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Logo of arthrestherBioMed Centralbiomed central web sitesearchsubmit a manuscriptregisterthis articleArthritis Research & Therapy
 
Arthritis Res Ther. 2004; 6(3): R273–R281.
Published online Apr 27, 2004. doi:  10.1186/ar1175
PMCID: PMC416450
CD14 mediates the innate immune responses to arthritopathogenic peptidoglycan–polysaccharide complexes of Gram-positive bacterial cell walls
Xiangli Li,1,2 Blair U Bradford,3 Frederick Dalldorf,4 Sanna M Goyert,5 Stephen A Stimpson,6 Ronald G Thurman,3 and Sergei S Makarovcorresponding author2,7,8
1Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
2Thurston Arthritis Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
3Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
4Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
5Division of Molecular Medicine, North Shore University Hospital, Cornell University Medical College, Manhasset, New York, USA
6GlaxoSmithKline, Research Triangle Park, North Carolina, USA
7Department of Endodontics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
8Comprehensive Center for Inflammatory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
corresponding authorCorresponding author.
Xiangli Li: xiangli_li/at/med.unc.edu; Sergei S Makarov: smak/at/med.unc.edu
Received December 30, 2003; Revisions requested January 16, 2004; Revised February 27, 2004; Accepted March 15, 2004.
Abstract
Bacterial infections play an important role in the multifactorial etiology of rheumatoid arthritis. The arthropathic properties of Gram-positive bacteria have been associated with peptidoglycan–polysaccharide complexes (PG-PS), which are major structural components of bacterial cell walls. There is little agreement as to the identity of cellular receptors that mediate innate immune responses to PG-PS. A glycosylphosphatidylinositol-linked cell surface protein, CD14, the lipopolysaccharide receptor, has been proposed as a PG-PS receptor, but contradictory data have been reported. Here, we examined the inflammatory and pathogenic responses to PG-PS in CD14 knockout mice in order to examine the role for CD14 in PG-PS-induced signaling. We found that PG-PS-induced responses in vitro, including transient increase in intracellular calcium, activation of nuclear factor-κB, and secretion of the cytokines tumor necrosis factor-α and interleukin-6, were all strongly inhibited in CD14 knockout macrophages. In vivo, the incidence and severity of PG-PS induced acute polyarthritis were significantly reduced in CD14 knockout mice as compared with their wild-type counterparts. Consistent with these findings, CD14 knockout mice had significantly inhibited inflammatory cell infiltration and synovial hyperplasia, and reduced expression of inflammatory cytokines in PG-PS arthritic joints. These results support an essential role for CD14 in the innate immune responses to PG-PS and indicate an important role for CD14 in PG-PS induced arthropathy.
Keywords: bacterial, cell surface molecules, rheumatoid arthritis, transcription factors
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