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Infection and Immunity, April 2004, p. 1964-1973, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.1964-1973.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Involvement of Salmonella Pathogenicity Island 2 in the Up-Regulation of Interleukin-10 Expression in Macrophages: Role of Protein Kinase A Signal Pathway

Kei-ichi Uchiya,1* Eduardo A. Groisman,2 and Toshiaki Nikai1

Department of Microbiology, Faculty of Pharmacy, Meijo University, Yagotoyama 150, Tenpaku-ku, Nagoya 468-8503, Japan,1 Howard Hughes Medical Institute and Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri 631102

Received 14 September 2003/ Returned for modification 25 November 2003/ Accepted 2 January 2004

Salmonellae are facultative intracellular bacteria capable of surviving within macrophages. Salmonella pathogenicity island 2 (SPI-2) is required for growth within macrophages and for virulence in mice. In this study, we show the involvement of SPI-2 in a signal transduction pathway that induces cytokine expression in Salmonella-infected macrophages. High levels of interleukin-10 (IL-10) mRNA were induced in macrophages by infection with wild-type salmonellae compared to a strain carrying a mutation in the spiC gene, which is encoded within SPI-2. The two strains had the same effect on the expression of proinflammatory cytokines such as IL-1{alpha}, IL-6, and tumor necrosis factor alpha. IL-10 expression was dose dependently blocked by treatment of infected macrophages with the protein kinase A (PKA) inhibitor H-89, while IL-10 expression was increased by the PKA activator dibutyryl cyclic AMP. Cyclic AMP-dependent PKA activity was higher in macrophages infected with wild-type salmonellae compared to the spiC mutant, and Ser132 phosphorylation of cyclic AMP response element-binding protein (CREB), which is an important mediator of PKA activation, correlated with the levels of PKA activity. Taken together, these results indicate that salmonellae cause an SPI-2-dependent increase in PKA activity that leads to CREB phosphorylation, resulting in up-regulation of IL-10 expression in Salmonella-infected macrophages. Suppression of IL-10 expression by an antisense oligonucleotide did not affect the growth of wild-type salmonellae within macrophages, whereas growth was dose dependently inhibited by H-89, suggesting that the PKA signaling pathway plays a significant role in intramacrophage Salmonella survival.

* Corresponding author. Mailing address: Department of Microbiology, Faculty of Pharmacy, Meijo University, Yagotoyama 150, Tenpaku-ku, Nagoya 468-8503, Japan. Phone: 81-52-832-1781. Fax: 81-52-834-8780. E-mail: kuchiya{at}ccmfs.meijo-u.ac.jp.

Editor: A. D. O'Brien

Infection and Immunity, April 2004, p. 1964-1973, Vol. 72, No. 4
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.4.1964-1973.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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