Phosphatidylinositol 3-Kinase Activation Attenuates the TLR2-Mediated Macrophage Proinflammatory Cytokine Response toFrancisella tularensisLive Vaccine Strain

Abstract

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.

CpG- and LPS-activated MAPK signaling in in vitro cultured salmon (Salmo salar) mononuclear phagocytes

“…However, another explanation is the potential autocrine action of M-CSF, or analogous growth factors, since in primary murine macrophages the p38 activation by CpGs, but not LPS, was suppressed by pretreatment with M-CSF which at the same time upregulated ERK phosphorylation [36]. In addition, it has been shown that the PI3K signalling suppresses TLR-induced p38 phosphorylation in innate immune cells including DCs [37] and macrophages [38]. Enhanced activity of PI3K in macrophages results in increased DUSP1 (a p38 specific phosphatase) expression, IL-10 production and, as a result, diminished p38 activation and lowered production of proinflammatory cytokines in response to pathogens [39].…”

Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain

“…TLR2 dimerization with TLR1 or TLR6 allows for recognition of both gram-positive and certain gram-negative bacteria (e.g., S. aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Francisella tularensis) (4,6,7,9). C29 significantly inhibited heat-killed P. aeruginosa-induced and heat-killed S. aureus (HKSA)-induced IL-8 mRNA in HEK-TLR2 cells (Fig.…”

“…TLR2 heterodimerizes with TLR6 or TLR1 to recognize diacyl lipopeptides or triacyl lipopeptides, respectively (2,3), present in gram-positive and gram-negative bacteria (4)(5)(6)(7)(8)(9).…”

IFN-γ Primes Macrophage Activation by Increasing Phosphatase and Tensin Homolog via Downregulation of miR-3473b

“…Some studies show that, in liver ischemic/reperfusion injury, PTEN can promote local macrophage activation, proinflammatory cytokine expression, and neutrophil accumulation through suppressing Akt/b-catenin-mediated NF-kB inhibition and promoting Foxo1-mediated NF-kB activation (27,28). Also, previous studies have shown that PI3K/Akt signaling could directly regulate MAPK activation (29) and GSK3 could directly crosstalk with NF-kB activation triggered by TLR agonists (30). Therefore, downregulating miR-3473b by IFN-g priming to suppress PI3K/Akt/ GSK3 signaling may also directly regulate TLR-triggered MAPK and NF-kB signaling to beef up macrophage activation.…”