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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 signaling 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.
This is the peer reviewed version of the following article: [Shenker, B. J., Walker, L. P., Zekavat, A., Dlakić, M., & Boesze-Battaglia, K. (2014). Blockade of the PI-3K signaling pathway by the Aggregatibacter actinomycetemcomitans cytolethal distending toxin induces macrophages to synthesize and secrete pro-inflammatory cytokines. Cellular Microbiology, 16(9), 1391–1404. http://doi.org/10.1111/cmi.12299], which has been published in final form at [http://doi.org/10.1111/cmi.12299]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Shenker, B. J., Walker, L. P., Zekavat, A., Dlakić, M., & Boesze-Battaglia, K. (2014). Blockade of the PI-3K Signaling Pathway by the Aggregatibacter Actinomycetemcomitans Cytolethal Distending Toxin Induces Macrophages to Synthesize and Secrete Pro-inflammatory Cytokines. Cell Microbiology, 16 (9), 1391-1404. http://dx.doi.org/10.1111/cmi.12299
Date Posted: 01 March 2022
This document has been peer reviewed.