Blockade of the PI-3K Signalling Pathway by the Aggregatibacter Actinomycetemcomitans Cytolethal Distending Toxin Induces Macrophages to Synthesize and Secrete Pro-Inflammatory Cytokines
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The Aggregatibactor actinomycetemcomitans cytolethal distending toxin (Cdt) induces G2 arrest and apoptosis in lymphocytes; these toxic effects are due to the active subunit, CdtB, which functions as a phosphatidylinositol-3,4,5-triphosphate (PIP3) phosphatase. We now extend our investigation and demonstrate that Cdt is able to perturb human macrophage function. THP-1- and monocyte-derived macrophages were found not to be susceptible to Cdt-induced apoptosis. Nonetheless, the toxin was capable of binding to macrophages and perturbing PI-3K signalling resulting in decreased PIP3 levels and reduced phosphorylation of Akt and GSK3β; these changes were accompanied by concomitant alterations in kinase activity. Exposure of monocytes and macrophages to Cdt resulted in pro-inflammatory cytokine production including increased expression and release of IL-1β, TNFα and IL-6. Furthermore, treatment of cells with either TLR-2, -3 or -4 agonists in the presence of Cdt resulted in an augmented pro-inflammatory response relative to agonist alone. GSK3β inhibitors blocked the Cdt-induced pro-inflammatory cytokine response suggesting a pivotal role for PI-3K blockade, concomitant decrease in GSK3β phosphorylation and increased kinase activity. Collectively, these studies provide new insight into the virulence potential of Cdt in mediating the pathogenesis of disease caused by Cdt-producing organisms.
Shenker, Bruce J., Lisa P. Walker, Ali Zekavat, Mensur Dlakić, and Kathleen Boesze-Battaglia. “ Blockade of the PI-3K Signalling Pathway by the A Ggregatibacter Actinomycetemcomitans Cytolethal Distending Toxin Induces Macrophages to Synthesize and Secrete Pro-Inflammatory Cytokines .” Cellular Microbiology 16, no. 9 (September 2014): 1391–1404. doi:10.1111/cmi.12299.