Salmonella entericaSerovar Typhimurium Infection Induces Cyclooxygenase 2 Expression in Macrophages: Involvement ofSalmonellaPathogenicity Island 2

Abstract

Salmonella pathogenicity island 2 (SPI-2) is required for intramacrophage survival and systemic infection in mice. We have recently reported that Salmonella enterica causes activation of the protein kinase A (PKA) signaling pathway in a manner dependent on SPI-2, resulting in the upregulation of interleukin-10 expression in macrophages (K. Uchiya et al., Infect. Immun. 72:1964Immun. 72: -1973Immun. 72: , 2004. We show in the present study the involvement of SPI-2 in a signal transduction pathway that induces the expression of cyclooxygenase 2 (COX-2), an inducible enzyme involved in the synthesis of prostanoids. High levels of prostaglandin E 2 (PGE 2 ) and prostacyclin (PGI 2 ), which are known to activate the PKA signaling pathway via their receptors, were induced in J774 macrophages infected with wild-type Salmonella compared to a strain carrying a mutation in the spiC gene, located within SPI-2. The increased production of both prostanoids was dependent on COX-2. COX-2 expression was dose dependently blocked by treatment with a specific inhibitor of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway, and the phosphorylation level of ERK1/2 was higher in macrophages infected with wild-type Salmonella compared to the spiC mutant. Taken together, these results indicate that Salmonella causes an SPI-2-dependent ERK1/2 activation that leads to increased COX-2 expression, resulting in the upregulation of PGE 2 and PGI 2 production in macrophages. A COX-2 inhibitor inhibited not only Salmonella-induced activation of the PKA signaling pathway but also growth of wild-type Salmonella within macrophages, suggesting that Salmonella utilizes the COX-2 pathway to survive within macrophages and that the mechanism involves activation of the PKA signaling pathway.

Francisella tularensis-Infected Macrophages Release Prostaglandin E2 that Blocks T Cell Proliferation and Promotes a Th2-Like Response

“…Other pathogens have been shown to use PG production to allow for better intracellular replication (35,47). Treatment of a macrophage cell line with indomethacin slows the intracellular growth of F. tularensis.…”

“…PGs can block T cell proliferation and skew the T cell response (14,18,46); it can also aid the infectious organism in intracellular replication (35,47). We predicted that PGs might be beneficial to the ability of F. tularensis to invade and replicate inside infected cells.…”

“…Legionella pneumophila causes IFN-␥-stimulated macrophages to produce PGE 2 , and blocks IFN-␥ secretion from CD4 ϩ T cells (34). S. enterica can also stimulate macrophages to secrete PGE 2 (35). Thus, intracellular bacteria use multiple mechanisms to modulate and evade the adaptive immune response.…”

Synthetic Prostacyclin Analogs Differentially Regulate Macrophage Function via Distinct Analog-Receptor Binding Specificities

“…Peebles, unpublished observation), and the inhibition of NK-cell mediated cytotoxicity (30). The overproduction of PGI 2 is believed to play a role in the pathogenesis of certain bacterial infections, perhaps by direct effects on innate immunity (31). However, data regarding the influence of PGI 2 on lung innate immunity are lacking.…”

Depletion of immature B cells duringTrypanosoma cruzi infection: involvement of myeloid cells and the cyclooxygenase pathway

“…Herein, we highlight the biological importance of this phenomenon by demonstrating for the first time the impact of Cox products on immature B cells during a protozoan infection. Considering that activation of the Cox pathway in myeloid cells was reported during other parasite and bacterial infections [46][47][48][49], it is likely that immature B cell depletion mediated by Cox products would be a common event during several infectious processes. Thus, our results open a new avenue for manipulation of the Cox pathway within the BM compartment in order to strengthen the B cell response during infections.…”