SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

T U M O R I M M U N O L O G Y P R O G R A M
SELECTED PUBLICATIONS
2003
Torroella-Kouri, M and Lopez, D. Mammary
tumor derived TGF-β impairs crucial innate immune
responses in tumor hosts. Journal of Immunology
and Immunopathology 5:31-38, 2003.
Torroella-Kouri, M , Keith, JC, Ivanova, M, and
Lopez, DM. IL-11-induced reduction of C/EBP
transcription factor binding may contribute to
the IL-12 down-regulation in tumor-bearing
mice. International Journal of Oncology 22:439-
48, 2003.
HIGHLIGHTS/DISCOVERIES
• Focused on the tumor-induced mechanisms
that explain the impaired expression of IL-12 in
the macrophages of the mice bearing the D1-
DMBA-3 mammary tumor.
• Demonstrated that indeed there is a decreased
IL-12 production in elicited peritoneal macrophages
from tumor-bearing mice, both at the
level of the protein (ELISA) as well as at the
level of the gene (RT-PCR and Northern blot).
They have shown that the expression of gene
p40 is profoundly decreased, although gene p35
has a slightly diminished expression as well in
macrophages of tumor bearers (IL-12 is a
heterodimer comprised of two independently
regulated genes, p40 and p35).
• Demonstrated that in message stability experiments
there is no difference in the mRNA stability
of the p40 message between normal and
tumor-bearing animals, meaning that the regulation
of the deficiency seems not to be posttranscriptional.
• Electromobility shift assays (EMSAs) with
nuclear extracts of macrophages from normal
and tumor animals have shown that of several
transcription factors that appear to be relevant
in the transcription of the p40 gene, there is a
diminished binding activity of NFκB and
C/EBP transcription factors to their sites in the
p40 promoter of tumor-bearing animals. It is
known that there are several factors produced
by the D1-DMBA-3 tumor that are able to
down-regulate IL-12. Among these,
phopsphatidylserine and prostaglandin E2,
which are produced by this tumor, have been
shown to down-regulate IL-12 in macrophages
of normal mice pretreated with these factors.
• Demonstrated that this mammary tumor produces
the anti-inflammatory and metastasispromoting
cytokine IL-11, and that IL-11
decreases IL-12 production as well, by diminishing
the expression of p40 gene (RT-PCR).
Researchers in her laboratory also have demonstrated
that IL-11 decreases the binding activity
of the C/EBP transcription factor, but not that
of NFκB to the p40 promoter in tumor bearing
animals.
• Demonstrated that the immunosuppressor
cytokine transforming growth factor-beta
(TGF-β) also is produced by the D1-DMBA-3
tumor, as well as by macrophages and T cells
from these tumor-bearing animals. TGF-β also
is known to down-regulate IL-12. On the other
hand, macrophages and B cells from tumorbearing
animals overproduce the cytokines IL-6
and tumor necrosis factor-alpha (TNF-α).
TNF-α is known to down-regulate IL-12, and
her laboratory has been able to demonstrate
that IL-6 decreases the production of this
cytokine as well. Therefore, there are different
tumor-associated factors that could be playing a
role in the impairment of IL-12 production in
the laboratory’s tumor model. Some of their
mechanisms have been worked out.
• Observed that two of these molecules, the phospholipid
PS and the cytokine IL-6 are novel
modulators of this important cytokine. Dr.
Torroella-Kouri plans to focus her laboratory’s
immediate research efforts on the elucidation
of the molecular mechanisms by which these
molecules down-regulate the expression of the
IL-12 genes.
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UM/Sylvester Comprehensive Cancer Center Scientific Report 2004