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TNF
a
and IL-6 production, while
b
-arrestin decreased their production by
synoviocytes.
153
Finally, mice deficient in
b
-arrestin 2 exhibited more
severe arthritis in the collagen-induced arthritis model.
153
The role of chemokine receptor CCR2 and
b
-arrestins has been inves-
tigated in inflammatory arthritis, with some studies suggesting that blocking
CCR2 signaling may ameliorate arthritis in animal models. A fusion protein
using GM-CSF and an N-terminal truncated version of CCL2 binding to
CCR2 led to altered conformational changes in the CCR2 homodimer
and failed to induce the recruitment of
b
-arrestin 2 to the receptor.
63
The fusion peptide was capable of blocking IL-17 production
in vitro
and
attenuated inflammatory arthritis
in vivo
in mice.
63
This study suggests that
suppressing expression of
b
-arrestins may protect joints from rheumatoid
arthritis.
Thus, strategies that regulate
b
-arrestin expression or activity may be
developed for patients with rheumatoid arthritis. For example, Paeoniflorin,
a monoterpene glucoside that decreased expression of
b
-arrestin 1 and
b
-arrestin 2, and increased
b
2AR and GRK2 in mesenteric lymph node
lymphocytes,
significantly attenuated arthritis
scores and reversed the
changes of cytokines.
154
6.4. Multiple sclerosis
Multiple sclerosis is characterized by the presence of plaques of demyelin-
ation throughout the central nervous system. The destruction of myelin is
believed to involve autoimmune mechanisms.
b
-Arrestin 1 autoantibodies
have been found in sera frommultiple sclerosis patients.
155
Multiple sclerosis
patients had a greater prevalence of positive T-cell proliferative responses to
b
-arrestin than healthy controls.
156
These studies suggest a role for
b
-arrestin
1 in the pathogenesis of multiple sclerosis.
b
-Arrestin 1 expression was
increased in brains of multiple sclerosis patients relative to nonmultiple scle-
rosis brains.
157
This suggests that
b
-arrestin 1 may be a negative regulator in
multiple sclerosis. In contrast, another study showed that
b
-arrestin 1
mRNA levels were reduced by phytohemagglutinin, but increased in inter-
feron
b
-1a-treated mononuclear leukocytes.
26
As IFN
b
-1a is known to
ameliorate the course of multiple sclerosis,
b
-arrestin 1 may be a downstream
mediator in multiple sclerosis. Additional studies suggest that
b
-arrestin 1 is
critical for CD4
รพ
T-cell survival and may be a factor in susceptibility to
autoimmunity.
46
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