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The Journal of Immunology, 2001, 166: 5161-5167.
Copyright © 2001 by The American Association of Immunologists

Induction of Cross-Tolerance by Lipopolysaccharide and Highly Purified Lipoteichoic Acid Via Different Toll-Like Receptors Independent of Paracrine Mediators1

Martin D. Lehner*, Siegfried Morath*, Kathrin S. Michelsen{dagger}, Ralf R. Schumann{dagger} and Thomas Hartung2,*

* Biochemical Pharmacology, University of Konstanz, Konstanz, Germany; and {dagger} Institut für Mikrobiologie, Universitätsklinikum Charité, Medizinische Fakultät der Humboldt-Universität zu Berlin, Berlin, Germany

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.




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