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Proposal
Cytokines and Inflammatory diseases, such
as MS --- Is there a Link?
Cytokines are secreted proteins that regulate
many biological activities, and plays an important role
in immunity. A new family of cytokines, IL-17, have
been identified and reveal a distinct ligand-receptor
signaling system. IL-17 is produced by a sub population
of T-cells, Th17 cells. Th17 cells and IL-17 are the
major encephalitogenic T cells and cytokines in the
EAE. Functional analysis of IL-17 has demonstrated its
ability to induce the production of other cytokines
and chemokines, such as Il-6, IL-8, G-CSF, GM-CSF, MCP-1
from a variety of cell types. Functional studies have
also provided evidence for the importance of IL-17 in
the regulation of immune system, its promotion of chronic
inflammatory response and Th2 responses. The cognate
receptors for the IL-17 family identified thus far are:
IL-17R, IL17RH-1. IL-17RL, IL17-RD, and IL-17RE. However,
the ligand specificities of many of these receptors
have not been established. The IL-17 signaling system
is operative in disparate tissues such as articular
cartilage, bone, meniscus, brain, hematopoietuc tissue,
kidney, skin and intestine. Thus, the evolving IL-17
family of ligands and receptors may play an important
role in the homeostasis of tissues in health and disease
beyond the immune system. The IL-17 receptor is a Type
1 transmembrane glycoprotein, and shares 84 and 72%
aa sequence identity with rat and human IL-17 R (receptor)
respectively.
Our research study will be focused to
determine the major site of action of IL-17 receptor
in the EAE is in the central nervous system (CNS). In
other words we will attempt to answer the question:
do CNS cells express the IL-17R?
Our research will be as follows:
CNS cells specific localization of IL-17R protein in
healthy vs. EAE mice by routine double label immunofluorescence.
Expression of IL-17R mRNA by RT-PCR
Expression of IL-17R protein in neonatal glial cells
by Flow cytometry.
Co-culturing of Th1 vs. Th17 cells with neonatal astrocytes/microglia
- alteration of the expression level of IL-17R
- functional significance of differential expression
and
- measurement of downstream products (e.g. cytokines,
chemokines).
Overall, we expect to verify that the CNS cells do
express the IL-17R. Increased understanding of the
role of complexity of the cytokine network, together
with characterization of its receptor would help to
uncover the molecular mechanisms of inflammatory diseases,
such as MS.
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