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Infection and Immunity, September 2000, p. 5183-5189, Vol. 68, No. 9
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Shiga Toxin-Induced Tumor Necrosis Factor Alpha Expression: Requirement for Toxin Enzymatic Activity and Monocyte Protein Kinase C and Protein Tyrosine Kinases

Gregory H. Foster, Cassandra S. Armstrong, Ramesh Sakiri, and Vernon L. Tesh*

Department of Medical Microbiology and Immunology, Texas A&M University Health Science Center, College Station, Texas 77843-1114

Received 2 December 1999/Returned for modification 6 March 2000/Accepted 20 June 2000

Infections with Shiga toxin (Stx)-producing bacteria cause bloody diarrhea which may progress to life-threatening complications, including acute renal failure and neurological abnormalities. The precise mechanism of disease progression is unclear, although evidence suggests that the localized production of the host proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha ) and interleukin-1 may exacerbate toxin-mediated vascular damage. Purified Stxs have been demonstrated to elicit proinflammatory cytokine synthesis from human peripheral blood mononuclear cells and monocytic cell lines in vitro. To understand toxin-monocyte interactions required for cytokine synthesis, we have treated differentiated THP-1 cells with purified wild-type toxins, enzymatic mutants, or B subunits and measured TNF-alpha production. Our data suggest that A subunit enzymatic activity is essential for cytokine production. THP-1 cells were treated with a series of protein kinase C (PKC), PKA, and protein tyrosine kinase inhibitors to examine the role of intracellular signaling molecules in Stx-mediated cytokine production. Treatment of cells with PKC and tyrosine kinase inhibitors blocked TNF-alpha secretion by Stx-stimulated THP-1 cells. Stx treatment directly activated PKC, which occurred at a point upstream of transcriptional activation of the gene encoding TNF-alpha .

* Corresponding author. Mailing address: Department of Medical Microbiology and Immunology, 407 Reynolds Medical Building, Texas A&M University Health Science Center, College Station, TX 77843-1114. Phone: (409) 845-1313. Fax: (409) 845-3479. E-mail: tesh{at}medicine.tamu.edu.

Infection and Immunity, September 2000, p. 5183-5189, Vol. 68, No. 9
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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