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Infection and Immunity, November 2004, p. 6351-6358, Vol. 72, No. 11
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.11.6351-6358.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Type II Heat-Labile Enterotoxins LT-IIa and LT-IIb and Their Respective B Pentamers Differentially Induce and Regulate Cytokine Production in Human Monocytic Cells

George Hajishengallis,1* Hesham Nawar,2 Richard I. Tapping,3 Michael W. Russell,2 and Terry D. Connell2

Department of Microbiology, Immunology, and Parasitology, Center of Excellence in Oral and Craniofacial Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana,1 Department of Microbiology and Immunology, Witebsky Center for Microbial Pathogenesis and Immunology, University of Buffalo, New York,2 Department of Microbiology, University of Illinois, Urbana, Illinois3

Received 17 May 2004/ Returned for modification 3 August 2004/ Accepted 11 August 2004

The type II heat-labile enterotoxins, LT-IIa and LT-IIb, exhibit potent adjuvant properties. However, little is known about their immunomodulatory activities upon interaction with innate immune cells, unlike the widely studied type I enterotoxins that include cholera toxin (CT). We therefore investigated interactions of LT-IIa and LT-IIb with human monocytic THP-1 cells. We found that LT-II enterotoxins were inactive in stimulating cytokine release, whereas CT induced low levels of interleukin-1ß (IL-1ß) and IL-8. However, all three enterotoxins potently regulated cytokine induction in cells activated by bacterial lipopolysaccharide or fimbriae. Induction of proinflammatory (tumor necrosis factor {alpha} [TNF-{alpha}]) or chemotactic (IL-8) cytokines was downregulated, whereas induction of cytokines with anti-inflammatory (IL-10) or mucosal adjuvant properties (IL-1ß) was upregulated by the enterotoxins. These effects appeared to depend on their A subunits, because isolated B-pentameric subunits lacked regulatory activity. Enterotoxin-mediated inhibition of proinflammatory cytokine induction in activated cells was partially attributable to synergism for endogenous production of IL-10 and to an IL-10-independent inhibition of nuclear factor {kappa}B (NF-{kappa}B) activation. In sharp contrast to the holotoxins, the B pentamers (LT-IIaB and, to a greater extent, LT-IIbB) stimulated cytokine production, suggesting a link between the absence of the A subunit and increased proinflammatory properties. In this regard, the ability of LT-IIbB to activate NF-{kappa}B and induce TNF-{alpha} and IL-8 was antagonized by the LT-IIb holotoxin. These findings support distinct immunomodulatory roles for the LT-II holotoxins and their respective B pentamers. Moreover, the anti-inflammatory properties of the holotoxins may serve to suppress innate immunity and promote the survival of the pathogen.

* Corresponding author. Mailing address: LSU Health Sciences Center, Department of Microbiology, Immunology, and Parasitology, Center of Excellence in Oral and Craniofacial Biology, 1100 Florida Ave., Box 130, New Orleans, LA 70119. Phone: (504) 619-8709. Fax: (504) 670-2736. E-mail: ghajis{at}lsuhsc.edu.

Editor: J. D. Clements

Infection and Immunity, November 2004, p. 6351-6358, Vol. 72, No. 11
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.11.6351-6358.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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