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@PHDTHESIS{Kamir:50297,
author = {Kamir, Daniela},
othercontributors = {Bernhagen, Jürgen},
title = {{A} {L}eishmania ortholog of macrophage migration
inhibitory factor modulates host macrophage responses},
address = {Aachen},
publisher = {Publikationsserver der RWTH Aachen University},
reportid = {RWTH-CONV-112848},
pages = {Getr. Zählung : Ill., graph. Darst.},
year = {2008},
note = {Aachen, Techn. Hochsch., Diss., 2008},
abstract = {Parasitic organisms have evolved specialized strategies to
evade host immune defense mechanisms. This thesis describes
the characterization of two Leishmania major-encoded
orthologs of the pro-inflammatory pleiotropic cytokine,
macrophage migration inhibitory factor (MIF). These two
MIF-like sequences show $22\%$ sequence identity when
aligned with human MIF, and are most likely the result of
gene duplication. The Lm1740MIF and Lm1750MIF genes $(58\%$
identity) are expressed in all developmental stages of L.
major. Interestingly, LmMIF expression levels were shown to
be significantly up-regulated in the procyclic life-stage of
the parasite, which exists solely in the host sand fly.
Furthermore, Lm1750MIF levels were 3–4 fold higher than
Lm1740MIF levels. The finding that LmMIF is expressed in
procyclic parasites might reveal a new function for MIF
within its vector, the sandfly. Furthermore, the work
described here postulated that Lm1740MIF might interact with
the macrophage surface receptor, CD74. To evaluate this
hypothesis, binding analyses using surface plasmon resonance
(Biacore) were carried out. The Kd of MIF was previously
approximated to be between 9 × 10-9 to 2.3 × 10-10.
Lm1740MIF showed a significant binding interaction with CD74
(Kd=2.9 × 10-8 M). Thus, there is sufficient structural
homology between Lm1740MIF and human MIF to permit
high-affinity binding to CD74. To investigate whether
Lm1740MIF induces ERK1/2 activation in a CD74-dependent
manner and to determine if it inhibits activation-induced
macrophage apoptosis similar to its mammalian counterpart,
the ability of Lm1740MIF to stimulate ERK1/2 phosphorylation
as well as to inhibit Ser15 phosphorylation of the tumor
suppressor p53 was tested. Macrophages treated with
Lm1740MIF were assessed for apoptosis by the ELISA method;
additionally, Western blot analyses for ERK1/2 and p53
activation were performed. The interaction between Lm1740MIF
and CD74 led to an similar signal transduction response in
macrophages obtained from both wild-type and C3H/HeJ mice,
indicating that signaling was not due to the presence of
contaminating endotoxin. Lm1740MIF was functionally active
in both ERK1/2 signaling and protection from apoptosis,
although the level of activity was generally lower than for
mammalian MIF, an observation that appeared consistent with
the lower Kd of Lm1740MIF for the CD74 receptor. For mouse
MIF, protection from apoptosis was dependent on CD74, and
the response was associated with a decrease in the
cytoplasmic content of Ser15-phosphorylated p53. The ability
of Lm1740MIF to inhibit apoptosis may facilitate the
persistence of Leishmania within macrophages and contribute
to its evasion from immune destruction. The precise cellular
pathway by which Lm1740MIF activates CD74 and whether
Lm1740MIF modulates additional pathways that are important
for either intracellular parasitism or for immune evasion
remains to be determined. In conclusion, the presented
results indicate that a Leishmania ortholog of the cytokine
MIF has the ability to activate the human MIF receptor and
influence the functional responses of monocytes/macrophages.
Because Leishmania is an intracellular infection of
monocytes/macrophages, Leishmania-encoded MIF is
hypothesized to sustain monocyte/macrophage survival and
contribute to the persistence of the parasite for completion
of its infectious life cycle. While these data are
consistent with a role for Leishmania MIF in modulating
host-immune responses, they do not exclude the possibility
that Lm1740MIF may function in the growth and/or replication
of the parasite.},
keywords = {Makrophagen-Inhibitionsfaktor (SWD) / Leishmania major
(SWD) / Makrophage (SWD) / Immunreaktion (SWD) / Protein p53
(SWD)},
cin = {513000-2},
ddc = {570},
cid = {$I:(DE-82)513000-2_20140620$},
typ = {PUB:(DE-HGF)11},
urn = {urn:nbn:de:hbz:82-opus-25165},
url = {https://publications.rwth-aachen.de/record/50297},
}
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