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| Antagonism of immunostimulatory CpG-oligodeoxynucleotides by quinacrine, chloroquine, and structurally related compounds |
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| Author(s): Macfarlane DE, Manzel L |
| Source: JOURNAL OF IMMUNOLOGY Volume: 160 Issue: 3 Pages: 1122-1131 Published: FEB 1 1998 |
| Times Cited: 146 References: 49 |
| Abstract: Phosphorothioate oligodeoxynucleotides containing CpG (CpG-ODN) activate immune responses. We report that quinacrine, chloroquine, and structurally related compounds completely inhibit the antiapoptotic effect of CpG-ODN on WEHI 231 murine B lymphoma cells and inhibit CpG-ODN-induced secretion of IL-6 by WEHI 231, They also inhibit IL-6 synthesis and thymidine uptake by human unfractionated PBMC induced by CpG-ODN, The compounds did not inhibit LPS-induced responses, Half-maximal inhibition required 10 nM quinacrine or 100 nM chloroquine, Inhibition was noncompetitive with respect to CpG-ODN. Quinine, quinidine, and primaquine were much less powerful. Quinacrine was effective even when added after the CpG-ODN. Near-toxic concentrations of ammonia plus bafilomycin A(1) (used to inhibit vesicular acidification) did not reduce the efficacy of the quinacrine, but the effects of both quinacrine and chloroquine were enhanced by inhibition of the multidrug resistance efflux pump by verapamil, Agents that bind to DNA, including propidium iodide, Hoechst dye 33258, and coralyne chloride did not inhibit CpG-ODN effect, nor did 4-bromophenacyl bromide, an inhibitor of phospholipase A(2). Examination of the structure-activity relationship of seventy 4-aminoquinoline and 9-aminoacridine analogues reveals that increased activity was conferred by bulky hydrophobic substituents on positions 2 and 6 of the quinoline nucleus, No correlation was found between published antimalarial activity and ability to block CpG-ODN-induced effects, These results are discussed in the light of the ability of quinacrine and chloroquine to induce remission of rheumatoid arthritis and lupus erythematosus. |
| Document Type: Article |
| Language: English |
| Reprint Address: Macfarlane, DE (reprint author), Univ Iowa, Iowa City, IA 52242 USA |
Addresses:
1. Univ Iowa, Iowa City, IA 52242 USA
2. Vet Affairs Med Ctr, Dept Med, Iowa City, IA 52242 USA |
| Publisher: AMER ASSOC IMMUNOLOGISTS, 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA |
| Subject Category: Immunology |
| IDS Number: YW269 |
| ISSN: 0022-1767 |
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