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Infection and Immunity, February 2002, p. 558-568, Vol. 70, No. 2
0019-9567/01/$04.00+0     DOI: 10.1128/IAI.70.2.558-568.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Porins from Salmonella enterica Serovar Typhimurium Activate the Transcription Factors Activating Protein 1 and NF-{kappa}B through the Raf-1-Mitogen-Activated Protein Kinase Cascade

Massimiliano Galdiero,1* Mariateresa Vitiello,1 Emma Sanzari,1 Marina D’Isanto,1 Annalisa Tortora,1 Anna Longanella,1 and Stefania Galdiero2

Istituto di Microbiologia, Facoltà di Medicina e Chirurgia, Seconda Università degli Studi di Napoli, 80138 Naples,1 Dipartimento di Chimica Biologica, Centro di Studio di Biocristallografia, Università degli Studi di Napoli Federico II, 80134 Naples, Italy2

Received 17 July 2001/ Returned for modification 17 August 2001/ Accepted 23 October 2001

In this study we examined the ability of Salmonella enterica serovar Typhimurium porins to activate activating protein 1 (AP-1) and nuclear factor {kappa}B (NF-{kappa}B) through the mitogen-activated protein kinase (MAPK) cascade, and we identified the AP-1-induced protein subunits. Our results demonstrate that these enzymes may participate in cell signaling pathways leading to AP-1 and NF-{kappa}B activation following porin stimulation of cells. Raf-1 was phosphorylated in response to the treatment of U937 cells with porins; moreover, the porin-mediated increase in Raf-1 phosphorylation is accompanied by the phosphorylation of MAPK kinase 1/2 (MEK1/2), p38, extracellular-signal-regulated kinase 1/2, and c-Jun N-terminal kinase. We used three different inhibitors of phosphorylation pathways: 2'-amino-3'-methoxyflavone (PD-098059), a selective inhibitor of MEK1 activator and the MAPK cascade; 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), a specific inhibitor of the p38 pathway; and 7ß-acetoxy-1{alpha},6ß,9{alpha}-trihydroxy-8,13-epoxy-labd-14-en-11-one (forskolin), an inhibitor at the level of Raf-1 kinase. PD-098059 pretreatment of cells decreases AP-1 and NF-{kappa}B activation by lipopolysaccharide (LPS) but not by porins, and SB203580 pretreatment of cells decreases mainly AP-1 and NF-{kappa}B activation by porins; in contrast, forskolin pretreatment of cells does not affect AP-1 and NF-{kappa}B activation following either porin or LPS stimulation. Our data suggest that the p38 signaling pathway mainly regulates AP-1 and NF-{kappa}B activation in cells treated with S. enterica serovar Typhimurium porins. Antibody electrophoretic mobility shift assays showed that JunD and c-Fos binding is found in cells treated with porins, in cells treated with LPS, and in unstimulated cells. However, by 30 to 60 min of stimulation, a different complex including c-Jun appears in cells treated with porins or LPS, while the Fra-2 subunit is present only after porin stimulation. These data suggest different molecular mechanisms of activation induced by porins or by LPS.

* Corresponding author. Mailing address: Istituto di Microbiologia, Facoltà di Medicina e Chirurgia, Seconda Università Tdegli Studi di Napoli, Larghetto S. Aniello a Caponapoli no. 2, 80138 Naples, Italy. Phone: 39-081-5665664. Fax: 39-081-5665663. E-mail: mgaldier{at}unina.it.

Editor: A. D. O’Brien

Infection and Immunity, February 2002, p. 558-568, Vol. 70, No. 2
0019-9567/01/$04.00+0     DOI: 10.1128/IAI.70.2.558-568.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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