Premium
PI3‐kinase activation attenuates the TLR2‐mediated macrophage proinflammatory cytokine response to F. tularensis infection
Author(s) -
Medina Edward A.,
Morris Ian R.,
Berton Michael T.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.lb353
Subject(s) - proinflammatory cytokine , wortmannin , tlr2 , mapk/erk pathway , protein kinase b , trif , kinase , p38 mitogen activated protein kinases , pi3k/akt/mtor pathway , microbiology and biotechnology , cytokine , tlr4 , francisella tularensis , biology , signal transduction , chemistry , immunology , toll like receptor , inflammation , immune system , innate immune system , biochemistry , virulence , gene
We sought to clarify the role of the PI3‐kinase/Akt pathway in regulating early (< 9 h) proinflammatory responses in macrophages infected with Francisella tularensis Live Vaccine Strain (LVS). LVS‐induced TNF‐α and IL‐6 secretion was markedly increased in macrophages from wildtype C57BL/6 mice pre‐exposed to the PI3‐kinase inhibitor wortmannin compared with vehicle pre‐exposed macrophages; the levels of phosphorylated p38 MAPK and ERK1/2 were also enhanced and remained elevated for a longer period of time. LVS infection rapidly induced MAPK phosphatase‐1 (MKP‐1) expression in a TLR2‐ and PI3‐kinase‐dependent manner. Peak levels of MKP‐1 correlated closely with the decline in p38 MAPK and ERK1/2 phosphorylation. MAPK activation and cytokine production were entirely TLR2‐dependent. Surprisingly, PI3‐kinase/Akt activation was TLR2‐independent; it was also TLR4‐, TLR9‐, TIRAP/Mal‐ and TRIF‐independent. PI3‐kinase activation was, however, dependent on MyD88. These data suggest that LVS infection restrains the TLR2‐triggered pro‐inflammatory response of macrophages via parallel activation of the PI3‐kinase pathway, which enhances MKP‐1 expression. This results in the accelerated deactivation of MAPKs and suppression of proinflammatory cytokine production. This inhibitory pathway may be activated by a novel MyD88‐dependent pattern recognition receptor that is engaged by LVS. This work was supported by NIH grant AI057986.