This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Google Scholar
Right arrow Articles by Cherla, R. P.
Right arrow Articles by Tesh, V. L.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cherla, R. P.
Right arrow Articles by Tesh, V. L.

 Previous Article  |  Next Article 

Infection and Immunity, September 2009, p. 3919-3931, Vol. 77, No. 9
0019-9567/09/$08.00+0     doi:10.1128/IAI.00738-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Shiga Toxin 1-Induced Proinflammatory Cytokine Production Is Regulated by the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Signaling Pathway{triangledown}

Rama P. Cherla, Sang-Yun Lee, Renée A. Mulder, Moo-Seung Lee, and Vernon L. Tesh*

Department of Microbial and Molecular Pathogenesis, College of Medicine, Texas A&M University System Health Science Center, College Station, Texas 77843-1114

Received 29 June 2009/ Accepted 4 July 2009

Shiga toxin 1 (Stx1) transiently increases the expression of proinflammatory cytokines by macrophage-like THP-1 cells in vitro. Increased cytokine production is partly due to activation of the translation initiation factor eIF4E through a mitogen-activated protein kinase (MAPK)- and Mnk1-dependent pathway. eIF4E availability for translation initiation is regulated by association with eIF4E binding proteins (4E-BP). In this study, we showed that Stx1 transiently induced 4E-BP hyperphosphorylation, which may release eIF4E for translation initiation. Phosphorylation of 4E-BP at priming sites T37 and T46 was not altered by Stx1 but was transiently increased at S65, concomitant with increased cytokine expression. Using kinase inhibitors, we showed that 4E-BP phosphorylation was dependent on phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) activation but did not require MAPKs. Stx1 treatment resulted in increased levels of cytosolic Ca2+. PI3K and Akt activation led to the phosphorylation and inactivation of the positive cytokine regulator glycogen synthase kinase 3{alpha}/β (GSK-3{alpha}/β). PI3K, Akt, and mTOR inhibitors and small interfering RNA knockdown of Akt expression all increased, whereas a GSK-3{alpha}/β inhibitor decreased, Stx1-induced soluble tumor necrosis factor alpha and interleukin-1β production. Overall, these findings suggest that despite transient activation of 4E-BP, the PI3K/Akt/mTOR pathway negatively influences cytokine induction by inactivating the positive regulator GSK-3{alpha}/β.

* Corresponding author. Mailing address: Department of Microbial and Molecular Pathogenesis, College of Medicine, 407 Reynolds Medical Building, Texas A&M University System Health Science Center, College Station, TX 77843-1114. Phone: (979) 845-1313. Fax: (979) 845-3479. E-mail: tesh{at}medicine.tamhsc.edu

{triangledown} Published ahead of print on 13 July 2009.

Editor: S. R. Blanke

Infection and Immunity, September 2009, p. 3919-3931, Vol. 77, No. 9
0019-9567/09/$08.00+0     doi:10.1128/IAI.00738-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Lee, M.-S., Cherla, R. P., Leyva-Illades, D., Tesh, V. L. (2009). Bcl-2 Regulates the Onset of Shiga Toxin 1-Induced Apoptosis in THP-1 Cells. Infect. Immun. 77: 5233-5244 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»