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Rabeximod reduces arthritis severity in mice by decreasing activation of inflammatory cells.

Hultqvist, Malin LU ; Kutty Selva, Nandakumar; Björklund, Ulf and Holmdahl, Rikard LU (2010) In Annals of the Rheumatic Diseases Jul 1. p.1527-1532
Abstract
OBJECTIVES: /st> The novel small molecule 9-chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo[2,3-b] quinoxaline (Rabeximod) reduces severity of arthritis in rodent models of rheumatoid arthritis (RA) and multiple sclerosis (MS). This study aimed to investigate the cellular target in vivo. METHODS: /st> Collagen antibody-induced arthritis (CAIA) is induced by monoclonal collagen type II antibodies and enhanced by lipopolysaccharide. It was investigated how and when Rabeximod operates on inflammatory cells after stimulation of either Toll-like receptor (TLR)4 (lipopolysaccharide) or TLR2 (lipomannan) in mice lacking functional signalling through TLR4 due to a spontaneous deletion of the Tlr4 gene. RESULTS:... (More)
OBJECTIVES: /st> The novel small molecule 9-chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo[2,3-b] quinoxaline (Rabeximod) reduces severity of arthritis in rodent models of rheumatoid arthritis (RA) and multiple sclerosis (MS). This study aimed to investigate the cellular target in vivo. METHODS: /st> Collagen antibody-induced arthritis (CAIA) is induced by monoclonal collagen type II antibodies and enhanced by lipopolysaccharide. It was investigated how and when Rabeximod operates on inflammatory cells after stimulation of either Toll-like receptor (TLR)4 (lipopolysaccharide) or TLR2 (lipomannan) in mice lacking functional signalling through TLR4 due to a spontaneous deletion of the Tlr4 gene. RESULTS: /st> Rabeximod efficiently prevented arthritis during the time window when TLR2 or TLR4 ligands activate inflammatory macrophages. The effect operated downstream of TLR activation as Rabeximod was highly therapeutic in CAIA enhanced through TLR2 stimuli in TLR4 deficient mice. In addition, it was found that the arthritis ameliorating effect of Rabeximod was time dependent, since inhibition of tumour necrosis factor alpha production from macrophages in vitro was more pronounced if administered close to stimulation. CONCLUSIONS: /st> Rabeximod suppresses arthritis by preventing activation of inflammatory cells, most likely macrophages, in a time dependent fashion, downstream of TLR2 and TLR4 stimulation. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Annals of the Rheumatic Diseases
volume
Jul 1
pages
1527 - 1532
publisher
British Medical Association
external identifiers
  • WOS:000280171700021
  • PMID:20542961
  • Scopus:77955452602
ISSN
1468-2060
DOI
10.1136/ard.2009.121178
language
English
LU publication?
yes
id
03077f3e-f669-42ac-af03-b266189ce141 (old id 1626152)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20542961?dopt=Abstract
date added to LUP
2010-07-05 19:31:31
date last changed
2016-10-13 04:28:20
@misc{03077f3e-f669-42ac-af03-b266189ce141,
  abstract     = {OBJECTIVES: /st> The novel small molecule 9-chloro-2,3-dimethyl-6-(N,N-dimethylaminoethylamino-2-oxoethyl)-6H-indolo[2,3-b] quinoxaline (Rabeximod) reduces severity of arthritis in rodent models of rheumatoid arthritis (RA) and multiple sclerosis (MS). This study aimed to investigate the cellular target in vivo. METHODS: /st> Collagen antibody-induced arthritis (CAIA) is induced by monoclonal collagen type II antibodies and enhanced by lipopolysaccharide. It was investigated how and when Rabeximod operates on inflammatory cells after stimulation of either Toll-like receptor (TLR)4 (lipopolysaccharide) or TLR2 (lipomannan) in mice lacking functional signalling through TLR4 due to a spontaneous deletion of the Tlr4 gene. RESULTS: /st> Rabeximod efficiently prevented arthritis during the time window when TLR2 or TLR4 ligands activate inflammatory macrophages. The effect operated downstream of TLR activation as Rabeximod was highly therapeutic in CAIA enhanced through TLR2 stimuli in TLR4 deficient mice. In addition, it was found that the arthritis ameliorating effect of Rabeximod was time dependent, since inhibition of tumour necrosis factor alpha production from macrophages in vitro was more pronounced if administered close to stimulation. CONCLUSIONS: /st> Rabeximod suppresses arthritis by preventing activation of inflammatory cells, most likely macrophages, in a time dependent fashion, downstream of TLR2 and TLR4 stimulation.},
  author       = {Hultqvist, Malin and Kutty Selva, Nandakumar and Björklund, Ulf and Holmdahl, Rikard},
  issn         = {1468-2060},
  language     = {eng},
  pages        = {1527--1532},
  publisher    = {ARRAY(0x83abe38)},
  series       = {Annals of the Rheumatic Diseases},
  title        = {Rabeximod reduces arthritis severity in mice by decreasing activation of inflammatory cells.},
  url          = {http://dx.doi.org/10.1136/ard.2009.121178},
  volume       = {Jul 1},
  year         = {2010},
}