Anthrax lethal toxin down-regulates type-IIA secreted phospholipase A(2) expression through MAPK/NF-kappaB inactivation.

Benoit Raymond (1) , Lucas Ravaux (2) , Sylvie Mémet (3) , Yongzheng Wu (1) , Aude Sturny-Leclère (3) , Dominique Leduc (1) , Chantal Denoyelle (2) , Pierre L. Goossens (4) , Miguel Payá (5) , Michel Raymondjean (2) , Lhousseine Touqui (1)

1 Défense innée et inflammation
2 PP - Physiologie et physiopathologie
3 Mycologie moléculaire
4 Toxines et Pathogénie Bactérienne
5 Departamento de Farmacología

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 A(2) (sPLA(2)-IIA) exhibits potent anthracidal activity. In vitro expression of sPLA(2)-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 sPLA(2)-IIA inhibition by LT. We first showed that chemical inhibitors of p38 and ERK MAPKs reduced sPLA(2)-IIA expression in AMs indicating that these kinases play a role in sPLA(2)-IIA expression. LT inhibited IL-1beta-induced p38 phosphorylation as well as sPLA(2)-IIA promoter activity in CHO cells. Inhibition of sPLA(2)-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-1beta-induced NF-kappaB 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 IkappaBalpha degradation or NF-kappaB nuclear translocation in AMs. Subcutaneous administration of LT to guinea pig before LPS challenge reduced sPLA(2)-IIA levels in broncho-alveolar lavages and ears. We conclude that sPLA(2)-IIA expression is induced via a sequential MAPK-NF-kappaB activation and that LT inhibits this expression likely by interfering with the transactivation of NF-kappaB 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.

Domaines: Pharmacologie

Benoit Raymond, Lucas Ravaux, Sylvie Mémet, Yongzheng Wu, Aude Sturny-Leclère, et al.. Anthrax lethal toxin down-regulates type-IIA secreted phospholipase A(2) expression through MAPK/NF-kappaB inactivation.. Biochemical Pharmacology, 2010, 79 (8), pp.1149-55. ⟨10.1016/j.bcp.2009.11.023⟩. ⟨pasteur-00512095⟩