Anthrax lethal toxin down-regulates type-IIA secreted phospholipase A2 expression through MAPK/NF-κB inactivation

Bacillus anthracis, the etiological agent of anthrax, produces lethal toxin (LT) that displays a metallo-proteolytic activity toward the N-terminus of the MAPK-kinases. We have previously shown that secreted type-IIA phospholipase A2 (sPLA2-IIA) exhibits potent anthracidal activity. In vitro expression of sPLA2-IIA in guinea pig alveolar macrophages (AMs), the major source of this enzyme in lung tissues, is inhibited by LT. Here, we examined the mechanisms involved in sPLA2-IIA inhibition by LT. We first showed that chemical inhibitors of p38 and ERK MAPKs reduced sPLA2-IIA expression in AMs indicating that these kinases play a role in sPLA2-IIA expression. LT inhibited IL-1β-induced p38 phosphorylation as well as sPLA2-IIA promoter activity in CHO cells. Inhibition of sPLA2-IIA promoter activity was mimicked by co-transfection with dominant negative construct of p38 (DN-p38) and reversed by the active form of p38-MAPK (AC-p38). Both LT and DN-p38 decreased IL-1β-induced NF-κB luciferase activity. This contrasted with the effect of AC-p38, which enhanced this activity. However, neither LT nor specific p-38 inhibitor interfered with LPS-induced IκBα degradation or NF-κB nuclear translocation in AMs. Subcutaneous administration of LT to guinea pig before LPS challenge reduced sPLA2-IIA levels in broncho-alveolar lavages and ears. We conclude that sPLA2-IIA expression is induced via a sequential MAPK-NF-κB activation and that LT inhibits this expression likely by interfering with the transactivation of NF-κB in the nucleus. This inhibition, which is operating both in vitro and in vivo, may represent a mechanism by which B. anthracis subvert host defense.

Inflammatory signals (LPS, IL-1β) induce sPLA2-IIA expression in alveolar macrophages via NF-κB and p38/ERK-dependent mechanism. Bacillus anthracis produces lethal toxin (LT) which abrogates this induction by cleaving MAPKK.Figure optionsDownload as PowerPoint slide