Cholera toxin potentiates influences of IFN-gamma through activation of NF-kappaB and release of tumor necrosis factor-alpha.
Cholera toxin (Ctx) is a potent adjuvant in the mucosal immune system. Previous studies have indicated that Ctx induces intestinal interferon-gamma (IFN-gamma) production and that adjuvant properties require activation of the IFN-gamma receptor (IFNGR). Thus, we hypothesized that Ctx potentiates IFN-gamma responses in intestinal epithelia. Initial studies suggested that Ctx enhances IFN-gamma-mediated barrier disruption in cultured intestinal epithelia. This response was attributable to liberation of a soluble mediator into conditioned supernatants, subsequently identified as tumor necrosis factor-alpha (TNF-alpha). Extensions of these findings revealed that the Ctx A subunit induces transcriptional activation of proinflammatory genes in addition to TNF-alpha (interleukin-8 [IL- 8], intracellular adhesion molecule-1 [ICAM-1], and IL-6) and that such transactivation is mediated by the transcriptional regulator NF-kappaB. We conclude that Ctx elicits a proinflammatory phenotype in intestinal epithelia and that potentiation of IFN-gamma-mediated barrier disruption by TNF-alpha may contribute to the overall adjuvant properties of Ctx.
Blumberg
Richard S
RS
Division of Gastroenterology, Brigham and Women's Hospital and Harvard Medical School, 20 Shattuck Street, Boston, MA 02115, USA.
Pitman
Richard S
RS
Taylor
Cormac T
CT
Colgan
Sean P
SP
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002772:Cholera Toxin / Q000494:pharmacology*; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism*; D010539:Permeability; D021122:Protein Subunits / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D000276:Adjuvants, Immunologic; D015850:Interleukin-6; D016209:Interleukin-8; D016328:NF-kappa B; D021122:Protein Subunits; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D002772:Cholera Toxin