This document discusses the role of cytokines and chemokines in several central nervous system diseases. It finds that pro-inflammatory cytokines like IL-1β, TNF-α, and IL-6 are overexpressed in epilepsy, Parkinson's disease, and Alzheimer's disease. Animal studies show that inducing chronic expression of IL-1β can cause dopaminergic neuron death. Chemokines like MCP-1, IL-8, and RANTES are also elevated in conditions like cerebral ischemia, Alzheimer's, and multiple sclerosis. Understanding the roles of cytokines and chemokines in diseases may lead to new treatment strategies.

1. Implication Of Cytokines In CNS Diseases

2. • Recent findings shown the possibility that inflammatory processes in the brain
contribute to the etiopathogenesis of seizures and to the establishment of a
chronic epileptic focus.
• Prototypical inflammatory cytokines such as IL-1β, TNF-α and IL-6 have
been shown to be over expressed in experimental models of seizures in brain
areas of seizure generation and propagation, prominently by glia and to a lesser
extent by neurons.
• Cytokine receptors are upregulated, and the related intracellular
signaling is activated.
• Cytokines have been shown to profoundly affect seizures in rodents; in
particular, IL-1β is endowed of proconvulsant activity in a large variety of
seizure models.
• The recent demonstration of functional interactions between cytokines and
classical neurotransmitters such as glutamate and GABA, suggest the possibility
that these interactions underlie the cytokine-mediated changes in neuronal
excitability, thus promoting seizure phenomena.
Cytokines And Epilepsy

3. • Parkinson's disease (PD) is characterized by degeneration of dopaminergic
neurons in the substantia nigra pars compacta (SNpc).
• The pro-inflammatory cytokines, IL-1β, TNF-α, IL-2 and IL-6, are
expressed at very low levels in healthy brain, but have been found at much
higher levels in PD patients, in the post-mortem brain as well as in serum
and cerebrospinal fluid in vivo.
• The death-signaling receptor, TNFR-1, has been found to be expressed
on dopaminergic neurons in human SNpc.
• Animal studies support an involvement of these pro-inflammatory
cytokines in PD. For example, induction of chronic expression of
IL-1β in adult rat SNpc using a recombinant adenovirus resulted in
dopaminergic cell death after three weeks.
Cytokines And Parkinsonism

4. • Aβ has been shown to increase expression of several cytokine mRNAs.
• Over expression of immune modifying cytokine IL-1 by microglia and
astrocytes has been shown to occur in AD in brain.
• TNF a cytokine produced by microglia that is known to promote cell death in
the CNS has been shown to be elevated in AD brain.
• Aβ-also have shown to induce production of chemokines in macrophages and
in astrocytes.
• Different alleles or polymorphisms of a gene may be associated with increased
risk of disease. The IL-1A 2,2 genotype of the IL-1 was noted to confer an
increased risk for AD in a group of neuropathologically confirmed AD patients.
• Another study showed that the interaction between pro-inflammatory IL-6 and
anti-inflammatory IL-10 ,was associated with higher risk of AD.
Cytokines And Alzheimer's Disease

6. Cytokines in Hematopoiesis

7. • Following focal or global ischaemia, GRO-α and MCP-1 mRNAs are
rapidly expressed.
• MCP-1 mRNA is initially expressed in astrocytes surrounding the
ischaemic tissue and subsequently in infiltrating macrophages and
reactive microglia in the infarcted tissue.
• Matsumoto et al. showed that IL-8 level is locally produced in reperfused
rabbit brain tissue and that a neutralizing anti-IL-8 antibody significantly
reduced brain edema and infarct size.
Chemokines In Cerebral Ischemia

8. • An upregulation of the CXCR2 protein (receptor for IL-8) occurs in senile
plaques adjacent to the hippocampus in the brains of Alzheimer's patients.
• Because IL-8 is able to promote survival of hippocampal neurones , a
possible involvement of IL-8/CXCR2 in compensatory and reparative
mechanisms in the Alzheimer's brain should be considered.
• IL-8 mRNA is also known to be regulated by amyloid peptides in human
monocytes.
Chemokines And Alzheimer's Disease

9. • Multiple sclerosis is a human chronic inflammatory and demyelinating
disease that induces subsequent neuronal death.
• Acute and chronic-active MS lesions have been shown to be immunoreactive
for MCP-1, MCP-2 and MCP-3 throughout the lesion centre (hypertrophic
astrocytes and inflammatory cells) while a strong decrease in immunoreactivity
was observed at its edge and only hypertrophic astrocytes were reactive for
chemokines outside the lesion.
• MCP-1 and IL-8 mRNA have also been detected in MS plaques and the levels
of MIP-1α, IP-10 and RANTES in the cerebrospinal fluid of MS patients are
increased over control values.
Chemokines And Multiple Sclerosis

10. • Chemokine expression is markedly upregulated in healing myocardial infarcts
and may play an important role in regulating leukocyte infiltration and activity
in modulating infarct angiogenesis as well as fibrous tissue deposition.
• The CC-chemokine-monocyte chemo attractant protein-1/CCL2 has important
effects in infarct healing.
• CXC chemokines are also induced in healing infarcts.
• Interleukin-8/CXCL8 may mediate neutrophil recruitment and activation and
may promote neovessel formation.
• Induction of the angiostatic and antifibrotic chemokine interferon-γ-inducible
protein-10/CXCL10 may serve to prevent premature wound angiogenesis and
fibrous tissue deposition in the infarct, until the injured myocardium has been
cleared from dead cells and debris and a fibrin-rich provisional matrix is formed.
• Understanding of the role of chemokines in myocardial ischemia may result in
novel strategies in the treatment of patients with ischemic heart disease.
Chemokines And Myocardial Ischemia