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Francisella tularensis Induces IL-23 Production in Human Monocytes¹

Jonathan P. Butchar^*, Murugesan V. S. Rajaram^*, Latha P. Ganesan^*, Kishore V. L. Parsa, Corey D. Clay, Larry S. Schlesinger and Susheela Tridandapani^2,*

^* Department of Internal Medicine, Biochemistry Program, and Center for Microbial Interface Biology, Division of Infectious Diseases, Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH 43210

Francisella tularensis, the causative agent of tularemia, is phagocytosed by immune cells such as monocytes and macrophages. Instead of being destroyed in the phagolysosome, the bacterium escapes the phagosome and replicates within the host cytosol. Recent studies indicate that phagosomal escape may have a major impact on the nature of the inflammatory cytokine response to infection. To better understand the host cell response to Francisella infection, we exposed human peripheral blood monocytes to Francisella novicida and analyzed transcriptional changes using high-density oligonucleotide microarrays. Results showed a nearly 300-fold up-regulation of transcripts for the p19 subunit of IL-23, and a nearly 18-fold up-regulation for the p40 subunit of IL-12. IL-23 is formed by the heterodimerization of p19 and p40, and is an important cytokine of the innate immune response. Up-regulation of p19 and p40 was confirmed at the protein level by Western blotting and ELISA analyses, and was found to be largely dependent on PI3K and NF-B activity. Studies using medium from infected monocytes with or without a p19 blocking Ab showed that the secreted IL-23 induced IFN- production from NK cells, suggesting a potential biologically important role for IL-23 in host defense. Finally, infection of human monocytes by the highly virulent Francisella SCHU S4 strain likewise led to IL-23 production, suggesting that the IL-23 response may be relevant during tularemia.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants U54-AI-057153, R01 AI059406, and P01 CA095426 from the National Institutes of Health. J.P.B. is supported by Institutional Training Grant T32CA090223 from the National Institutes of Health.

² Address correspondence and reprint requests Dr. Susheela Tridandapani, Room 405B Davis Heart and Lung Research Institute, Department of Internal Medicine, The Ohio State University, 473 West 12th Avenue, Columbus, OH 43210. E-mail address: tridandapani.2{at}osu.edu

³ Abbreviations used in this paper: PBM, peripheral blood monocyte; MOI, multiplicity of infection.

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