Astrocytes have a dynamic role in regulating neuronal function, and play an active and dual role in CNS inflammatory diseases such as multiple sclerosis. MS is a progressive and neurodegenerative disease of the CNS. A major pathological hallmark of MS is the presence of demyelinated lesions. In the active phase of this Wortmannin ATM disease, which is known to be caused in the recruitment and activation of various cell types such as T cells, macrophages and dendritic cells etc, mast cells and astrocytes have been reported as an effector Inhibitors,Modulators,Libraries cells, although these cells remain to be further determined. An accumulation of mast cells in MS pla ques and normal appearing white matter observed by his topathological analysis, an elevation of mast cell specific enzyme in the cerebrospinal fluid of MS patients, and an increase of mast cell markers show the implication of mast cells in the pathophysiology of MS.
Moreover, Mast cells related to experimental allergic encephalomyelitis Inhibitors,Modulators,Libraries in monkey and mice as an animal model of MS were previously reported by others and our laboratories. However, it has been reported that mast cells are dispensable for develop ment of disease, although they accumulate in the brain and CNS and the reconstitution of mast cell population in W W mice, which Inhibitors,Modulators,Libraries are deficient in c kit receptor, restores induction of early and severe disease to wild type levels. Astrocytes participate in immune function through the specific loss of a cytokine receptor like gp130, or through reduction of nuclear Inhibitors,Modulators,Libraries factor B signaling.
Astrocytes lead to chronic inflammation and progressive neurodegeneration by overexpression of several cytokines such as interleukin 1b, tumor necrosis factor a, interferon g, IL 6, IL 12, and transforming growth factor b, and by overexpression of chemokine like CCL2. The cytokine TNF a is also an important factor in the regulation of neuro nal apoptotic cell death. TNF a mRNA expression Inhibitors,Modulators,Libraries in blood mononuclear cells is correlated with disease activ ity in relapsing remitting MS, while high IL 6 levels in the CNS and TNF a release in astrocytes are correlated with the development of EAE in rats. Thus, future challenges include determining how individual cytokines and chemokines produced by astrocytes influ ence the development of inflammation and the behavior of infiltrating immune cell populations.
In the CNS, the co stimulatory molecule CD40 is expressed in a variety of cells including astrocytes and microglia, and the natural ligand of CD40 belongs to concerning the TNFR superfamily. Interaction of CD40 on astrocytes and CD40L on the infiltrating T cells and other resident CNS cells such as monocytic cells, natural killer cells and mast cells, trigger a series of intra cellular signaling events that promote the production of a wide array of cytokines, chemokines and neurotoxins.