Abstract
TNF-α has emerged as the major pro-inflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). LPS is a potent stimulator of TNF-α production by human monocytes. Ceramide, a structural homolog of LPS and a second messenger in the sphingomyelin signal transduction pathway has been shown to stimulate TNF-α production from murine macrophages. We have previously shown that GSTM, an anti-rheumatic drug inhibits LPS stimulated TNF-α production by normal PBMCs. We studied the ability of ceramide to stimulate TNF-α production by human PBMCs and the mechanism of action of GSTM on ceramide and LPS induced TNF-α production. LPS induced significant TNF-α production in PBMCs and THP-1. However, C2 ceramide stimulated TNF-α production in 5 of 10 PBMCs (ceramide responder); it did not do so in the other 5 PBMCs (ceramide non-responder) or the THP-1 cell line. GSTM inhibited LPS stimulated TNF-α productions in PBMCs of all 5 ceramide responders both at protein and mRNA expression level. We also found that GSTM inhibited LPS induced NF-κB level only in ceramide responder. Thus, we for the first time report that GSTM inhibits LPS stimulated TNF-α production through ceramide pathway and anti-inflammatory activity of GSTM in treatment of RA may depend on its ability to inhibit NF-κB activation and TNF-α production.
Original language | English (US) |
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Pages (from-to) | 1-10 |
Number of pages | 10 |
Journal | Cellular Immunology |
Volume | 219 |
Issue number | 1 |
DOIs | |
State | Published - 2002 |
Keywords
- Ceramide
- Cytokines
- Human
- Inflammation
- Lipopolysaccharide
- RT-PCR and transcription factors
ASJC Scopus subject areas
- Immunology