Plasma levels of interleukin-12 and interleukin-18 in
Plasmodium falciparum malaria patients in South Darfur
Mohammed I Abdul Fattah *, Mahmoud M Badr*, Yaser A Shahin **,
*Department of Microbiology and Immunology,**Departement of
Gastroentrology and Hepatology
Faculty of Medicine , Benha University, Egypt.
Abstract :
The interaction between cytokines such as interleukin-12 ( IL-12 )and IL-18 plays an
important role in malaria pathogenesis and outcome , modulating the immunoresponce
in Plasmodium falciparum ( P. falciparum ) malaria. This work aimed at detecting the
plasma levels of IL-12 and IL-18 in P. falciparum malaria patients and to correlate the
production of these cytokines with the severity of the disease .this study was conducted
on two groups : Group I , consisted of 80 patients with P. falciparum malaria infection
they were classified into two groups according to disease severity , 30 patients with
severe malaria and 50 patients with mild malaria .Group II,consisted of 30 healthy
persons as a control group. The levels of IL-12 and IL-18 were higher (16.2±8.3 pg/ml
and 2682.8 ± 332.0 pg/ml , respectively ) in patients with mild malaria than in patients
with severe form of the disease (12.3±6.42 pg/ml and 1226± 267.2 pg/ml respectively )
A positive correlation was observed between IL-12 and IL-18.These findings suggest
that the production of these cytokines may be coregulated and both have an
immunoregulatory effect on the immune response to P. falciparum infection ,
so can be used as a reliable parameter to predict the progression of the disease and
may be used as an immunotherapy against P.falciparum malaria infection , especially
in the early phase of the disease. Further studies are needed to find out the relation
between these cytokines and individual forms and complications of P. falciparum
malaria infection .
Introduction
Malaria is caused by the infection of hemoprotozoan parasites belonging to the genus
Plasmodium. There are four parasite species , namely, Plasmodium falciparum,P. vivax,
P. ovale and P. malariae, responsible for human malaria infections. P. falciparum and
P. vivax are the two most causative agents of severe malaria ; infection with P.
falciparum causes the most severe disease and is responsible for more than 95% of
malaria deaths worldwide [1].
The clinical symptoms and pathological consequences of human malaria are associated
with the asexual blood stage of the parasite life cycle . The clinical symptoms range
from light headache or mild fever to extremely severe, life-threatening complications
such as cerebral malaria, sever anemia, renal failure, hypoglycaemia, circulatory
collapse, repeated generalized convulsions and pulmonary edema [2].
Among these clinical complications, cerebral malaria and severe anemia are commonly
observed in children, while pulmonary and renal disorders often occur in adults . Both
parasite and host factors determine the severity and outcome of malaria infection [3].
There has been rather little work characterizing innate immune responses to malaria,
assessing their role in protection or their potential to modulate adaptive responses.
Innate immune mechanisms represent the first line of defense against invading
1
pathogens. For severe, acute infections such as malaria, the ability to mount an effective
innate response may mean the difference between life and death [4]
Pro-inflammatory cytokines ( eg. IL-12 and IL-18 ) , have been associated with
protective cell-mediated immunity by their capacity to induce parasite killing by
monocytes/ macrophages and neutrophils. Anti-inflammatory cytokines counteract the
production and possible cytopathic effects of pro-inflammatory cytokines and may thus
be associated with malaria susceptibility [5].
Human interleukin 12 (IL-12), also known as natural killer cell stimulatory factor
(NKSF) and cytotoxic lymphocyte maturation factor (CLMFIL-12), is a major cytokine
involved in the control of CD4_ Th1 responses and NK cells. IL-12 has been shown to
be involved in protective immunity against malaria by regulating gamma interferon
(IFN- γ ), tumor necrosis factor alpha (TNF- α ), and nitric oxide responses in
experimental studies [6].
IL-18 is structurally related to IL-1β and is produced by monocytes and macrophages
in response to microbial products such as lipopolysaccharides . Experimental studies
have shown that IL-18 plays a dominant role in the IL-12-mediated IFN- γ induction in
T cells . In mice deficient for the IL-18 gene, little or no IFN- γ is produced despite the
presence of IL-12, which suggests that IL-18 is a key player in regulation of IFN- γ
production [7]. Furthermore, IL-12 and IL-18 synergistically up regulate IFN- γ
production of macrophages, T cells, and NK cells including the enhancement of NKand T-cell-mediated cytotoxic activities [8].
In vivo, TNF- α production is associated with parasite clearance and resolution of fever
, but elevated levels of TNF- α has also been associated with cerebral malaria. A priori,
one would expect a crucial role for IL-12—and possibly also IL- 18—in initiation of the
inflammatory cytokine cascade [9] . Accordingly, associations have been reported
between circulating levels of IL-12 and IL-18 and risk of severe P. falciparum malaria
[1,4,8 ].
In a prospective epidemiological study, IL-12 production was positively associated
with IFN- γ and TNF- α production and negatively associated with parasitemia [8] .
Complications of severe anemia and cerebral malaria are the major cause of morbidity
and mortality, but recent evidence suggests that the host’s immunologic response plays
a relevant role in the pathophysiology of this disease in humans [10]
The balance between Th1 and Th2 immune response and between pro-inflammatory
and anti-inflammatory cytokines is important in determining the level of malaria
parasitemia, disease outcome and rates of recovery , while the overproduction of both
pro-inflammatory and anti-inflammatory cytokines can be responsible for disease
severity and mortality [11].
The aim of this work was to detect the plasma levels of IL-12 and IL-18 in patients with
malaria in South Darfur and to correlate the production of these cytokines with the
severity of the disease .
Subjects and Methods :
This study was conducted on eighty patients with P. falciparum malaria during the
period between July 2009 to february 2010 in Nyala Specialised Hospital , South
2
Darfur, Sudan. These patients constituted ( Group I ) ,Their age ranged between 2 to 35
years ( 16.43±5.7 ) ,they were 49 males and 31 females.
According to the symptoms, physical signs , laboratory findings of malaria at the onset
of the disease , hematological parameters, hyperparasitemia and evidence of
neurological involvement , these patients were classified into two groups.
Group I (A) _Severe malaria_ (complicated) : They were 30 patients , their age ranged
between 2 to 39 years ( 19.6±6.1 ) , they were 19 males and 11 females. The inclusion
criteria were established microscopically by the presence of the P. falciparum parasite ,
that was confirmed with P. falciparum rapid test and by the clinical and physical signs
according to the WHO criteria: evidence of neurological compromission (prostration,
lethargy), gastrointestinal symptoms, severe anemia (Ht<20%, Hb<6 g/dl),
hyperparasitemia corresponding to >5 parasitised red cells/100 red blood cells or >5%
parasitemia, hypoglycemia (serum glucose less than 40 mg/dl), acidosis with
respiratory distress, oliguria, cardiovascular shock, jaundice and diffuse hemorrhages.
Group I (B) _Mild malaria_ (uncomplicated) : They were 50 patients , their age ranged
between 3 to 32 years ( 15.6±4.8 ) , they were 30 males and 20 females, their
classification was established microscopically by the presence of <5 parasitised red
cells/100 red blood cells or <5% parasitemia, with fever, headache and myalgia without
any indication of severe malaria.
Group II :Thirty healthy persons were also included in the study , their age ranged
between 6 to 40 years ( 18± 7.4 ), they were 19 males and 11 females. All subjects
enrolled as control group were negative at the thick-smear examination for P.
falciparum, rapid test , without febrile episodes during the previous 6 months and
without signs of anemia (Hb>10 g/dl).
1-Preparation of blood films and detection of P. falciparum :
Thin and thick blood films were done to all subjects using finger – prick blood samples
stained with standard Giemsa stain and examined by light microscopy. Diagnosis of
P.falciparum infection was confirmed by dipstick test kits "ICT Malaria Pf" (ICT
Diagnostics, Australia) containing: test cards, reagent A (lysing solution), capillary
tubes coated with EDTA and product insert, describing test procedure.
The ICT Malaria P.falciparum test was performed according to the test procedure
described in the product insert briefly as follows:
The test card was opened and the blood sample was taken by the capillary tube from the
patient’s pricked finger, was put on the purple area of the sample pad of the dipstick
strip located in the right hand side of the card. Once the purple pad was saturated with
blood sample, one drop of reagent A was poured immediately above the purple pad (two
drops below the blood spot and four drops on to a cleaning pad) located on the top of
the left side of the card. After running up the lysed blood up to a limit line on the strip,
the card was closed. The result could then be read through a viewing window 3-5
minutes after the color of blood has almost cleared.
The test was considered positive when two lines were visible and negative when only a
control line was observed. In case that no line or only the test line appeared, the result
was considered to be invalid.
3
Venous blood ( 3 ml ) was collected from all subjects using the heparinised vaccutainer
system , sera were separated immediately and frozen in -20◦C till the time of ELISA run
.
2-Detection of IL-12 and IL-18 by ELISA :
Interleukin -12 levels were determined by ELISA (NEOGEN corporation , Nandino
Blvd. Lexington ,USA ) with a minimum detection level of 8 pg/ml.
Briefly , coated ELISA plates with 96 wells . Standerd IL-12 and samples were added and
incubated at room teprature for 2 h. Detection antibody was added and incubated at room
temperature for 1 h. Avidin-HRP were added into each well and incubated for 30
minutes at room temperature . TMB Substrate was added and incubated for 15 minutes
at room temperature then stop solution was added , and the plates were read in an
ELISA reader at a wavelenghth of 450 nM.
Interleukin -18 levels were determined by ELISA ( MBL international corporation
Massachusetts , USA ) with a minimum detection level of 12.5 pg/ml.
Briefly , coated ELISA plates with 96 wells . Standerd IL-18 and samples were added and
incubated at room teprature for 1 h. Subsequently , peroxidase-conjugated anti – IL-18 was
added and incubated at room temperature for 1 h. Peroxidase substrate solution was added
into each well and incubated for 30 minutes at room temperature , then stop solution
was added , and the plates were read in an ELISA reader at a wavelenghth of 450 nM.
Results were tabulated and statistically analyzed using a statistical software
(KyPlot, Kioshi Yoshioka, Japan 1999-2001v2)
Results :
Age and sex distribution in the studied groups are shown in ( table 1) . Laboratory
findings of patients and control subjects are shown in ( table 2 ). In this study we found
that there was a high significant difference between patients and controls in RBCs count
, Hb. concentrations , Ht., MCHC, platelets conts and RBlG levels ( P<0.001 ) , while
there was a significant difference in MCV, MCH and S.bilirubin ( P<0.01 ).
We also found that there was a high significant difference between patients with severe
malaria ( Group I – A ) and patients with mild malaria ( Group I-B ) in Hb
concentrations , Ht , platelets counts , RBlG ,and S.bilirubin ( P<0.001 ) , and a
significant difference in RBCs counts and MCV ( P<0.01 ), while there was no
significant difference in Hb. levels and Ht ( P>0.05 ) .
The correlation coefficients between IL-12 and IL-18 were r = 0.52 ( P<0.001 ) in
Group I (A) and 0.41 ( P<0.05 )in group I (B)
Table (1) : Age and sex distribution in the studied groups ;
Males
Females
Total
Age (years)
4
Group I - A
19
11
30
19.6 ± 6.1
Group I - B
30
20
50
15.6 ± 4.8
Group II
19
11
30
18.0 ± 7.4
Table (2): Laboratory parameters in subjects of the study
Group I
A
Group II
B
RBCs
1.78±0.84
(Million/mm3)
Hb
3.96±1.43
(G/dl.)
Ht
11.96±4.2
(%)
MCV
81.6±13.4
( U3 )
MHC
28.1±4.18
( yy )
MCHC
31.16±5.5
(%)
1
Platelets
150±90
( mm3 )
RBl.G
36±4.8
(mg/dl)
S.Bilirubin
3.2±0.63
( mg/dl )
* HS : high significant
Comparisons
3.82±0.91
4.11±0.66
Group I vs Group II
t
P
Sig.
11.71 <0.001
HS
8.61±1.61
11.82±2.5
0.735
<0.001
HS
0.882
<0.001
HS
26.2±5.31
29.3±4.16
0.513
<0.001
HS
0,721
<0.001
HS
72.3±11.8
86.6±10.7
1.052
<0.01
S
2.461
<0.01
S
26.2±3.87
35.8±3.75
1.743
<0.01
S
0.46
>0.05
NS
32.08±4.6
38.22±3.1
1.271
<0.001
HS
0.269
>0.05
NS
238±170
318±99
6.41
<0.001
HS
8.72
<0.001
HS
86±7
105±11
8.64
<0.001
HS
15.36
<0.001
HS
0.7±0.12
0.5±0.41
1.34
<0.01
S
0.561
<0.001
HS
* S : significant
Group IA vs Group IB
t
P
Sig.
8.54
<0.01
S
* NS : non significant
Table (3) : Plasma levels of IL-12 and IL-18 in the studied groups :
Group I
A
IL-12
12.3±6.42
( pg/ml )
1226±
IL-18
267.2
( pg/ml )
* HS : high significant
Group II
B
16.2±8.3
7.8±2.8
Comparisons
Group I vs Group II
t
P
Sig.
2.703 <0.001
HS
2682.8 ±
110±
21.68 <0.001
332.0
104.1
* S : significant
* NS : non significant
HS
Group IA vs Group IB
t
P
Sig.
1.631 <0.01
S
9.361
<0.001
HS
Discussion :
Malaria remains one of the leading global health concerns with over 300 million clinical
cases and more than 1 million deaths on annual basis1. Being a predominantly
tropical disease, malaria is one of the top three killers among communicable diseases in
Africa [11].
Cytokines are key mediators in the cellular program of innate and adaptive immune
responses to P. falciparum, controlling both the induction and the regulation of
important effector immune responses. A critical balance between early pro- and
5
anti-inflammatory cellular responses is crucial both for effectively controlling
parasitemia and for preventing pathology [12].
In our study we found that plasma levels of IL-12 were elevated in patients with severe
malaria ( 12.3±6.42 pg/ml ) and patients with mild malaria ( 16.2±8.2 pg/dl ) more than
controls ( 7.8±2.8 pg/ml ) and we found a significant difference between patients with
severe malaria ( Group I-A ) and patients with mild malaria ( Group I-B ) (p<0.01 ) and
a high significant difference between malaria patients (Group I) and controls (Group II )
( p<0.001 ).
Also we found that the plasma levels of IL-18 were elevated in severe malaria patients
( 1226±267.2 pg/ml) and patients with mild malaria ( 2682±332.0 pg/ml) than in control
group ( 110±104.1pg/ml ) , we found a high significant difference between patients with
severe malaria and patients with mild malaria , also there were a high significant
difference between malaria patients and controls (p<0.001 ) ( table 3).
Our results are in consistent with Malaguarnera et al., 2002 [13] , who studied the
plasma levels of IL-12 and IL-18 in 105 African children affected by mild and severe
P. falciparum malaria from Ouagadougou , Burkina Faso and correlated its levels with
disease severity and found that the levels of IL-18 and IL-12 were higher(25·7 ±7.6 and
17.1± 7·8 pg/ml, respectively) in children with mild malaria than in children with a
severe form of the disease (21·5 ±10 pg/ml and 13·2 ± 5·5 pg/ml, respectively).
A positive correlation was observed between IL-18 and IL-12. His findings suggested
that the production of these two cytokines may be coregulated and both have an
immunoregulatory effect on the immune response in P. falciparum infection.
It was concluded that IL-18 may be involved in the regulation of IL-12 production ,
both could have a critical role in the adaptive immune response to malaria through
induction of IFN- γ , which has a central role in the cell-mediated immune response
against blood-stage infection, inducing phagocytosis and killing. Moreover IL-12 and
IL-18 synergistically induce anti-CD3 stimulated T cells or anti CD40-stimulated B
cells to differentiate into highly IFN- γ producing cells [14] .
The molecular mechanism underlying the synergy between IL-18 and 12 may be
explained in part by reciprocal modulation of cytokine receptor expression. Specifically,
IL-18 has been demonstrated to up-regulate IL-12 R expression, while IL-12 has been
shown to up-regulate expression of IL-18R [15] .
Also , Chaisavaneeyakorn et al., 2003 [8], who compared plasmaIL-12 and IL-18 levels
in six groups of children classified as: aparasitemic, asymptomatic, mild malaria, highdensity uncomplicated malaria (UC), moderate malarial anemia (MMA), or severe
malarial anemia (SMA). IL-12 levels were significantly reduced in children with SMA
(P < 0.05) but not in other groups compared to children in the aparasitemic control
group. IL-18, was produced more frequently (70%) in children with UC (P _ 0.06) than
in children in the aparasitemic control group (32%). However, in the SMA group the
IL-18 response rate declined to 30%, which was similar to that in the aparasitemic
control group, which showed a 32% response rate. This finding suggested that the IL-18
response may be impaired in children with SMA. The results from his study supported
the hypothesis that impairment of IL-12 and/or IL-18 response may contribute to the
development of severe malarial anemia in areas of holoendemicity for malaria [8].
6
The finding that IL-12 was significantly lower in children with SMA was in agreement
with rodent studies [16] and previous human studies involving Gabonese
Children, [17], the lowest level of IL-12 was in children with SMA although children
with MMA and UC also had lower levels of IL-12 [17].
These findings closely agree with the results from a study conducted in Burkina Faso,
where the levels of IL-12 have been shown to be significantly reduced in children with
severe disease compared to those with mild malaria [18].
Luty et al. [19] have suggested that malaria pigments may contribute to the suppression
of IL-12 production. Using a rodent model, Xu et al. [20] have shown that IL-12 p40
gene expression is profoundly inhibited by Plasmodium berghei infection. They have
further shown that IL-10 may play a role in this inhibition and that it may be regulated
by transcriptional regulation of the IL-12 gene [20].
Since IL-12 is involved in directly activating protective immunity against both liver
stage and blood stage parasites, a severe defect in the IL-12 response could directly
affect protective immune pathways and contribute to anemia development.
He found that IL-18 levels were lower or absent in healthy children but elevated
following symptomatic P. falciparum infection as reported in a previous study [21].
Our results goes hand in hand with that obtained with Malaguarnera et al., 2002,[22],
who studied, the levels of IL-12 in 73 African children, , with severe and mild
P. falciparum malaria . The levels of IL-12 were found to be significantly elevated
(21·6 ± 18·3 pg/ml) in patients who suffered less severely from the disease. In contrast,
the levels of IL-12 were found to be lower (13·1 ± 7·11 pg/ml) in patients who suffered
more severely from of the disease.
He also established a critical role for IL-12 in the adaptive immune response to malaria,
inducing development, proliferation and activity of Th1 cells . The outcome of the
disease, such as susceptibility to severe anaemia and other aspects of malarial
pathophysiology, could depend on the response of host macrophages to parasite
products and, consequently, impaired IL-12 production [22]. Luty et al .[19] and
Perkins et a.[17] demonstrated that the low levels of IL- 12 play a role in exacerbation
of anaemia and other clinical complications, that provided evidence that high levels of
IL-12 play an important role in the defense against P. falciparum infection and in
protection against systemic damage induced by the presence of the parasite. Since IL-12
has an important role as the initiator of cell-mediated immunity, it could be used in
therapy as a potent stimulator of the cell-mediated immune response against P.
falciparum. Similar results were obtained by Musumeci et al., 2003 [11].
Different results were obtained by Nagamine et al.,2003 [23] , who studied serum levels
of IL-18, IFN- γ and IgE in 96 patients with P.falciparum malaria in Bangkok ,
Thailand and stated that Il-18 were elevated in all groups of patients with P. falciparum
malaria compared to normal levels . In addition , IL-18 levels were significantly higher
in the severe group than in the uncomplicated group for samples obtained on
admission..
Similar results were obtained by Kojima et al., 2004 [24], also he was found a
significant correlation between IL-18 levels and the extent of parasitemia in the severe
group .
7
It is well known that the peripheral parasitemia does not necessary reflect the total
parasite burden in the host infected with P. falciparum and that the total burden of
parasites may be much larger than the population that the circulating , as sequestration
of peripheral RBC take place in various organs and tissues [24].
Therefore , the elevation of IL-18 levels and its correlation with the extent of
parasitemia may be a simple reflection of immune response to protect from further
severity . Patients with CM showed decreased levels of IL-18 production especialy in
the late stage .The reason for such decrease in IL-18 production was not clear it was
explained by the suppressor effect of nitric oxide on the action of caspase -1 that
regulates IL-18 production by cleaving proIL-18 to induce mature IL-18, thereby
inducing reduction of IL-18 levels . The impaired IL-18 response was suggested in
African children with severe malarial anemia in areas of holoendemicity of malaria
[24].
Conclusion
We can conclude that IL-12 and IL-18 are upregulated during acute P.falciparum
malaria infection , playing a rule in pathogenesis and defence against it . These
cytokines may be used to detect the progression of the disease providing a useful
prognostic parameters , also can be used as an immunotherapy to P.falciparum malaria
infection especially in the early phase of the disease. Further studies are needed to find
out the relation between these cytokines and individual forms and complications of P.
falciparum malaria infection .
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potential role of interleukin 18 in severe Falciparum malaria . Acta Tropica 89 , 279-284
‫ في بالزما الدم في مرضي المالريا‬18- ‫ واالنترلوكين‬12-‫تعيين مستوي االنترلوكين‬
‫الخبيثة في جنوب دارفور‬
**‫محمد إبراهيم عبد الفتاح *محمود محمد بدر* ياسر أحمد شاهين‬
‫*قسم الميكروبيولوجيا والمناعة الطبية ** قسم أمراض الكبد والجهاز الهضمي –كلية طب بنها‬
‫ ) في مرضي‬18- ‫ و انترلوكين‬12- ‫يهدف هذا البحث الي تعيين مستوي السيتوكينات ( انترلوكين‬
.‫المالريا الخبيثة وربط مستواها بشدة المرض‬
:‫وقد شملت هذه الدراسة مجموعتين من األفراد‬
) ‫ مريضا يعانون من المالريا الخبيثة‬80 ( ‫ المجموعة األولي‬: ‫وقد تم تقسيمهم الي مجموعتين فرعيتين‬
‫ مريضا مصابون بمالريا خبيثة مضاعفة‬30 ‫المجموعة األولي ( أ ) وتشمل‬
.‫ مريضا مصابون بمالريا خبيثة غير مضاعفة‬50 ‫المجموعة األولي ( ب ) وتشمل‬
.‫ شخصا طبيعيا ال يعانون من المالريا وذلك كعينة ضابطه‬30 ‫المجموعة الثانية وتشمل‬-
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‫ولقد وجد أن مستوي السيتوكينات المعنية في البحث يزداد في مرضي المالريا الخبيثة أكثر‬
‫من األشخاص الغير مصابين بالمالريا‬
‫ويكون مستوي ارتفاعهما أكثر في المرضي الذين يعانون من المالريا الغير مضاعفة عن‬
‫المرضي المصابون بالمالريا المضاعفة ‪.‬‬
‫ونستنتج من ذلك احتمالية وجود دور لهذه السيتوكينات في تحفيز المناعة للوقاية من مرض‬
‫المالريا الخبيثة كما تؤثر في شدة المرض وحدوث المضاعفات ‪ ,‬مما يمكننا من االعتماد‬
‫عليهما لتوقع شدة المرض وحدوث المضاعفات ويفتح المجال لالستعانة بهما كعالج لتقليل حدة‬
‫المرض ومضاعفاته وخاصة في المراحل األولي لحدوثه ‪.‬‬
‫وننصح بإجراء المزيد من االبحاث حول عالقتهما بمراحل المرض و مضاعفاته كل علي حده‪.‬‬
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