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Anthrax lethal factor cleaves MKK3 in macrophages and inhibits the LPS/IFNγ‐induced release of NO and TNFα
Author(s) -
Pellizzari Rossella,
Guidi-Rontani Chantal,
Vitale Gaetano,
Mock Michèle,
Montecucco Cesare
Publication year - 1999
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(99)01502-1
Subject(s) - kinase , tumor necrosis factor alpha , p38 mitogen activated protein kinases , lipopolysaccharide , cytolysis , cytosol , protein kinase a , bacillus anthracis , macrophage , biology , microbiology and biotechnology , chemistry , biochemistry , enzyme , bacteria , immunology , in vitro , cytotoxicity , genetics
The lethal toxin of Bacillus anthracis consists of two proteins, PA and LF, which together induce lethal effects in animals and cause macrophage lysis. LF is a zinc‐endopeptidase which cleaves two mitogen‐activated proten kinase kinases (MAPKKs), Mek1 and Mek2, within the cytosol. Here, we show that also MKK3, another dual‐specificity kinase that phosphorylates and activates p38 MAP kinase, is cleaved by LF in macrophages. No direct correlation between LF‐induced cell death and cleavage of these MAPKKs was found in macrophage cell lines and primary peritoneal cells exhibiting different sensitivity to LF. However, we present the first evidence that sublytic doses of LF cleave Meks and cause a substantial reduction in the production of NO and tumour necrosis factor‐α induced by lipopolysaccharide/interferonγ. We suggest that this effect of LF is relevant during the first stages of B. anthracis infection, when a reduction of the inflammatory response would permit growth and diffusion of the bacterium.