Synergy and Cross-Tolerance Between Toll-Like Receptor (TLR) 2- and TLR4-Mediated Signaling Pathways

Abstract

A family of Toll-like receptor (TLR) mediates the cellular response to bacterial cell wall components; murine TLR2 and TLR4 recognize mycoplasmal lipopeptides (macrophage-activating lipopeptides, 2 kDa (MALP-2)) and LPS, respectively. Costimulation of mouse peritoneal macrophages with MALP-2 and LPS results in a marked increase in TNF-α production, showing the synergy between TLR2- and TLR4-mediated signaling pathways. Macrophages pretreated with LPS show hyporesponsiveness to the second LPS stimulation, termed LPS tolerance. The LPS tolerance has recently been shown to be primarily due to the down-regulation of surface expression of the TLR4-MD2 complex. When macrophages were treated with MALP-2, the cells showed hyporesponsiveness to the second MALP-2 stimulation, like LPS tolerance. Furthermore, macrophages pretreated with MALP-2 showed reduced production of TNF-α in response to LPS. LPS-induced activation of both NF-κB and c-Jun NH2-terminal kinase was severely impaired in MALP-2-pretreated cells. However, MALP-2-pretreated macrophages did not show any reduction in surface expression of the TLR4-MD2 complex. These findings indicate that LPS-induced LPS tolerance mainly occurs through the down-regulation of surface expression of the TLR4-MD2 complex; in contrast, MALP-2-induced LPS tolerance is due to modulation of the downstream cytoplasmic signaling pathways.

Increased macrophage activation mediated through toll‐like receptors in rheumatoid arthritis

“…This was also the case for macrophages from the joints of patients with other forms of inflammatory arthritis. Further, it is possible that the reduced response by macrophages in other forms of inflammatory arthritis (compared with that by RA macrophages) may be due to greater prior in vivo activation of these macrophages in response to endogenous TLR ligands, resulting in toler-ance to a repeat challenge by microbial TLR ligands (50)(51)(52).…”

The immunomodulator ginsan induces resistance to experimental sepsis by inhibiting Toll‐like receptor‐mediated inflammatory signals

“…In support of this hypothesis, endotoxin or LPS tolerance is a well-established phenomenon in which pre-exposure to a sublethal dose of LPS blunts subsequent lethal LPS-induced mortality, and this effect was closely associated with diminished production of proinflammatory cytokines [34,35]. In addition to LPS tolerance, several non-LPS bacterial cell wall components, including bacterial lipoprotein (BLP), also induce tolerance [36,37]. Unlike LPS or BLP, however, ginsan exhibited a wide spectrum of bacterial tolerance in Gram-positive, Gram-negative, and polymicrobial septic models and did not induce lethal shock, even at high concentrations.…”

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.…”