Anti-rheumatic gold compounds as sublethal modulators of monocytic LPS-induced cytokine secretion.
The objective of this study was to quantify the ability of sublethal concentrations of several gold compounds to differentially modulate the monocytic secretion of key cytokines that are important in the etiology of rheumatic diseases. Human THP1 monocytic cells were exposed to the anti-rheumatic drugs auranofin (AF), gold sodium thiomalate (GSTM) or HAuCl4 (Au(III)) for 24-72 h. Succinate dehydrogenase (SDH) activity of the monocytes was used to determine sublethal concentrations. Monocytes were then exposed to sublethal concentrations of gold compounds for 72 h, and the activator lipopolysaccharide (LPS) was added (or not) to cultures for the last 6h. The secretion of IL6, IL8, IL10, and TNFalpha were measured in cell supernatants using ELISA. Cytokine secretion was compared among concentrations and gold compounds. SDH experiments established a sublethal concentration range of 0-75 microM for GSTM and Au(III) and 0-0.5 microM for AF. In cytokine experiments, none of the compounds alone activated secretion of any of the cytokines, but all differentially (50-440%, p<0.05) increased LPS-induced secretion of IL6 and IL8 over TNFalpha and IL10. In conclusion, sublethal concentrations of AF, GSTM, and Au(III) all may differentially modulate activation of monocytic cells, and this differential modulation may be important in the mechanisms of action of these compounds.
Stern
I
I
Medical College of Georgia, Augusta, Georgia, USA.
Wataha
J C
JC
Lewis
J B
JB
Messer
R L W
RL
Lockwood
P E
PE
Tseng
W Y
WY
D018501:Antirheumatic Agents / Q000633:toxicity*; D001310:Auranofin / Q000633:toxicity*; D002460:Cell Line; D002712:Chlorides / Q000633:toxicity*; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D017612:Gold Compounds / Q000633:toxicity*; D006052:Gold Sodium Thiomalate / Q000633:toxicity*; D006801:Humans; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D013385:Succinate Dehydrogenase / Q000378:metabolism
D018501:Antirheumatic Agents; D002712:Chlorides; D016207:Cytokines; D017612:Gold Compounds; D006052:Gold Sodium Thiomalate; D001310:Auranofin; C024568:gold tetrachloride, acid; D013385:Succinate Dehydrogenase