| ironjustice@aol.com 2005-12-29, 10:59 am |
| 1: Curr Med Chem. 2005;12(25):2947-62. Related Articles, Links
Anti-inflammatory immunotherapy for multiple sclerosis/experimental
autoimmune encephalomyelitis (EAE) disease.
Kanwar JR.
Department of Molecular Medicine & Pathology, Faculty of Medicine and
Health Science, university of Auckland, Auckland, New Zealand.
j.kanwar@auckland.ac.nz
Multiple sclerosis (MS) and its animal model, experimental autoimmune
encephalomyelitis (EAE), are inflammatory diseases of the central
nervous system (CNS) characterized by localized areas with
demyelination. Disease is believed to be an autoimmune disorder
mediated by activated immune cells such as T- and B-lymphocytes and
macrophages/microglia. Lymphocytes are primed in the peripheral tissues
by antigens, and clonally expanded cells infiltrate the CNS. They
produce large amounts of inflammatory cytokines, nitric oxide (NO) that
lead to demyelination and axonal degeneration. Although several studies
have shown that oligodendrocytes (OLGs), the myelin-forming glial cells
in the CNS, are sensitive to cell death stimuli, such as cytotoxic
cytokines, anti-myelin antibodies, NO, and oxidative stress, in vitro,
the mechanisms underlying injury to the OLGs in MS/EAE remain unclear.
The central role of glutamate receptors in mediating excitotoxic
neuronal death in stroke, epilepsy, trauma and MS has been well
established. Glutamate is the major excitatory amino acid transmitter
within the CNS and it's signaling is mediated by a number of
postsynaptic ionotropic and metabotropic receptors. Inflammation can be
blocked with anti-cell adhesion molecules MAb, simultaneously protected
oligodendrocytes and neurons against glutamate-mediated damage with the
AMPA/kainate antagonist NBQX, and the NMDA receptor antagonist GPE,
could thus be effective therapies for multiple sclerosis.
PMID: 16378498 [PubMed - in process]
--------------------------------------------------------------------------------
<<snip>>
Our results suggest modulation of iron metabolism as a potential
approach for
anti-inflammatory therapy.
<<snip>>
Cell. 2004 Nov 12;119(4):529-42. Related Articles, Links
Ferritin Heavy Chain Upregulation by NF-kappaB Inhibits
TNFalpha-Induced
Apoptosis by Suppressing Reactive Oxygen Species.
Pham CG, Bubici C, Zazzeroni F, Papa S, Jones J, Alvarez K, Jayawardena
S, De
Smaele E, Cong R, Beaumont C, Torti FM, Torti SV, Franzoso G.
The Ben May Institute for Cancer Research and The university of
Chicago, 924
East 57th Street, Chicago, IL 60637 USA.
During inflammation, NF-kappaB transcription factors antagonize
apoptosis
induced by tumor necrosis factor (TNF)alpha. This antiapoptotic
activity of
NF-kappaB involves suppressing the accumulation of reactive oxygen
species
(ROS) and controlling the activation of the c-Jun N-terminal kinase
(JNK)
cascade. However, the mechanism(s) by which NF-kappaB inhibits ROS
accumulation
is unclear. We identify ferritin heavy chain (FHC)-the primary iron
storage
factor-as an essential mediator of the antioxidant and protective
activities of
NF-kappaB. FHC is induced downstream of NF-kappaB and is required to
prevent
sustained JNK activation and, thereby, apoptosis triggered by TNFalpha.
FHC-mediated inhibition of JNK signaling depends on suppressing ROS
accumulation and is achieved through iron sequestration. These findings
establish a basis for the NF-kappaB-mediated control of ROS induction
and
identify a mechanism by which NF-kappaB suppresses proapoptotic JNK
signaling.
Our results suggest modulation of FHC or, more broadly, of iron
metabolism as a
potential approach for anti-inflammatory therapy.
PMID: 15537542 [PubMed - in process]
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