Systemically Administered Ligands of Toll-Like Receptor 2, -4, and -9 Induce Distinct Inflammatory Responses in the Murine Lung

Abstract EN

Objective.

To determine whether systemically administered TLR ligands differentially modulate pulmonary inflammation.

Methods.

Equipotent doses of LPS (20 mg/kg), CpG-ODN (1668-thioat 1 nmol/g), or LTA (15 mg/kg) were determined via TNF activity assay.

C57BL/6 mice were challenged intraperitoneally.

Pulmonary NFκB activation (2 h) and gene expression/activity of key inflammatory mediators (4 h) were monitored.

Results.

All TLR ligands induced NFκB.

LPS increased the expression of TLR2, 6, and the cytokines IL-1αβ, TNF-α, IL-6, and IL-12p35/p40, CpG-ODN raised TLR6, TNF-α, and IL12p40.

LTA had no effect.

Additionally, LPS increased the chemokines MIP-1α/β, MIP-2, TCA-3, eotaxin, and IP-10, while CpG-ODN and LTA did not.

Myeloperoxidase activity was highest after LPS stimulation.

MMP1, 3, 8, and 9 were upregulated by LPS, MMP2, 8 by CpG-ODN and MMP2 and 9 by LTA.

TIMPs were induced only by LPS.

MMP-2/-9 induction correlated with their zymographic activities.

Conclusion.

Pulmonary susceptibility to systemic inflammation was highest after LPS, intermediate after CpG-ODN, and lowest after LTA challenge.