RESEARCH - Suppression of TNF production from mononuclear cells by a novel synthetic compound, CLX-090717

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Rheumatology Advance Access published online on November 16, 2008

Rheumatology, doi:10.1093/rheumatology/ken398

Suppression of tumour necrosis factor production from mononuclear

cells by a novel synthetic compound, CLX-090717

P. F. Sumariwalla1, C. D. Palmer1, L. B. Pickford2, M. Feldmann1, B.

M. J. Foxwell1 and F. M. Brennan1

1Kennedy Institute of Rheumatology, Imperial College London, London,

UK and 2Theracos Inc., Sunnyvale, CA, USA.

Abstract

Objectives. To evaluate the clinical efficacy of a novel synthetic

peroxisome proliferator-activated receptor gamma (PPAR-) agonist,

CLX-090717, in several in vitro cell culture systems and murine CIA,

an experimental model of RA.

Methods. Peripheral blood monocytes purified by elutriation, and

rheumatoid synovial cells isolated from clinical tissue were cultured

with CLX-090717 and TNF- release was measured. Molecular mechanism of

action was analysed by western blotting and electrophoretic mobility

shift assay. Thioglycollate-elicited murine peritoneal macrophages

were cultured with CLX-090717 and lipopolysaccharide (LPS)-induced

TNF- release was assayed. Therapeutic studies were done in mice with

established arthritis by evaluating clinical parameters and histology.

In addition, type II collagen response of lymphocytes from mice with

CIA was examined.

Results. CLX-090717 significantly inhibited spontaneous TNF- release

by RA synovial membrane cells, as well as LPS-induced TNF- release

from human and murine monocytic cells. Inhibition of TNF- in monocytes

was mediated partially through a nuclear factor-B (NF--dependent

pathway, as judged by sustained levels of IB in cytosolic extracts and

a reduced level of LPS-induced NF-B activity in nuclear extracts.

CLX-090717 reduced clinical signs of arthritis and damage to joint

architecture when administered therapeutically to arthritic mice.

Mechanisms of action in CIA involved the reduction in proliferation of

arthritic lymphocytes to antigen in vitro as well as reduced TNF-

release.

Conclusions. Our data suggest that the synthetic compound CLX-090717

has potential as a small molecular weight anti-inflammatory

therapeutic for chronic inflammatory conditions.

http://rheumatology.oxfordjournals.org/cgi/content/abstract/ken398v1?papetoc

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