Salmonella pathogenicity island 2-dependent expression of suppressor of cytokine signaling 3 in macrophages

Salmonella pathogenicity island 2 (SPI-2), which is located at centisome 30.7 on the chromosome of Salmonella enterica serovar Typhimurium, is required for growth within macrophages and systemic infection in mice. We recently reported that the infection of macrophages with Salmonella induces the expression of cyclooxygenase-2 in a manner dependent on SPI-2 (K. Uchiya and T. Nikai, Infect. Immun. 72:6860-6869, 2004). In the present study, gene expression analysis using a cDNA array further showed the involvement of SPI-2 in the expression of suppressor of cytokine signaling 3 (SOCS-3), which is involved in the inhibition of cytokine signaling via the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. A high level of SOCS-3 expression was induced in J774 macrophages infected with wild-type Salmonella compared to that in macrophages infected with a strain carrying a mutation in the spiC gene within SPI-2. Other members of the SOCS family were not detected in Salmonella-infected macrophages. The SPI-2-induced up-regulation of SOCS-3 expression was dependent on activation of the extracellular signal-regulated kinase 1/2 (ERKI/2) signaling pathway. Furthermore, the inhibition of gamma-interferon-induced STAT-1 and interieukin-6-induced STAT-3 tyrosine phosphorylation correlated with the expression of SOCS-3. Taken together, these results indicate that Salmonella causes SPI-2-dependent activation of ERK1/2, leading to SOCS-3 expression, which in turn inhibits cytokine signaling via the JAK/STAT pathway.