INVESTIGATING INTERLEUKIN-18 INVOLVEMENT AND ITS MODULATORY EFFECTS ON MAJOR CYTOKINES RELEASE DURING MALARIA INFECTION IN MICE
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Date
2010-10
Authors
HASBALLAH, KARTINI
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Abstract
IL-18 is a potent pro inflammatory cytokine that plays multiple roles in immune'
responses and inflammatory activities in many disease conditions, but its involvement in
the underlying pathogenesis of malaria has not been fully elucidated. In this study, the
role and involvement of IL-18 during malaria infection was investigated and the impact
of its pathway modulation on the course of the infection and the major cytokines
released during the infection was preliminary evaluated. Plasmodium berghei ANKA
infection in ICR mice were used as malaria model througho~t the study. The animals
were inoculated intravenously with 2 x 107 parasitized red blood cells (PRBCs) obtained
from a donor mouse infected with the parasite. The control animals received an
equivalent volume and dilution (0.2 mL, i.v.) of normal mouse RBC. Results
demonstrated that the malarial mice showed sick behavioral. changes on day 4 after
inoculation when the levels of parasitaemia were ~ 60% and then continued to increase
until circulating parasitaemia reached around 80%. The infected mice succumbed to
hyperparasitaemia 5-6 days after infection. ICR mice also showed significant decrease in
body temperature and body weight during the peak parasitaemia. IL-18 concentrations in
the plasma determined by means of ELISA, showed significant elevation thrOl~ghout the
infection and a positive correlation with parasitaemia development. Since malaria
infection causes multi organ dysfunction, tissues from major organs known to be
affected during malaria infection which include the spleen, liver, brain, lungs and kidney
were examined for IL-18 expression using SDS-PAGE and Western blot analysis. The
study revealed that IL-18 was expressed in different intensity in the spleen, liver, brain
and lungs. No IL-18 was detected in the kidney of mice during the infection. IL-18
production during malaria infection was modulated by treatment with rrnIL-18BP,
ArnIL-18 and rrnIL-18. Treatment with rrnIL-18BP and ArnIL-18 inhibited the
parasitaemia development at early phase of infection. Significant inhibition on parasites'
development occurred on day 1 until day 3 after treatment. Body weight as well as body
temperature of malarial mice decreased on day 4 until day 6 from thei~ initial values
after the treatment. rrnIL-18 treatment caused the parasitaemia levels to increase rapidly
followed by a decrease in body weight and body temperature. Earlier mortality was also
observed in the malarial mice treated with rrnIL-18. Results also showed that inhibition
ofIL-18 by treatment with rrnIL-18BP and ArnIL-18 significantly reduced the release of
pro-inflammatory cytokines IFNy, TNFa, IL-6 and IL-la levels and on the other hand
increased the level of anti-inflammatory cytokine IL-IO significantly. In contrast,
augmentation of IL-18 production significantly increased the levels of the proinflammatory
cytokines and reduced the level of the anti-inflammatory cytokine in the
serum during the infection. In conclusion, the results from this study suggest that IL-18
is involved during malaria infection and it may well playa crucial role in mediating the
severity of the disease. Its pathway modulation produced a significant impact on the
cytokine network during the infection which may suggest that modulating IL-18
production during malaria infection could be a promising therapeutic concept for malaria
therapy.
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Keywords
INVESTIGATING INTERLEUKIN , INFECTION IN MICE