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.
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-1beta (IL-1beta) 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-1beta) 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 kappaB (NF-kappaB) 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-kappaB 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.
Hajishengallis
George
G
Louisiana State University Health Sciences Center, Department of Microbiology, Immunology, and Parasitology, Center of Excellence in Oral and Craniofacial Biology, 1100 Florida Ave., Box 130, New Orleans 70119, USA. ghajis@lsuhsc.edu
Nawar
Hesham
H
Tapping
Richard I
RI
Russell
Michael W
MW
Connell
Terry D
TD
D001427:Bacterial Toxins / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology*; D002460:Cell Line; D002772:Cholera Toxin / Q000276:immunology / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis*; D004768:Enterotoxins / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology*; D004926:Escherichia coli / Q000276:immunology; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D016328:NF-kappa B / Q000096:biosynthesis
D001427:Bacterial Toxins; D016207:Cytokines; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D016753:Interleukin-10; D002772:Cholera Toxin; C027538:heat-labile enterotoxin, E coli