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|Title: ||Interleukin-6 class cytokines regulate the development of inflammatory CNS lesions|
|Authors: ||Hellings, N.|
Hendriks, J. J. A.
de Vries, H.
Eijnde, B. O.
Van den Haute, C.
|Issue Date: ||2012|
|Citation: ||IMMUNOLOGY, 137 (s1), p. 31-31|
|Abstract: ||Purpose/Objective: The interleukin-6 class cytokines leukemia
inhibitory factor (LIF) and oncostatin M (OSM) are upregulated in
multiple sclerosis (MS) lesions, but their effects on CNS lesion
development are far from understood. LIF and OSM potentially
influence immune responses as well as CNS resident cells during
neuroinflammatory conditions. Importantly, since they activate different
receptors, LIF and OSM can influence these parameters to different
extents. This study was designed to elucidate the role of OSM
and LIF in MS lesion development.
Materials and methods: Stereotactic application of lentiviral vectors
was performed to achieve a stable expression and secretion of LIF or
OSM in the CNS of adult mice. Experimental autoimmune encephalomyelitis
(EAE) was induced in C57BL6J mice with MOG-peptide.
Receptor expression on human immune cell subsets was determined by
flow cytometry. Primary cultures of oligodendrocytes and macrophages
were used to study direct effects on these cell types. Immunohistochemistry
and real time PCR were applied to elucidate the in vivo
effects of local cytokine expression.
Results: Our previous study showed that gene therapeutic expression of
LIF in the CNS significantly reduced immune-mediated demyelination.
Our in vitro studies show that LIF protects oligodendrocytes from
inflammatory insults. Now, we demonstrated that treatment after disease
onset still ameliorates EAE symptoms. To define which immune cells
play a crucial role in the immunomodulatory actions of LIF, expression
of the LIF receptor was determined on human immune cells. Monocytes
express the LIF receptor subunits at high levels, while there is only a
limited population of T cells and B cells that express the receptor. LIF
reduces production of toxic mediators by macrophages. In contrast to
LIF, local expression of OSM did not simply alleviate symptoms but
suppressed the incidence of EAE. While we did find a local inflammatory
response at the site ofOSMexpression, infiltration of typical EAE-related
immune cells in the CNS was blocked. CNS-targeted OSM production
was necessary, since systemic administration of the cytokine did not
affect development of autoimmune induced CNS lesions.
Conclusions: Our study demonstrates that OSM and LIF play an
important but distinct role in lesion development in neuroinflammatory
disease. These cytokines and their downstream signalling molecules
are potential candidates for therapy.|
|Notes: ||[Hellings, N.; Janssens, K.; Hendriks, J. J. A.; Vanwijmeersch, B.; Eijnde, B. O.; Stinissen, P.; Slaets, H.] Hasselt Univ, Biomed Res Inst BIOMED, Diepenbeek, Belgium. [de Vries, H.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Van den Haute, C.; Baekelandt, V.] Katholieke Univ Leuven, Lab Neurobiol & Gene Therapy, Louvain, Belgium.|
|ISI #: ||000309189100074|
|Type: ||Journal Contribution|
|Appears in Collections: ||Biomedical Research Institute|
Healthcare & Economics
Immunology - Biochemistry
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