Project description:Listeria monocytogenes (LM) is a Gram-positive, facultative intracellular bacterium responsible for disseminated infections in immunocompromised individuals which can result in septicaemia and meningitis (1). Effective control of listeriosis requires both innate and adaptive immune responses with the principal mediators of bacterial killing being neutrophils and macrophages (2). Key cytokines driving the innate immune response are IFN-γ (3) and TNF (4), which promote macrophage activation and drive the production of anti-microbial mediators such as reactive oxygen intermediates (ROI) and reactive nitrogen intermediates (RNI). Several studies using gene deficient mice demonstrated that ROI and RNI are required for optimal pathogen killing (5-8), but that macrophages also utilise an alternative, unknown mechanism besides ROI and RNI to efficiently control bacterial infection. Mice deficient for the transcription factor NF-IL6 are highly susceptible to a number of intracellular bacterial and fungal infections, including LM (9-12). NF-IL6-deficient mice infected with LM were unable to prevent bacterial dissemination, despite production of nitric oxide (NO), IFN-γ and TNF being equivalent to WT controls (12). From these results, we hypothesized that NF-IL6 acts downstream from IFN-γ and TNF during the activation of macrophage effector functions against LM (2). To facilitate the identification of putative effector genes in this unknown pathway, we compared gene expression profiles of WT and NF-IL6 deficient LM-infected macrophages by differential microarray. REFERENCES 1. Gellin, B. G. & Broome, C. V. (1989) Jama 261, 1313-1320. 2. Brombacher, F. & Kopf, M. (1996) Res Immunol 147, 505-511. 3. Buchmeier, N. A. & Schreiber, R. D. (1985) Proc Natl Acad Sci U S A 82, 7404-7408. 4. Havell, E. A. (1989) J Immunol 143, 2894-2899. 5. Dinauer, M. C., Deck, M. B., & Unanue, E. R. (1997) J Immunol 158, 5581-5583. 6. Endres, R., Luz, A., Schulze, H., Neubauer, H., Futterer, A., Holland, S. M., Wagner, H., & Pfeffer, K. (1997) Immunity 7, 419-432. 7. MacMicking, J. D., Nathan, C., Hom, G., Chartrain, N., Fletcher, D. S., Trumbauer, M., Stevens, K., Xie, Q. W., Sokol, K., Hutchinson, N., et al. (1995) Cell 81, 641-650. 8. Shiloh, M. U., MacMicking, J. D., Nicholson, S., Brause, J. E., Potter, S., Marino, M., Fang, F., Dinauer, M., & Nathan, C. (1999) Immunity 10, 29-38. 9. Pizarro-Cerda, J., Desjardins, M., Moreno, E., Akira, S., & Gorvel, J. P. (1999) J Immunol 162, 3519-3526. 10. Screpanti, I., Romani, L., Musiani, P., Modesti, A., Fattori, E., Lazzaro, D., Sellitto, C., Scarpa, S., Bellavia, D., Lattanzio, G., et al. (1995) Embo J 14, 1932-1941. 11. Sugawara, I., Mizuno, S., Yamada, H., Matsumoto, M., & Akira, S. (2001) Am J Pathol 158, 361-366. 12. Tanaka, T., Akira, S., Yoshida, K., Umemoto, M., Yoneda, Y., Shirafuji, N., Fujiwara, H., Suematsu, S., Yoshida, N., & Kishimoto, T. (1995) Cell 80, 353-361. Keywords: bone marrow derived macrophages, interferon-gamma, macrophage activation, macrophage effector activity, NF-IL6, gene-deficient mouse model, Listeria monocytogenes, intracellular pathogen
2007-09-12 | GSE6256 | GEO