Induction of cross-tolerance by lipopolysaccharide and highly purified lipoteichoic acid via different toll-like receptors independent of paracrine mediators

Exposure of macrophages to LPS induces a state of by po responsiveness to s ubsequent stimulation with LPS termed LPS desensitization or tolerance. To date, it Is not known whether similar mechanisms of macrophage refractorine ss are induced on contact with components of Gram-positive bacteria. In the present study, we demonstrate that pretreatment with highly purified lipot eichoic acid (LTA) results in suppression of cytokine release on restimulat ion 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 response s to the other stimulus ("cross-tolerance"), suggesting that signaling path ways shared by TLR2 and TLR4 are impaired during tolerance. Finally, we sho w that LPS- or LTA-induced cross-tolerance is not transferred to hyporespon sive cells cocultured with LPS/LTA-responsive macrophages, showing that sol uble mediators do not suffice for tolerance induction in neighboring cells.