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Regulation of Proinflammatory Cytokine Expression by Shiga Toxin 1 and/or Lipopolysaccharides in the Human Monocytic Cell Line THP-1

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

Received 20 October 2003/ Returned for modification 6 January 2004/ Accepted 2 February 2004

Infection with Shiga toxin (Stx)-producing bacteria and the subsequent release of Stxs and endotoxins into the bloodstream may damage blood vessels in the colon, kidneys, and central nervous system, leading to bloody diarrhea, acute renal failure, and neurological complications. The proinflammatory cytokines tumor necrosis factor alpha (TNF-) and interleukin-1ß (IL-1ß) may contribute to the pathogenesis of Stx-induced vascular lesions by up-regulating toxin receptor expression on endothelial cells. We previously showed that macrophages treated with purified Shiga toxin 1 (Stx1) or lipopolysaccharides (LPS) secrete TNF- and IL-1ß. Northern blot analysis revealed that treatment of the human monocytic cell line THP-1 with LPS induced a rapid and transient increase in steady-state TNF- and IL-1ß transcripts. In contrast, Stx1 induced slower but prolonged elevations in cytokine transcripts. The presence of both stimulants resulted in optimal cytokine mRNA induction in terms of kinetics and prolonged expression. Compared to LPS, Stx1 was a poor inducer of IL-1ß protein expression, although levels of soluble IL-1ß induced by all treatments continually increased over 72 h. IL-1ß transcripts were not induced by Stx1 B-subunits. Using the transcriptional inhibitor actinomycin D, we determined that treatment with Stx1 or Stx1 plus LPS induced cytokine transcripts with increased stability compared to transcripts induced by LPS alone. For all treatments, IL-1ß mRNA decay was slower than TNF-. Collectively, our data suggest that Stxs affect cytokine expression, in part, at the posttranscriptional level by stabilizing mRNAs. Optimal TNF- expression occurs when both Stxs and LPS are present.

Editor: A. D. O'Brien

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