TY - JOUR
T1 - Mycobacterial PIMs inhibit host inflammatory responses through CD14-dependent and CD14-independent mechanisms
AU - Court, Nathalie
AU - Rose, Stéphanie
AU - Bourigault, Marie Laure
AU - Front, Sophie
AU - Martin, Olivier R.
AU - Dowling, Jennifer K.
AU - Kenny, Elaine F.
AU - O'Neill, Luke
AU - Erard, François
AU - Quesniaux, Valerie F J
PY - 2011/9/16
Y1 - 2011/9/16
N2 - Mycobacteria develop strategies to evade the host immune system. Among them, mycobacterial LAM or PIMs inhibit the expression of pro-inflammatory cytokines by activated macrophages. Here, using synthetic PIM analogues, we analyzed the mode of action of PIM anti-inflammatory effects. Synthetic PIM 1 isomer and PIM 2 mimetic potently inhibit TNF and IL-12 p40 expression induced by TLR2 or TLR4 pathways, but not by TLR9, in murine macrophages. We show inhibition of LPS binding to TLR4/MD2/CD14 expressing HEK cells by PIM 1 and PIM 2 analogues. More specifically, the binding of LPS to CD14 was inhibited by PIM 1 and PIM 2 analogues. CD14 was dispensable for PIM 1 and PIM 2 analogues functional inhibition of TLR2 agonists induced TNF, as shown in CD14-deficient macrophages. The use of rough-LPS, that stimulates TLR4 pathway independently of CD14, allowed to discriminate between CD14-dependent and CD14-independent anti-inflammatory effects of PIMs on LPS-induced macrophage responses. PIM 1 and PIM 2 analogues inhibited LPS-induced TNF release by a CD14-dependent pathway, while IL-12 p40 inhibition was CD14-independent, suggesting that PIMs have multifold inhibitory effects on the TLR4 signalling pathway.
AB - Mycobacteria develop strategies to evade the host immune system. Among them, mycobacterial LAM or PIMs inhibit the expression of pro-inflammatory cytokines by activated macrophages. Here, using synthetic PIM analogues, we analyzed the mode of action of PIM anti-inflammatory effects. Synthetic PIM 1 isomer and PIM 2 mimetic potently inhibit TNF and IL-12 p40 expression induced by TLR2 or TLR4 pathways, but not by TLR9, in murine macrophages. We show inhibition of LPS binding to TLR4/MD2/CD14 expressing HEK cells by PIM 1 and PIM 2 analogues. More specifically, the binding of LPS to CD14 was inhibited by PIM 1 and PIM 2 analogues. CD14 was dispensable for PIM 1 and PIM 2 analogues functional inhibition of TLR2 agonists induced TNF, as shown in CD14-deficient macrophages. The use of rough-LPS, that stimulates TLR4 pathway independently of CD14, allowed to discriminate between CD14-dependent and CD14-independent anti-inflammatory effects of PIMs on LPS-induced macrophage responses. PIM 1 and PIM 2 analogues inhibited LPS-induced TNF release by a CD14-dependent pathway, while IL-12 p40 inhibition was CD14-independent, suggesting that PIMs have multifold inhibitory effects on the TLR4 signalling pathway.
UR - http://www.scopus.com/inward/record.url?scp=80052861988&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0024631
DO - 10.1371/journal.pone.0024631
M3 - Article
C2 - 21949737
AN - SCOPUS:80052861988
SN - 1932-6203
VL - 6
JO - PLoS ONE
JF - PLoS ONE
IS - 9
M1 - e24631
ER -