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Kinetic of RelA Activation Controls Magnitude of TLR-Mediated IL-12p40 Induction¹

Konrad A. Bode^*, Frank Schmitz, Leonardo Vargas, Klaus Heeg^* and Alexander H. Dalpke^2,*

^* Department of Medical Microbiology and Hygiene, University of Heidelberg, Heidelberg, Germany; Institute for Medical Microbiology, Immunology, and Hygiene, University of Munich, Munich, Germany; and Clinical Research Center, Karolinska University Hospital, Stockholm, Sweden

IL-12 is a crucial cytokine for dendritic cell-mediated induction of Th 1 cell differentiation. TLR ligands induce IL-12 to differing extents. Stimulation of dendritic cells allowed for the differentiation of three groups of TLRs; potency to induce IL-12 decreased in the order of TLR7/9, TLR3/4, and TLR1/2/6 stimulation. The MAPK, PI3K, and IRF (IFN regulatory factor) signaling pathways could be ruled out to be the cause for the differences in IL-12p40 induction. However, we observed that stimulation of dendritic cells with different TLR ligands resulted in striking differences in the kinetics of NF-B activation. LPS induced a rapid but short-lived activation of RelA, whereas CpG-DNA stimulation resulted in prolonged RelA activity at the IL-12p40 promoter. Only TLR2 and TLR4 ligands were capable of inducing S536 phosphorylation of RelA, which has been proposed to be responsible for early termination of NF-B activation. It is suggested that differences in the kinetics of a common TLR signaling module affect the biological response patterns of various TLRs, with IL-12p40 being a gene that needs prolonged NF-B activation.

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 project has been supported by Deutsche Forschungsgemeinschaft Grant DFG Da 592/2 (to A.H.D.).

² Address correspondence and reprint requests to Prof. Alexander H. Dalpke, Department of Medical Microbiology and Hygiene, Hygiene-Institute, University of Heidelberg, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany. E-mail address: alexander.dalpke{at}med.uni-heidelberg.de

³ Abbreviations used in this paper: TIR, Toll/IL-1R; BMDC, bone marrow-derived dendritic cell; Btk, Bruton’s tyrosine kinase; ChIP, chromatin immunoprecipitation; Ct, threshold cycle; IKK, IB kinase; IRF, interferon regulatory factor; TRIF, TIR domain-containing adaptor-inducing IFN-β.