Mechanism of action of disease modifying anti-rheumatic agent, gold sodium thiomalate (GSTM).
GSTM has been used for long in the treatment of rheumatoid arthritis (RA). However, its mechanism of action is still poorly understood. In the last decade, tumor necrosis factor-alpha (TNF-alpha) has emerged as the major pro-inflammatory cytokine in the pathogenesis of RA. We studied the effect of GSTM on spontaneous and LPS-stimulated TNF-alpha production by human peripheral blood mononuclear cells (PBMCs) of normal volunteers. PBMCs were isolated from 20 normal volunteers and cultured in the presence of absence of lipopolysaccharide (LPS 10 ng/ml) and GSTM (1 microgram/ml). TNF-alpha level was measured using commercial enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). The TNF-alpha response to LPS was heterogeneous. PBMCs of 24 subjects showed high LPS-stimulated TNF-alpha production (LPS-responsive group), whereas that of six individuals had low LPS-stimulated TNF-alpha production (LPS-non-responsive group). GSTM-stimulated spontaneous TNF-alpha production and inhibited LPS-stimulated TNF-alpha production in 16 of 24 (75%) individuals of LPS-responsive group and one of six individuals (17%) of LPS-non-responsive group. The suppression of TNF-alpha by GSTM was also demonstrated at the mRNA level. We conclude that there is a heterogeneity among normal population for TNF-alpha production in response to LPS, and GSTM inhibits LPS-stimulated TNF-alpha production, primarily in LPS responders. Further study is needed to establish the relationship between LPS responsiveness and GSTM suppression.
Mangalam
A K
AK
Department of Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow-226014, India.
Aggarwal
A
A
Naik
S
S
D000328:Adult; D018501:Antirheumatic Agents / Q000494:pharmacology*; D002469:Cell Separation; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006052:Gold Sodium Thiomalate / Q000494:pharmacology*; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D018501:Antirheumatic Agents; D004731:Endotoxins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D006052:Gold Sodium Thiomalate; C044101:endotoxin, Escherichia coli