age, gender, ethnic background, smoking,

alcohol, substance abuse, and antipsychotic treatment, may also explain these

discrepancies (Banks, 2000; Haack et al., 1999; van Kammen et al., 1999b).

III. Polyunsaturated Fatty Acids and Cytokines

Both n-6 and n-3 polyunsaturated fatty acids involve regulation of the inflam-

matory response system. n-6 PUFAs, particularly AA, have proinflammatory

features, as AA is the precursor of proinflammatory eicosanoids, prostaglandin

E2 (PGE2), and leukotriene B4 (LTB4) and increase the production of IL-1,

TNF-�, and IL-6 (Hayashi et al., 1998; Soyland et al., 1994; Tashiro et al.,

1998). However, n-3 PUFA eicosapentaenoic acid (EPA) and DHA suppress

the production of AA-derived eicosanoids, thus having anti-inflammatory and

immunosuppressive eVects (Calder, 1998; Meydani et al., 1991). Several groups

have reported that n-3 PUFA-enriched diets (e.g., fish oil) can lead to partial

replacement of AA by EPA in inflammatory cell membranes and significantly

reduce the ex vivo production of proinflammatory cytokines (Calder, 1998; Endres

et al., 1993; Espersen et al., 1992; Gallai et al., 1995; James et al., 2000; Meydani

et al., 1991; Soyland et al., 1994). Therefore, an imbalance of n-6/n-3 PUFAs may

result in an increased production of proinflammatory cytokines. Smith (1991)

proposed that an abnormal fatty acid composition might be related to the inflam-

matory response system underlying the pathophysiology of major depression.

Maes et al. (2000b) have further substantiated the role of PUFAs in predicting

the response of proinflammatory cytokines to psychological stress.

In schizophrenia, an increased breakdown of membrane phospholipids

through the PLA2 reaction has been reported, as well as increased circulating

levels of IL-2 and IL-6 (see earlier discussion). Interleukins have been shown to

stimulate the PLA2-mediated hydrolysis of phospholipids. Evidence from the

bilateral infusion of IL-6 into the rat hippocampus further supports the notion

that IL-6 can activate arachidonic acid metabolic pathways in the brain

(Ma and Zhu, 2000). Moreover, Yao et al. (2003) demonstrated significant correl-

ations between increased CSF levels of IL-6 and decreased RBC levels of PUFAs

in schizophrenic patients on and oV haloperidol treatment. Taken together, these

findings suggest that decreased membrane PUFAs may be related in part to an

MEMBRANCE PHOSPHOLIPIDS AND CYTOKINE INTERACTION 309

immune disturbance in schizophrenia, possibly resulting from increased PLA2

activity mediated through the proinflammatory cytokines.

However, reduced levels of AA in membrane phospholipids could conceiv-

ably lead to a decreased synthesis of proinflammatory eicosanoids. One of the

AA metabolites, prostaglandin D2, mediates vasodilatation during the inflam-

matory response. Thus, the reduced AA availability may, in part, explain a

variety of clinical observations in schizophrenia that are usually ignored by the

receptor-based etiological hypotheses (Horrobin, 1998). Indirect evidence for a

dysregulated inflammatory response in schizophrenia stems from the observation

of a lower risk of arthritis and other inflammatory diseases (Mellsop, 1972; Oken

and Schulzer, 1999; Torrey and Yolken, 2001; Vinogradov et al., 1991), greater

resistance to pain (Davis et al., 1979), remission of psychosis during fever

(Horrobin, 1977), and decreased prostaglandin-dependent niacin skin flushing

(Glen et al., 1996; Horrobin, 1980; Hudson et al., 1995; Messamore et al., 2003;

Rybakowski and Weterle, 1991). These eVects might be secondary to reduced

eicosanoids signaling.

IV. Stress and Immune Response

A. Oxidative Stress

Antioxidant status is defined as the balance between antioxidants and proox-

idants in living organisms (Papas, 1996). An imbalance resulting from an exces-

sive formation of free radicals can lead to oxidative stress, and subsequently

cellular toxicity. During inflammatory processes, infiltrating cells can produce

large amounts of reactive oxygen species. In addition to being cytotoxic, these

ROS also act as important mediators regulating various cellular and immuno-

logical processes (Droge, 2002). Under physiologically relevant concentration,

hydrogen peroxide was shown to either increase the production of T-cell growth

factor (Roth and Droge, 1987) or induce the gene expression of IL-2 (Los et al.,

1995) and IL-6 ( Junn et al., 2000). The enhancement of IL-2 production was

associated with a decrease in the intracellular glutathione (GSH) level (Los et al.,

1995) and was reversed by the addition of exogenous GSH (Roth and Droge,

1991). Hehner et al. (2000) further demonstrated enhancement of T-cell receptor

signaling by a shift in the intracellular GSH redox state. Taken together, these

findings suggest that the intact immune system requires a delicate balance

between antioxidant and prooxidant status (Droge et al., 1994).

As mentioned in Section I,C,3, there is increasing evidence of perturbations

in the antioxidant defense system in schizophrenia. Such an imbalanced AODS

may provide the basis for an increased release of specific cytokines (e.g., increased

310 YAO AND VAN KAMMEN

levels of IL-2 and IL6), as well as membrane abnormalities that have been

reported in patients with schizophrenia.

B. Psychological Stress

Increasing evidence has shown that the production of proinflammatory cyto-

kines such as IL-1, IL-6, and INF-� may be aVected by psychological stress.

Levels of in vitro production of IL-2 were increased in medical students during

the examination periods (Glaser et al., 1990). Maes et al. (1998a,b) showed that

the in vitro production of proinflammatory cytokines (IL-6, TNF-�, and INF-�)and IL-10 were increased significantly by stress due to academic examination.

Moreover, volunteers subjected to sleep deprivation also exhibited increased

levels of plasma IL-1 and IL-2 (Moldofsky et al., 1989). Similarly, stress-induced

cytokine releases were also increased in animal models. In rat studies, levels of

serum IL-6 and the expression of IL-6 messenger RNA in the brain (Shizuya

et al., 1997; Takaki et al., 1994), as well as brain levels of IL-1� and IL-1 mRNA

(Minami et al., 1991; Nguyen et al., 1998), were enhanced by physical restraint.

In a longitudinal community study assessing the relationship between chronic

stress and IL-6 production, Kiecolt-Glaser et al. (2003) found that the average rate

of increase in IL-6 from caregivers for a spouse with dementia was four times

higher than that of noncaregivers. These authors suggest that chronic stressors

may accelerate the risk of a host of age-related diseases by prematurely aging

the immune response.

V. Conclusion

Although the potential key role that lipids may play in schizophrenia is not

fully understood, the increasing evidence to date suggests that an altered lipid en-

vironment can have a significant impact on the behavior of neurotransmitter

systems. For example, demyelinating diseases have been considered to be associ-

ated with behavioral disturbance (Hyde et al., 1992). Multiple lines of evidence

have converged to implicate oligodendroglial dysfunction with subsequent abnor-

malities in myelin maintenance and repair underlying the pathogenetic mechan-

ism of schizophrenia, particularly in the more severely ill patients (for reviews see

Bartzokis et al., 2003; Davis et al., 2003). The dry mass of central nervous system

(CNS) myelin is characterized by a high proportion of lipid (70–85%) (Morell and

Quaries, 1999). In humans, approximately 45% of total lipids in myelin or white

matter are phospholipids. Thus, it is conceivable that CNS membrane phospho-

lipids are reduced in schizophrenia, which is consistent with the hypothesis of

MEMBRANCE PHOSPHOLIPIDS AND CYTOKINE INTERACTION 311

Fig. 1. An overview of phospholipids turnover, arachidonic acid signaling, and schizophrenic

symptomatology (adapted from Skosnik and Yao, 2003). PC, phosphatidylcholine; PI, phosphatidy-

linositol; PS, phosphatidylserine; PE, phosphatidylethanolamine; AODS, antioxidant defense system;

NT, neurotransmitters; RO, reactive oxygen; apoD, apolipoprotein D; PLA2, phospholipase A2; PLC,

phospholipase C; LOX, lipooxygenase; AA, arachidonic acid; DAG, diacylglycerol; COX,

cyclooxygenase; 2-AG, 2-arachidonoyl glycerol; GAP, growth-associated protein; PGG2, prosta-

glandin G2; PGH2, prostaglandin H2; PGD2, prostaglandin D2; CB, cannabinoid.

312 YAO AND VAN KAMMEN

myelin-related dysfunction in schizophrenia. Further investigations are needed to

confirm the altered myelin-related genes as reported by Davis et al. (2003).

Membrane defects, such as those induced by decreased polyunsaturated

fatty acids in phospholipids, can significantly alter a broad range of membrane

(e.g., gray and white matters) functions and ipso facto behavior through multiple

‘‘downstream’’ eVects. A number of putative mechanisms have been identified

to explain the decreased PUFAs in schizophrenia, including an increased turn-

over of phospholipids and a decreased incorporation of arachidonic acid. Both

increased oxidative stress and altered immune function may be responsible

for increased phospholipid breakdown. This association is particularly relevant

in relation to phospholipids/PUFA because AA can be converted to a variety

of biologically active eicosanoids that serve as potent messengers in regulating

the inflammatory response. Direct evidence of immune changes in schizophrenia

have come to light, particularly in the activities of several cytokines known to be

abnormal in autoimmune dysfunction. Given the diverse physiological function

of AA, the specific behavioral symptomatology of schizophrenia is related mostly

to the eVect of AA changes that regulate neurodevelopment, neurotransmitter

homeostasis, second messenger signaling, and neuromodulatory activity

in schizophrenia (Fig. 1). Hence, in the current conceptualization, AA may be

at a nexus point in the cascade leading to the syndrome of schizophrenia and

represents a common biochemical pathway leading to the highly heterogeneous

symptomatology and course of schizophrenia.

Changes in membrane fatty acids not only have been associated with the

severity of symptomatology, but also provide a theoretical basis for predicting a

potential psychotropic eVect of PUFA supplementation. Work utilizing eicosa-

pentaenoic acid (EPA), the molecular precursor of DHA, has shown some prom-

ise in ameliorating many of the clinical characteristics of schizophrenia (Peet et al.,

1996, 2001; Peet and Horrobin, 2002; Puri et al., 2000; Richardson et al., 2000),

as well as cognitive impairments associated with dyslexia and attention deficit

hyperactivity disorder (Richardson et al., 1999; Stordy, 1999). More recently,

Arvindakshan et al. (2003a) have shown that supplementation with a combination

of n-3 fatty acids (EPA/DHA, 3:2) and antioxidants (vitamins E and C) may im-

prove the outcome of schizophrenia. While these data are promising, an EPA

trial performed by Fenton et al. (2001) failed to induce beneficial changes in

residual symptoms, mood, or cognition as compared to placebo in patients with

schizophrenia. Although the patient group in this study had a longer duration

and severity of illness, these findings raise some doubt of the beneficial eVect of

omega-3 fatty acid treatment in schizophrenia. In short, the present review exem-

plified multiple metabolic defects involving phospholipid and cytokine pathways

in schizophrenia.

MEMBRANCE PHOSPHOLIPIDS AND CYTOKINE INTERACTION 313

Acknowledgments

This study was supported in part by the Highland Drive VA Pittsburgh Healthcare System and

research grants from the Department of Veterans AVairs (Merit Review and Research Career

Scientist Award) and the National Institute of Mental Health (MH43742, MH44841, and MH58141).

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