Inhibition of interleukin-12 production by auranofin, an anti-rheumatic gold compound, deviates CD4(+) T cells from the Th1 to the Th2 pathway.
1. Interleukin-12 (IL-12) may play a central role in the development and progression of rheumatoid arthritis by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN-gamma and low IL-4 production. In this study we investigated the effect of auranofin (AF), an anti-rheumatic gold compound, on IL-12 production in mouse macrophages and dendritic cells, and studied whether AF-mediated inhibition of IL-12 production could regulate a cytokine profile of antigen (Ag)-primed CD4(+) Th cells. 2. Treatment with AF significantly inhibited IL-12 production in lipopolysaccharide (LPS)-stimulated macrophages and also in CD40L-stimulated dendritic cells. AF-pretreated macrophages reduced their ability to induce IFN-gamma and increased the ability to induce IL-4 in Ag-primed CD4(+) T cells. AF did not influence the cell surface expression of the class II MHC molecule and the costimulatory molecules CD80 and CD86. 3. Addition of recombinant IL-12 to cultures of AF-pretreated macrophages and CD4(+) T cells restored IFN-gamma production in Ag-primed CD4(+) T cells. 4. The in vivo administration of AF resulted in the inhibition of IL-12 production by macrophages stimulated in vitro with LPS or heat-killed Listeria monocytogenes (HKL), leading to the inhibition of Th1 cytokine profile (decreased IFN-gamma and increased IL-4 production) in Ag-primed CD4(+) T cells. 5. These findings may explain some known effects of AF including anti-rheumatic effects and the inhibition of encephalitogenicity, and point to a possible therapeutic use of AF in the Th1-mediated immune diseases such as autoimmune diseases.
Kim
T S
TS
Immunology Laboratory, College of Pharmacy, Chonnam National University, Kwangju 500-757, Korea. taekim@chonnam.ac.kr
Kang
B Y
BY
Lee
M H
MH
Choe
Y K
YK
Hwang
S Y
SY
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001310:Auranofin / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D018664:Interleukin-12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D018417:Th1 Cells / Q000187:drug effects* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000378:metabolism
D018501:Antirheumatic Agents; D016207:Cytokines; D018664:Interleukin-12; D001310:Auranofin