AAC
Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bottrel, R. L. A.
Right arrow Articles by Reis, L. F. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bottrel, R. L. A.
Right arrow Articles by Reis, L. F. L.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, April 1999, p. 856-861, Vol. 43, No. 4
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

The Immune Response Modifier Imiquimod Requires STAT-1 for induction of Interferon, Interferon-Stimulated Genes, and Interleukin-6

Renata L. A. Bottrel,1,dagger Yi-Li Yang,2 David E. Levy,3 Mark Tomai,4 and Luiz F. L. Reis1,5,*

Department of Microbiology, ICB, UFMG, Belo Horizonte,1 and Laboratory of Inflammatory Response, Ludwig Institute for Cancer Research, São Paulo, SP,5 Brazil; Institute for Molecular Biology, University of Zurich, Zurich, Switzerland2; Department of Pathology, New York University School of Medicine, New York, New York3; and 3M Pharmaceuticals, St. Paul, Minnesota4

Received 21 May 1998/Returned for modification 22 September 1998/Accepted 3 February 1999

Imiquimod is an oral inducer of interferon (IFN) and several other proinflammatory cytokines and has been successfully used topically as an antiviral agent for the treatment of genital warts. We have investigated the molecular mechanisms by which imiquimod induces the expression of IFNs, IFN-stimulated genes (ISGs), and proinflammatory cytokines in vivo, using mice deficient in various components of the IFN signaling system. Mice deficient in the transcription factor interferon regulatory factor 1 (IRF-1) or in the serine/threonine protein kinase PKR responded normally to imiquimod, producing high levels of circulating IFN and induction of several ISGs. On the other hand, when mice deficient in STAT-1 were treated, a 32-fold reduction in the level of circulating IFN was observed, together with a lack of induction of 2-5 oligo adenylate synthetase (2-5 OAS) and IRF-1 genes. Interestingly, there was also a lack of induction of interleukin-6 (IL-6) gene expression, although tumor necrosis factor was induced and readily detected in serum. In mice deficient in the type I IFN receptor, imiquimod induced levels of IFN similar to those in control mice, but again, neither 2-5 OAS, IRF-1, nor IL-6 genes were induced in mutant mice. Our results suggest that STAT-1 plays a critical role in the mechanism of gene activation by imiquimod. Moreover, induction of IL-6 gene expression appears to be dependent on components of the IFN signaling cascade.

* Corresponding author. Mailing address: Ludwig Institute for Cancer Research, Rua Prof. Antonio Prudente 109, 4o andar, São Paulo, SP, Brazil, 01509-010. Phone: 55-11-2704922. Fax: 55-11-2707001. E-mail:lreis{at}nodel.com.br.

dagger Present address: Laboratory of Lymphocyte Biology, Department of Biochemistry and Immunology, ICB, UFMG, Belo Horizonte, MG, Brazil, CEP 31270-901.

Antimicrobial Agents and Chemotherapy, April 1999, p. 856-861, Vol. 43, No. 4
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:



Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
Clin. Vaccine Immunol. Clin. Microbiol. Rev.
J. Clin. Microbiol. ALL ASM JOURNALS

Copyright © 1999 by the American Society for Microbiology. All rights reserved.