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IL-6 and Maturation Govern TLR2 and TLR4 Induced TLR Agonist Tolerance and Cross-Tolerance in Dendritic Cells¹

Julia Geisel^*, Frauke Kahl^*, Martina Müller^*, Hermann Wagner, Carsten J. Kirschning, Ingo B. Autenrieth^* and Julia-Stefanie Frick^2,*

^* Institute of Medical Microbiology and Hygiene, University of Tübingen, Tübingen, Germany; and Institute of Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, Munich, Germany

Stimulation of naive mouse dendritic cells (DC) with LPS or Pam₃CSK₄ (P3C) induces production of TNF- via TLR4- or TLR2-signaling. Although tolerance in macrophages has been studied in detail, we investigated the role of TLR agonist concentration and IL-6 for tolerance in DC. P3C- or LPS-primed DC were nonresponsive to P3C or LPS restimulation in terms of TNF- but not IL-6 production. The mechanisms involved in tolerance were dependent on the concentration of the TLR ligand used for DC priming. DC primed with LPS or P3C at high concentrations developed a maturation dependent, IL-6 independent tolerance associated with inhibition of TLR signaling upstream of IB as indicated by decreased IB degradation. In contrast, priming of DC with LPS or P3C at low concentrations resulted in IL-6-dependent tolerance, which was abolished in IL-6 deficient DC, and was not accompanied by maturation of DC or by down-regulation of TLR2 or TLR4. In homotolerogenic DC primed with LPS or P3C at high concentrations, degradation of IB upon restimulation with LPS or P3C was inhibited suggesting tolerance mechanism(s) upstream of IB; in contrast, cross-tolerance in DC primed with LPS or P3C at low concentrations was not associated with reduced IB degradation suggesting tolerance mechanisms downstream of IB. Our data indicate that in naive DC TLR4- and TLR2-stimulation results in homo- and cross-tolerance; the mechanisms involved in tolerance depend on the concentration of the TLR agonist used for DC priming and are governed by IL-6 and maturation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by grants from Deutsche Forschungsgemeinschaft and Interdisciplinary Center for Clinical Research (University of Tübingen, Tübingen, Germany).

² Address correspondence and reprint requests to Dr. J.-S. Frick, Institute of Medical Microbiology and Hygiene, University of Tübingen, Elfriede-Aulhorn-Strasse 6, Tübingen, Germany. E-mail address: julia-stefanie.frick{at}med.uni-tuebingen.de

³ Abbreviations used in this paper: DC, dendritic cells; IRAK, IL-1 receptor-associated kinase; SOCS, suppressor of cytokine signaling.

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