Modulation of Innate and Acquired Immune Responses by Escherichia coli Heat-Labile Toxin:Distinct Pro- and Anti-Inflammatory Effects of the Nontoxic AB Complex and the Enzyme Activity

摘要

We have examined the roles of enzyme activity and the notoxic AB complex of heat-labile toxin (LT) from Escherichia coli on its adjuvant and immunomodulatory properties.LTK63,an LT mutant that is completely devoid of enzyme activity,enhanced Th1 responses to couinjuvant dose.In contrast,LTR72,a partially detoxified mutant,enhanced Th2 responses and when administered intranasally to mice before infection with Bordetella pertussis suppressed Th1 responses and delayed bacterial clearance from the lungs.LTR72 or wild-type LT inhibited Ag-induced IFN-#gamma# production by Th1 cells,and LT enhanced IL-5 production by Th2 cells in vitro.Each of the toxins enhanced B7-1 expression on macrophages,but enhancement of B7-2 expression was dependent on ezyme activity.We also observed distinct effects of the nontoxic AB complex and enzyme activity on inflammatory cytokine production.LT and LTR72 suppressed LPS and IFN-#gamma# induced TNF-#alpha# and IL-12 production,but enhaced IL-10 secretion by macrophages in vitro and suppressed IL-12 production invivo in amurine model of LPS-induced shock.In contrast,LTK63 augmented the production of IL-12 and TNF-#alpha#,Furthermore,LTK63 enhanced NF-KB translocation,whereas Iow doses of LTR72 or LT failed to activate NF-kB,but stimulated cAMP production.Thus,E.coli LT appears to be capable of suppressing Th1 respokses and enhancing Th2 responses throught the modulatory effects of enzyme activityt on NF-kB activation and IL-12 production.In contrast,the notoxic AB complex can stimulate acquired immune responses by activating components of the innate immune system.