Abstract:
BACKGROUND:CCR2 plays a key role in regulating monocyte trafficking to sites of inflammation and therefore has been the focus of much interest as a target for inflammatory disease. METHODS:Here we examined the effects of CCR2 blockade with a potent small molecule antagonist to determine the pharmacodynamic consequences on the peripheral blood monocyte compartment in the context of acute and chronic inflammatory processes. RESULTS:We demonstrate that CCR2 antagonism in vivo led to a rapid decrease in the number of circulating Ly6Chi monocytes and that this decrease was largely due to the CXCR4-dependent sequestration of these cells in the bone marrow, providing pharmacological evidence for a mechanism by which monocyte dynamics are regulated in vivo. CCR2 antagonism led to an accumulation of circulating CCL2 and CCL7 levels in the blood, indicating a role for CCR2 in regulating the levels of its ligands under homeostatic conditions. Finally, we show that the pharmacodynamic changes due to CCR2 antagonism were apparent after chronic dosing in mouse experimental autoimmune encephalomyelitis, a model in which CCR2 blockade demonstrated a dramatic reduction in disease severity, manifest in a reduced accumulation of monocytes and other cells in the CNS. CONCLUSION:CCR2 antagonism in vivo has tractable pharmacodynamic effects that can be used to align target engagement with biologic effects on disease activity.
journal_name
J Inflamm (Lond)journal_title
Journal of inflammation (London, England)authors
Wang Y,Cui L,Gonsiorek W,Min SH,Anilkumar G,Rosenblum S,Kozlowski J,Lundell D,Fine JS,Grant EPdoi
10.1186/1476-9255-6-32subject
Has Abstractpub_date
2009-11-11 00:00:00pages
32issn
1476-9255pii
1476-9255-6-32journal_volume
6pub_type
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journal_title:Journal of inflammation (London, England)
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journal_title:Journal of inflammation (London, England)
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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journal_title:Journal of inflammation (London, England)
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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pub_type: 杂志文章
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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abstract:: Interleukin-6 is a multifunctional cytokine that is critical for T/B-cell differentiation and maturation, immunoglobulin secretion, acute-phase protein production, and macrophage/monocyte functions. Extensive research into the biology of IL-6 has implicated IL-6 in the pathophysiology and pathogenesis of RA. An anti-...
journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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更新日期:2017-08-09 00:00:00
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
doi:10.1186/1476-9255-11-10
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pub_type: 杂志文章
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
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journal_title:Journal of inflammation (London, England)
pub_type: 杂志文章
doi:10.1186/1476-9255-6-7
更新日期:2009-03-27 00:00:00