Induction of Bacterial Lipoprotein Tolerance Is Associated with Suppression of Toll-like Receptor 2 Expression

Abstract

Tolerance to bacterial cell wall components including lipopolysaccharide (LPS) may represent an essential regulatory mechanism during bacterial infection. Two members of the Toll-like receptor (TLR) family, TLR2 and TLR4, recognize the specific pattern of bacterial cell wall components. TLR4 has been found to be responsible for LPS tolerance. However, the role of TLR2 in bacterial lipoprotein (BLP) tolerance and LPS tolerance is unclear. Pretreatment of human THP-1 monocytic cells with a synthetic bacterial lipopeptide induced tolerance to a second BLP challenge with diminished tumor necrosis factor-␣ and interleukin-6 production, termed BLP tolerance. Furthermore, BLP-tolerized THP-1 cells no longer responded to LPS stimulation, indicating a cross-tolerance to LPS. Induction of BLP tolerance was CD14-independent, as THP-1 cells that lack membranebound CD14 developed tolerance both in serum-free conditions and in the presence of a specific CD14 blocking monoclonal antibody (MEM-18). Pre-exposure of THP-1 cells to BLP suppressed mitogen-activated protein kinase phosphorylation and nuclear factor-B activation in response to subsequent BLP and LPS stimulation, which is comparable with that found in LPStolerized cells, indicating that BLP tolerance and LPS tolerance may share similar intracellular pathways. However, BLP strongly enhanced TLR2 expression in non-tolerized THP-1 cells, whereas LPS stimulation had no effect. Furthermore, a specific TLR2 blocking monoclonal antibody (2392) attenuated BLP-induced, but not LPS-induced, tumor necrosis factor-␣ and interleukin-6 production, indicating BLP rather than LPS as a ligand for TLR2 engagement and activation. More importantly, pretreatment of THP-1 cells with BLP strongly inhibited TLR2 activation in response to subsequent BLP stimulation. In contrast, LPS tolerance did not prevent BLPinduced TLR2 overexpression. These results demonstrate that BLP tolerance develops through downregulation of TLR2 expression.

Linking the “two-hit” response following injury to enhanced TLR4 reactivity

“…In contrast, prior exposure of monocytes or macrophages to TLR2 or TLR4 agonists can result in a lower, proinflammatory cytokine response by cells when these cells are restimulated with the same or similar agonists [41,42]. However, most investigators studying injury have not observed suppressed/tolerized TLR2 or TLR4 responses [22,30,43].…”

Ligand-induced differential cross-regulation of Toll-like receptors 2, 4 and 5 in intestinal epithelial cells

“…Interestingly, the effects in these cell types are in agreement to that what we observed for intestinal mIC cl2 epithelial cells. Tolerance and cross-tolerance between TLR2 and TLR4 upon long-term (24 h) TLR activation has been attributed to changes in expression of TLRs, as well as to the function of several signaling molecules including IRAK-1, NF-B and MAP kinases (Dobrovolskaia et al, 2003;Li et al, 2000Li et al, , 2006Medvedev et al, 2000Medvedev et al, , 2002Otte et al, 2004;Wang et al, 2002). Whether differences in signalling molecules also contribute to the here observed TLR (cross)-regulation upon short-term TLR activation in mIC cl2 cells awaits detailed investigation of the cell signalling dynamics.…”

Lipoteichoic Acid Isolated from Lactobacillus plantarum Inhibits Lipopolysaccharide-Induced TNF-α Production in THP-1 Cells and Endotoxin Shock in Mice

“…Recent studies have reported that endotoxin-or bacterial lipoprotein-induced tolerance down-regulated the phosphorylation of ERK, JNK, and p38 in mouse macrophages and human THP-1 cells, respectively (14,31). In addition, the LPS-induced activation of the MAPK pathways plays an important role in mediating NF-B activation.…”