Decreased Interleukin-2 Production in Korean
Yong Ku Kim, Min Soo Lee, and Kwang Yoon Suh
Background: It has been postulated that autoimmune
process may play a role in the pathogenesis of symptoms
in some schizophrenic patients. Findings of altered inter-
leukin (IL) regulation have been regarded as additional
proof that schizophrenia has an autoimmunological back-
Methods: Sixteen patients who fulfilled DSM-IV criteria
for schizophrenia and who were drug free for at least six
months and the same number of age- and sex-matched
controls were recruited. The severity of symptoms in
schizophrenia was assessed by BPRS. Phytohemagglutinin
(PHA)-stimulated production and serum level of IL-1?,
IL-2, and IL-6 were measured by enzyme-linked immuno-
sorbent assay (ELISA).
Results: There was a significant decrease of IL-2 produc-
tion (p ? .01) in schizophrenic patients and a significant
increase of IL-2 serum level (p ? .01). No significant
difference of IL-1? and IL-6 was found. Some patients and
controls had measurable serum level of IL-1? and IL-6.
No significant correlation between production and serum
level of IL-1?, -2, -6 and age, duration of illness, and
BPRS score in schizophrenics was found.
Conclusions: This is the first study to describe a decrease
of IL-2 production and increase of IL-2 serum level in
non-Caucasian schizophrenic patients. These findings are
further evidence that autoimmune process is present,
regardless of ethnic origin, in some schizophrenic pa-
Biol Psychiatry 1998;43:701–704 © 1998 Soci-
ety of Biological Psychiatry
Key Words: Schizophrenia, interleukin, autoimmune hy-
immune system. Abnormalities in ILs concentrations may
nterleukins (ILs) are known as soluble mediators that
have many critical interactions among cells of the
reflect the presence of an infectious or immune process. Of
all the immunologic findings reported in association with
schizophrenia, alterations of ILs regulation have been
regarded as an additional proof that some schizophrenia
has an infectious-autoimmune background (Kirch 1993).
These finding include decreased IL-2 production after
mitogen stimulation (Ganguli et al 1989, 1995; Villemain
et al 1989), increased serum IL-2 receptor (Ganguli and
Rabin 1989; Rapaport et al 1989), increased serum IL-6
(Shintani et al 1991; Ganguli et al 1994), and increased
CSF IL-2 (Licinio et al 1993; McAllister 1995) concen-
trations. Moreover, there was a report that serum soluble
IL-2 receptor concentrations were elevated in Korean as
well as in Caucasian schizophrenics (Rapaport et al 1994).
These findings may be further evidence that immune
process is present, regardless of ethnicity, in some schizo-
phrenic patients. We therefore, as part of an attempt to
explore this issue, examine whether Korean schizophren-
ics may be accompanied by alterations of in vivo serum
level of and in vitro mitogen-induced production of IL-1?,
IL-2, and IL-6.
Methods and Materials
Sixteen patients (seven women, nine men; mean age: 32 years,
range: 24–39 years), who fulfilled DSM-IV criteria (APA 1994)
for schizophrenia (nine paranoid type, seven undifferentiated
type) and who were neuroleptic-free for at least 6 months
(including six neuroleptic-naive, first onset), and the same
number of age-matched and sex-matched healthy controls were
included in the present study. Patients had been admitted in an
acute psychotic state and informed consent was obtained after the
procedure had been fully explained. The mean duration of illness
was 4.12 (SD ? 0.54) years. We excluded patients with a history
of a concomitant psychiatric illness, such as drug or alcohol
abuse, and abnormal laboratory findings i.e., blood—hemoglo-
bin, hematocrit, erythrocyte sedimentation rate, leukocyte, serum
electrolyte, renal function test, liver function test; urine analysis;
Veneral Disease Research Laboratory (VDRL) test; chest X ray
of lung and heart; electrocardiogram (EKG); and electroenceph-
alogram (EEG). Healthy controls were recruited from hospital
staffs, nurses, and residents. Current or past personal or familial
history of psychiatric illness, a diagnosed autoimmune illness,
and drug or alcohol abuse of each control were excluded by a
nonstructured clinical interview. All subjects were free of
This article was presented in part at the 148th annual meeting of the American
Psychiatric Association, Miami, Florida, May 20–25, 1995.
From the Department of Psychiatry, College of Medicine, Korea University, Seoul,
Address reprint requests to Yong Ku Kim, M.D., Department of Psychiatry, College
of Medicine, Korea University, 126-1, 5-Ka, Anam-Dong, Sungbuk-Ku, Seoul
Received November 25, 1996; revised June 16, 1997; accepted July 11, 1997.
© 1998 Society of Biological Psychiatry0006-3223/98/$19.00
chronic and acute (i.e., infectious or allergic diseases for at least
2 weeks before study) physical illness associated with abnormal
cell-mediated immunity. Thirty mL of fasting blood were col-
lected from 8:00 A.M.–9:00 A.M. on the day following admission
and immediately centrifuged at 3000 rpm for 10 minutes.
Peripheral blood mononuclear cells (PBMC) were isolated by
Ficoll-Paque density gradient separation and were washed triple
in cold Hanks’ balanced salt solution (GIBCO). The PBMC were
suspended in RPMI 1640 medium (GIBCO) containing 1%
penicillin (10,000 unit/mL), 1% streptomycin sulfate (10 mg/
mL), amphotericin B (25 mg/mL), and 1% L-glutamine
(GIBCO). 1 ? 106PBMC/mL were suspended in RPMI-1640
medium supplemented with 15% heat inactivated fetal bovine
serum (GIBCO) and 1.5% phytohemagglutinin-M (PHA-M,
GIBCO). The cultures were incubated for 24 hours at 37°C in a
humidified atmosphere containing 5% CO2. At the end of the
incubation period, culture media were collected, cells were
separated by centrifugation, and supernatants were kept at
?70°C until assayed. From culture supernatant and serum,
IL-1?, IL-2, and IL-6 levels were measured in duplicate by
enzyme-linked immunosorbent assay (ELISA) using IL-1?,
IL-2, and IL-6 EIA kit (DRG-instruments GmbH, Frankfurt,
Germany) at the Department of Clinical Pathology and Immu-
nology, Korea University. The lower level of detection for IL-1?
was 4.3 pg/ml, for IL-2 was 4.5 pg/mL, and for IL-6 was 2.0
pg/ml. The co-efficients of variation for IL-1?, IL-2, and IL-6
were less than 10%. The patients’ psychopathology was assessed
on the day of the blood sampling using the Brief Psychiatric
Rating Scale (BPRS) (Overall and Gorham 1962). Statistical
analyses to test the differences in the means between the patients
and the controls were calculated using the Student’s t-test and
correlations were calculated using the Pearson’s product moment
correlation test. All results were expressed using the mean ? SD.
The mean (?SD) IL-2 production in the schizophrenic
patients (1905.3 ? 554.5 pg/mL) was significantly lower
than their matched healthy controls (2790.2 ? 573.5
pg/ml, t ? ?4.46; df ? 30; p ? 0.001, unpaired Student’s
t-test) (Figure 1). There were no significant differences in
the mean IL-1? and IL-6 production between schizo-
phrenic patients and controls. A detectable serum level (?
4.5 pg/ml) of IL-2 was found in 16 patients (100%) and in
eight healthy controls (50%). The mean level of IL-2 was
significantly higher in the schizophrenic patients (184.8 ?
49.6 pg/mL) than the normal controls (104.2 ? 96.4
pg/mL, t ? 2.67; df ? 22; p ? 0.01) (Figure 2). Serum
IL-1? level was detected in six of 16 patients (37.5%) and
in four of 16 controls (25%). Almost no serum IL-6 was
detected in schizophrenic patients and controls. There was
a significant correlation between IL-1? and IL-6 produc-
tion (r ? 0.86, p ? 0.001). No significant correlations
between IL-1?, IL-2, and IL-6 productions and age,
duration of illness, and BPRS total score in schizophrenic
patients were found.
The major finding of this study is lower level of IL-2
production in the culture supernatant of non-Caucasian
schizophrenic patients than of healthy comparison sub-
jects. Several lines of researchers have already demon-
strated decreased IL-2 production in Caucasian schizo-
Figure 1. Interleukin-2 production in 16 normal controls and 16
schizophrenic patients. *, p ? .001 by Student’s t-test.
Figure 2. Interleukin-2 serum level in 8 normal controls and 16
schizophrenic patients. *, p ? .01 by Student’s t-test.
702Decreased IL-2 in Korean Schizophrenic Patients
phrenic patients (Ganguli et al 1989, 1995; Villemain et al
1989). To our knowledge, this is the first study to describe
low IL-2 production in non-Caucasian schizophrenic pa-
tients. Furthermore, our patients were acute psychotic and
the mean BPRS scores was 59.4 (SD ? 14.2). Our result
is consistent with a previous report (Ganguli et al 1989)
that decreased IL-2 production was associated with an
acute state of schizophrenia. But there was no significant
correlation between IL-2 production and BPRS scores in
schizophrenic patients. This result suggests that decreased
IL-2 production could not simply be an epiphenomenon of
The finding of the IL-2 abnormality in schizophrenia is
particularly intriguing, since patients with autoimmune
disease, such as rheumatoid arthritis, systemic lupus ery-
thematosis, and multiple sclerosis, have the same finding
(i.e., low IL-2 production) (Kroemer et al 1991). Interest-
ingly, it is known that schizophrenia and rheumatoid
arthritis very seldom occur in the same individuals (Eaton
et al 1992). It has been hypothesized that different alleles
of the same gene may be responsible for susceptibility to
both diseases (Knight 1982). Therefore, inheritance of the
allele for rheumatoid arthritis may prevent an individual
from simultaneously processing the allele for schizophre-
At least, two hypothesis have been suggested to account
for low IL-2 production in schizophrenic patients. Ville-
main et al (1989) have suggested lower IL-2 production
was intrinsic to the schizophrenic patients’ T-cell, since
IL-2 production showed normal sensitivity to prostaglan-
din E2-mediated down-regulation by autologous mono-
cytes. Alternatively, there was T-cell exhaustion theory
that lowered IL-2 production may be induced by a conse-
quence of overproduction of in vivo IL-2. It has been
suggested that the low lymphocyte production of IL-2 in
patients with an autoimmune disease occurs because the
T-cells are activated and the lymphocyte-derived IL-2 has
been released into serum (Kroemer et al 1991). To date,
there was no report that Caucasian schizophrenics have
increased IL-2 serum level, and only a previous study
(Gattaz et al 1992) failed to find any difference in serum
level of IL-2 between 16 schizophrenic patients and 15
normal controls. But our results raise the possibility that
schizophrenic patients have higher IL-2 serum level than
healthy controls. Though only eight of 16 healthy controls
(50%) had a detectable serum level (? 4.5 pg/mL) of IL-2,
all patients had a detectable IL-2 level by the present
experimental method. Also the mean level of IL-2 was
significantly higher in 16 schizophrenic patients than in
eight normal controls.
Smith (1992) has already proposed that excessive IL-2
and IL-2-receptor in serum might play an etiologic role in
schizophrenia. Also, Licinio et al (1993) reported elevated
IL-2 level in cerebrospinal fluid (CSF) of neuroleptic-free
schizophrenic patients and postulated that central IL-2
might contribute to dopaminergic neurotransmission, au-
toimmune response, and abnormal brain morphology in
some schizophrenic patients. Recently, McAllister et al
(1995) found that increased CSF IL-2 level during halo-
peridol treatment was a significant predictor of worsening
in schizophrenia. Moreover, in a recent study, we have
replicated that 26 schizophrenic men have higher IL-2
serum level than age-matched normal controls by using
quantitative “sandwich” ELISA, known to be more sensi-
tive than simple ELISA (Kim and Lee 1996). These
findings may support the exhaustion hypothesis in schizo-
phrenia. A further replication study in progress that
includes larger members of patients will be needed to
resolve this important issue.
We could not find significant differences in IL-1? and
IL-6 productions between schizophrenic patients and nor-
mal controls. IL-1? and IL-6 are known as part of the
acute phase response while IL-2 has a more important role
in cellular immunity. The fact that IL-1? and IL-6 pro-
ductions were not elevated in our patients may suggest that
our results were not due to nonspecific factors, such as
systemic inflammatory disorder. The significant correla-
tion between IL-1? and IL-6 productions could be ex-
plained in a sense that both ILs can be simultaneously
released from activated monocyte, and can induce produc-
tion of one another (Durum and Oppenheim 1989).
We did not detect serum IL-1? and IL-2 levels in
schizophrenic patients and controls by ELISA. IL-1?
levels were below the level of detection in six of 16
schizophrenic patients (37.5%) and four of 16 controls
(37.5%). No detectable serum levels of IL-6 were found in
schizophrenic patient or controls. From these findings, it is
suggested that our result is not due to acute phase
response, although a future study using more sensitive
methods than our ELISA will be needed.
In the present study, we do not know whether this
abnormality of IL-2 system is a “trait” or “state” defect in
some patients with schizophrenia. If IL-2 production
measured in a state of remission in the same patients has
returned to “normal,” it may be considered as “state”
To our knowledge, it is not known whether Korean
schizophrenics would differ from other schizophrenic
samples from the literature regarding IL-2. However,
Rapaport et al (1994) has reported that both Caucasian
patient and controls had significantly higher serum IL-2R
levels than their Korean counterparts and has hypothesized
that these differences of sIL-2R levels reflect some type of
baseline differences in immune parameters between racial
groups, as is commonly seen with human leukocyte
antigen (HLA) frequencies. Therefore, we suggest that a
Y.K. Kim et al703
study of racial heterogeneity in immune studies of psychi-
atric disorder will be needed.
In conclusion, our data confirms and extends previous
findings that IL-2 production is decreased in schizophrenic
patients. In addition, we suggest that decreased IL-2
production may be associated with increased IL-2 serum
level in the same patients. These findings are compatible
with the possibility that Korean schizophrenic patients
have an ongoing autoimmune process.
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704Decreased IL-2 in Korean Schizophrenic Patients