The Toxicologist - Society of Toxicology

significant increases in the various tested biomarkers in the E-deficient and E-normal
groups, when compared to the corresponding controls in each of those groups.
However, the DCA- and TCA-induced increases within the E-deficient subgroups
were significantly greater than those of the corresponding subgroups within the Enormal
group. Previous studies in our lab suggested phagocytic activation as a defense
mechanism against DCA- and TCA-induced long-term hepatotoxicity. The
present results, including phagocytic activation and antioxidant enzyme activities
suggest up-regulation of those mechanisms in response to vitamin E deficiency to
accommodate for the loss of protection by vitamin E against DCA and TCA longterm
toxicities. (Supported by NIH/NIEHS grant # R15ES013706-01A2)
252 XENOBIOTIC-INDUCED ENDOPLASMIC RETICULUM
STRESS TRIGGERS PRO-INFLAMMATORY NF-κB
SIGNALS VIA REPRESSION OF PEROXISOME
PROLIFERATOR-ACTIVATED RECEPTOR γ
Y. Moon and S. Park. Microbiology and Immunology, Pusan National University
School of Medicine and Medical Research Institute, Yangsan, Republic of Korea.
Endoplasmic reticulum (ER) stress is a causative factor of human inflammatory
bowel diseases (IBD). ER stress mediators including CCAAT-enhancer-binding
protein (C/EBP) homologous protein (CHOP) are elevated in intestinal epithelia
from patients with IBD. The present study arose from the question of how chemical
ER stress and CHOP protein were associated with nuclear factor-κB (NF-κB)mediated
epithelial inflammatory response. In a human intestinal epithelial cell culture
model, chemical ER stresses induced pro-inflammatory cytokine interleukin-8
(IL-8) expression and the nuclear translocation of CHOP protein. CHOP was positively
involved in ER-activated IL-8 production and was negatively associated with
expression of peroxisome proliferator-activated receptor γ (PPARγ). ER stress-induced
IL-8 production was enhanced by NF-κB activation that was negatively regulated
by PPARγ. Mechanistically, ER stress-induced CHOP suppressed PPARγ
transcription by sequestering C/EBPβ and limiting availability of C/EBPβ binding
to the PPARγ promoter. Due to the CHOP-mediated regulation of PPARγ action,
ER stress can enhance pro-inflammatory NF-κB activation and maintain increased
level of IL-8 production in human intestinal epithelial cells. In contrast, PPARγ was
a counteracting regulator of gut inflammatory response through attenuation of NFκB
activation. The collective results support the view that balances between CHOP
and PPARγ are crucial for epithelial homeostasis and disruption of these balances in
mucosal ER stress can etiologically affect the progress of human IBD (This research
was supported by Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education, Science and
Technology (No. 2009-0087028)).
253 PRO-INFLAMMATORY CYTOKINE AND
COMPLEMENT RECEPTOR 3 (CR3) RESPONSES TO
FUNGAL CELL WALL MANNAN AND MANNAN
BINDING LECTIN (MBL) IN HUMAN WHOLE BLOOD
AND MONOCYTES.
A. M. Nilsen 1 , I. Rauk 1 , M. Løvik 1, 2 and L. N. Johannessen 1 . 1 Cancer Research
and Molecular Medicine, Norwegian University of Science and Technology,
Trondheim, Norway and 2 Division of Environmental Medicine, Norwegian Institute
of Public Health, Oslo, Norway.
A correlation between fungal exposure and aggravation of respiratory symptoms in
asthmatic individuals is well documented. In severe asthma, mannan binding lectin
(MBL) has been found to modulate the inflammatory cytokine production. We
have observed a reduced production of TNF-α by monocytes after exposure to S.
cerevisiae cell wall mannan in adult humans with mild asthma, (Johannessen et al.,
2008), suggesting a role for MBL even in mild disease. The hypothesis of the present
work was that MBL influences the mannan-induced production of pro-inflammatory
cytokines as well as the activation of complement, all parts of the asthmatic
response. Whole blood from healthy volunteers was exposed to 100 μg/ml mannan
and 100 or 500 ng/ml MBL, and human monocytes from buffy coats were exposed
to 100 μg/ml mannan and 100 to 1500 ng/ml MBL for up to six hours. The MBL
concentrations used were similar to those observed in mild asthma and in healthy
controls. Differences between groups were tested by t-tests and two-way ANOVA
with significance level p