Transcriptional regulation of gene expression in
neurons and immune cells
The organization of the nervous and immune systems is
characterized by obvious differences and striking parallels. Both systems need
to relay information across very short and very long distances.
The nervous system communicates over both long and
short ranges primarily by means of more or less hardwired intercellular
connections, consisting of axons, dendrites, and synapses. Long-range
communication in the immune system occurs mainly via the ordered and guided
migration of immune cells and systemically acting soluble factors such as
antibodies, cytokines, and chemokines. Its short-range communication either is
mediated by locally acting soluble factors or transpires during direct
cell–cell contact across specialized areas called “immunological synapses”
(Kirschensteiner et al., 2003). These parallels in intercellular communication
are complemented by a complex array of factors that induce cell growth and
differentiation: these factors in the immune system are called cytokines; in
the nervous system, they are called neurotrophic factors.
Neither the cytokines nor the neurotrophic factors
appear to be completely exclusive to either system (Neumann et al., 2002). In
particular, mounting evidence indicates that some of the most potent members of
the neurotrophin family, for example, nerve growth factor (NGF) and
brain-derived neurotrophic factor (BDNF), act on or are produced by immune
cells (Kerschensteiner et al., 1999)
There are, however, other neurotrophic factors, for example the
insulin-like growth factor-1 (IGF-1), that can behave similarly (Kermer et al.,
2000).
These factors may allow the two systems to “cross-talk”
and eventually may provide a molecular explanation for the reports that
inflammation after central nervous system (CNS) injury has beneficial effects
(Moalem et al., 1999).
In order to shed
some more light on such a cross-talk, therefore, transcription factors
modulating mu-opioid receptor (MOPr) expression in neurons and immune cells are
investigated.
Several studies,
primarily focused on the upstream region of the OPRM1 promoter, have
investigated transcriptional regulation of MOPr expression. Presently, however, it is still not
completely clear how positive and negative transcription regulators
cooperatively coordinate cell- or tissue-specific transcription of the OPRM1
gene, and how specific growth factors influence its expression.
The human mu-opioid
receptor gene (OPRM1) promoter contains a DNA sequence binding the repressor
element 1 silencing transcription factor (REST) that is implicated in
transcriptional repression. Therefore we are interested in investigating
whether insulin-like growth factor I (IGF-I), which affects various aspects of
neuronal induction and maturation, regulates OPRM1 transcription in neuronal
cells in the context of the potential influence of REST by using a series of
OPRM1-luciferase promoter/reporter constructs in neuroblastoma-derived SH-SY5Y
cells and PC12 cells.
IGF-I and its
receptors, on one hand, are widely distributed throughout the nervous system
during development, and their involvement in neurogenesis has been extensively
investigated (Arsenijevic et al. 1998; van Golen and Feldman 2000).
On the other
hand, REST plays a complex role in neuronal cells by differentially repressing
target gene expression (Lunyak et al. 2004; Coulson 2005; Ballas and Mandel
2005). REST expression decreases during
neurogenesis, but has been detected in the adult rat brain (Palm et al. 1998)
and is up-regulated in response to global ischemia (Calderone et al. 2003) and
induction of epilepsy (Spencer et al. 2006).
Thus, the REST concentration seems to influence its function and the
expression of neuronal genes, and may have different effects in embryonic and
differentiated neurons (Su et al. 2004; Sun et al. 2005). In a previous study,
REST was elevated during the early stages of neural induction by IGF-I in
neuroblastoma cells. REST may
contribute to the down-regulation of genes not yet required by the
differentiation program, but its
expression decreases after five days of treatment to allow for the acquisition
of neural phenotypes.
T-cell receptor
(TCR) recognizes peptide antigens displayed in the context of the major
histocompatibility complex (MHC) and gives rise to a potent as well as branched
intracellular signalling that convert naïve T-cells in mature effectors, thus
significantly contributing to the genesis of a specific immune response. By
exposing wild type Jurkat CD4+ T-cells to a mixture of CD3 and CD28 antigens we
fully activate TCR and study whether its signalling influence OPRM1 expression.
Results were that TCR engagement determined a significant induction of OPRM1
expression through the activation of transcription factors AP-1, NF-kB and
NFAT. Eventually, I investigated MOPr turnover once it has been expressed on
T-cells outer membrane. It turned out that DAMGO induced MOPr internalisation
and recycling, whereas morphine did not.
Overall, from the
data collected by now, it can be concluded that that a reduction in REST is a
critical switch enabling IGF-I to up-regulate human MOPr, helping these
findings clarify how human MOPr expression is regulated in neuronal cells, and
that TCR engagement up-regulates OPRM1 transcription in T-cells. My results
that neurotrophic factors and TCR engagement, as well as it is reported for
cytokines, seem to up-regulate OPRM1 in both neurons and immune cells suggest
an important role for MOPr as a molecular bridge between neurons and immune
cells; therefore, MOPr could play a key role in the cross-talk between immune
system and nervous system and in particular in the balance between
pro-inflammatory and pro-nociceptive stimuli and analgesic and neuroprotective
effects.
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