Gold sodium thiomalate (GSTM) inhibits lipopolysaccharide stimulated tumor necrosis factor-alpha through ceramide pathway.
TNF-alpha has emerged as the major pro-inflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). LPS is a potent stimulator of TNF-alpha 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-alpha production from murine macrophages. We have previously shown that GSTM, an anti-rheumatic drug inhibits LPS stimulated TNF-alpha production by normal PBMCs. We studied the ability of ceramide to stimulate TNF-alpha production by human PBMCs and the mechanism of action of GSTM on ceramide and LPS induced TNF-alpha production. LPS induced significant TNF-alpha production in PBMCs and THP-1. However, C(2) ceramide stimulated TNF-alpha 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-alpha productions in PBMCs of all 5 ceramide responders both at protein and mRNA expression level. We also found that GSTM inhibited LPS induced NF-kappaB level only in ceramide responder. Thus, we for the first time report that GSTM inhibits LPS stimulated TNF-alpha production through ceramide pathway and anti-inflammatory activity of GSTM in treatment of RA may depend on its ability to inhibit NF-kappaB activation and TNF-alpha production.
Kumar Mangalam
Ashutosh
A
Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, 226014, Lucknow, India.
Aggarwal
Amita
A
Naik
Sita
S
D000328:Adult; D018501:Antirheumatic Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002518:Ceramides / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006052:Gold Sodium Thiomalate / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000032:analysis / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism
D018501:Antirheumatic Agents; D002518:Ceramides; D008070:Lipopolysaccharides; C064769:N-acetylsphingosine; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D006052:Gold Sodium Thiomalate; D013110:Sphingosine