Induction of Cross-Tolerance by Lipopolysaccharide and Highly Purified Lipoteichoic Acid Via Different Toll-Like Receptors Independent of Paracrine Mediators

Abstract

Exposure of macrophages to LPS induces a state of hyporesponsiveness to subsequent stimulation with LPS termed LPS desensitization or tolerance. To date, it is not known whether similar mechanisms of macrophage refractoriness are induced on contact with components of Gram-positive bacteria. In the present study, we demonstrate that pretreatment with highly purified lipoteichoic acid (LTA) results in suppression of cytokine release on restimulation with LTA in vitro and in vivo in both C3H/HeN and C3H/HeJ mice, but not in macrophages from Toll-like receptor (TLR)-2-deficient mice. Furthermore, desensitization in response to LPS or LTA exposure also inhibits responses to the other stimulus (“cross-tolerance”), suggesting that signaling pathways shared by TLR2 and TLR4 are impaired during tolerance. Finally, we show that LPS- or LTA-induced cross-tolerance is not transferred to hyporesponsive cells cocultured with LPS/LTA-responsive macrophages, showing that soluble mediators do not suffice for tolerance induction in neighboring cells.

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

“…The inhibition of LPSinduced TNF-␣ production, however, was not exhibited in the simultaneous treatment of pLTA and LPS or pLTA posttreatment following LPS. These results suggest that pLTA-induced tolerance is different from LPS-or S. aureus LTA (aLTA)-induced tolerance which results in bilateral hyporesponsiveness to subsequent stimulation with LPS or aLTA (15).…”

“…Excessive inflammation can, however, cause inflammatory diseases such as septic shock, Legionnaire's disease, systemic lupus erythematosus, Crohn's disease, atherosclerosis, and so on (21). To treat these inflammatory diseases, researchers have tried to induce tolerance against endotoxin, which induces excessive inflammation, and several reports have shown that bacterial cell wall components induced homologous tolerance (15,16,22,23). However, most bacterial cell walls used in tolerance-induction tests were isolated from pathogenic bacteria, making them harmful for use in clinical applications.…”

Differential effects of CpG‐DNA in Toll‐like receptor‐2/‐4/‐9 tolerance and cross‐tolerance

“…It seems that tolerance induction is an interplay of altered conditions at several steps of signal transduction. Whereas initial findings in human cells stressed the importance of inhibitory cytokines such as interleukin (IL)-10 or transforming growth factor (TGF)-b, 31 experiments using knockout mice 14,32 and co-culture experiments 15 did not support a major contribution of these mediators. Also, while down-regulation of TLR-4 has been postulated to contribute to tolerance, 33 other reports demonstrated cellular refractoriness independent of TLR-4 regulation, 13 and no similar findings of an involvement of receptor down-regulation in cellular refractoriness were obtained for other TLRs.…”

“…8,[10][11][12] In light of the finding that 10 cellular responses to different microbial stimuli are mediated by different 11 TLRs, studies were initiated to determine whether, in analogy to LPS tolerance, pretreatment with microbial non-LPS stimuli also induces hyporesponsiveness to subsequent restimulation. Indeed, it has been reported that stimulation with prototypical ligands for TLR-2 (+TLR-1 or -6), [13][14][15][16][17][18] TLR-4, TLR-5 19 and TLR-9 20,21 also induces this state of hyporesponsiveness towards subsequent stimulation with the same ligand. Moreover, stimuli signalling via TLR-2 and TLR-4, 14,15 as well as TLR-4 and TLR-9, 20 can substitute for each other, mediating cross-tolerance in vitro as well as in vivo.…”

“…LTA had been purified from Staphylococcus aureus and had previously been characterized as being essentially dependent on TLR-2. 15 Highly purified LPS from Salmonella minnesota (smooth form) was kindly provided by U. Seydel (Borstel, Germany). It was solely recognized by TLR-4.…”