The Escherichia coli heat-labile enterotoxin induces apoptosis of immature lymphocytes in vivo via a glucocorticoid-dependent pathway.
Escherichia coli heat-labile enterotoxin (LT) exhibits a broad range of immunomodulatory activities, including the induction of lymphocyte-programmed cell death. However, the nature of the lymphoid populations sensitive to LT-induced apoptosis and the mechanisms used by this toxin to promote such activity are still unclear. In this study, we demonstrate that LT induces in mice a rapid increase in the levels of circulating corticosterone, resulting in a dramatic induction of cell death of immature CD4+CD8+, B220+IgM- and IgM+IgD- T and B cell progenitors, respectively. Apoptosis of these cell populations is similar to that reported after experimental treatment with corticosteroids, it is inhibited by mifepristone, a glucocorticoid receptor antagonist, and does not occur in adrenalectomized animals. These results clearly indicate that endogenous glucocorticoids are the mediators of the LT-induced cell death, which involves Bcl-2-dependent apoptotic pathways. The LT-mediated programmed cell death requires systemic exposure and the enzymatic activity of LT, since a mutant devoid of any enzymatic activity have no pro-apoptotic effect at any dose tested.
Tamayo
Esther
E
Departamento de Biología Molecular, Unidad Asociada al CIB/CSIC, Santander, Spain.
Merino
Ramón
R
González-Rojas
Jovanna
J
Marquina
Regina
R
Santiuste
Inés
I
Amado
José Antonio
JA
Rappuoli
Rino
R
Del Giudice
Giuseppe
G
Merino
Jesús
J
D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D001427:Bacterial Toxins / Q000235:genetics; D002454:Cell Differentiation / Q000276:immunology; D003345:Corticosterone / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D004768:Enterotoxins / Q000235:genetics / Q000502:physiology*; D004926:Escherichia coli / Q000472:pathogenicity*; D029968:Escherichia coli Proteins / Q000235:genetics / Q000502:physiology*; D016131:Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*
D001427:Bacterial Toxins; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C027538:heat-labile enterotoxin, E coli; D003345:Corticosterone