title: Modulation of human monocytes by Escherichia coli heat-labile enterotoxin B-subunit; altered cytokine production and its functional consequences.
abstract: In murine systems, the B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is a potent immunomodulator capable of suppressing Th1-mediated autoimmune diseases. This results from its ability to bind cell surface receptors, principally GM1-ganglioside, and as a consequence down-regulate the pathological T helper type 1 (Th1) response. The capacity of EtxB to alter human T-cell responses has not been investigated. Here we show that EtxB, but not the receptor non-binding mutant EtxB (G33D), triggers the release of interleukin (IL)-10, IL-6 and tumour necrosis factor-alpha (TNF-alpha) by human monocytes. The production of IL-8, transforming growth factor-beta (TGF-beta) or IL-12 was not enhanced by EtxB. Indeed, EtxB was shown to inhibit IL-12 secretion in monocytes stimulated with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) by an IL-10-independent mechanism. When EtxB-treated monocytes were used as antigen presenting cells in an allogeneic mixed lymphocyte reaction (MLR), IL-10 and IFN-gamma production were increased in comparison to levels seen in cultures stimulated with untreated monocytes; proliferation was unaltered. This modulation of the T-cell response was not only evident in the primary MLR triggered by EtxB-treated monocytes, but also upon restimulation of the responding T cells with fresh untreated monocytes; indicating that presentation by EtxB-treated monocytes leads to altered T-cell differentiation. Sorting experiments showed that IL-10 secreting T cells from the MLR cultures were strong suppressors of T-cell proliferation following their addition into a fresh primary MLR.
authors.affiliation: University of Bristol, Department of Pathology and Microbiology, School of Medical Sciences, UK.
authors.forename: Victor
authors.initials: V
authors.lastname: Turcanu
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hirst
authors.forename: Neil A
authors.initials: NA
authors.lastname: Williams
mesh_terms: D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins / Q000276:immunology*; D018929:Cell Culture Techniques; D002455:Cell Division / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis*; D004306:Dose-Response Relationship, Immunologic; D004768:Enterotoxins / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology; D029968:Escherichia coli Proteins; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D016207:Cytokines; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; C027538:heat-labile enterotoxin, E coli