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and protein levels were significantly elevated in peripheral bloodmononuclear
cells of cryptococcal meningitis patients.
27
b
-Arrestin 1 and 2 expression is
reduced in blood leukocytes during acute kidney transplantation.
28
The mod-
ulation of
b
-arrestin expression by cytokines is involved in regulating related
effector pathways.
b
-Arrestins regulate macrophage chemotaxis induced by chemokines
and serine proteases. Chemokine CCL4 (MIP-1
b
) binding to CCR5
induces the translocation of
b
-arrestins, PI3K, and Pyk2 to the membrane
and forms a multikinase signaling complex mediating macrophage migra-
tion.
29
Knockdown of
b
-arrestins 1 and 2 by small interfering RNA
(siRNA) impairs complex formation and inhibits macrophage chemotaxis
toward CCL4.
29
Chemokine CCL2 (MCP-1) binds with the CCR2 recep-
tor, leading to the formation of a CCR2/
b
-arrestin/GRK2 complex in
human monocytes/macrophages. This process promotes the rapid desensi-
tization of CCL2-induced calcium flux responses, which are essential for
chemotaxis in macrophages.
30
Protease-activated receptor-2 (PAR-2) acti-
vation has been shown to enhance
b
-arrestin and ERK1/2-regulated assem-
bly of the actin cytoskeleton in pseudopodia, promoting polarized
pseudopodia extension and facilitating macrophage chemotaxis.
31
Collec-
tively, these studies demonstrate that
b
-arrestins are an integrated regulator
of macrophage-mediated innate immune responses.
2.2.
-Arrestins and polymorphonuclear leukocytes
PMNs are essential for host defense against infection, and the activation of
PMNs is pivotal in the process of innate immunity.
32,33
b
b
-Arrestin 1 is
highly expressed in peripheral blood leukocytes including PMNs.
22
b
-Arrestin 1 and 2 are critical modulators of inflammatory responses in
PMNs, including PMN cytokine production, recruitment,
34
and granule
release.
35
b
-Arrestins and GRK2 associated with the CCR2 receptor play
an important role in CCL2 (MCP-1)-regulated leukocyte activation and
migration following CCL2 binding.
30
PMNs from
b
-arrestin 2-deficient
mice show enhanced release of inflammatory cytokines, including TNF-
a
and IL-6, compared with WT PMNs.
34
b
-Arrestin 2 deficiency results
in augmented PMN recruitment with increased expression of CD18 and
CD62L and enhanced PMN infiltration in the lungs after cecal ligation
and puncture (CLP
34
). Furthermore,
b
-arrestins regulate interleukin (IL)-
8-induced granule exocytosis in PMNs, which is critical for the innate
immune response against infectious bacteria.
35
b
-Arrestin 2 plays a negative
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