Regulation of IL-12p40
In this project Konrad Bode is interested in the recognition processes mediated by Toll-like receptors. Ongoing investigations try to elucidate molecular signal transduction mechanisms that differ between Toll-like receptors. In this respect CpG-DNA has the peculiarity to induce high amounts of IL-12 as compared to lipopolysaccharide or lipoteichoic acid. Consequently, CpG-DNA is a powerful stimulus for the induction of Th1 directed immune responses.
It has been reported that regulation of IL-12 transcription has two restriction points: Nucleosomal remodeling is necessary to render the promoter region accessible for the subsequent binding of transcription factors. We were able to show that only TLR-9 stimulation sufficiently induced nucleosomal remodeling at the endogenous promoter region thus facilitating transcription factor binding and subsequently IL-12p40 secretion. These findings identify inducible changes in the chromatin structure of genes as a new mechanism of regulation in TLR signaling.
Recently, we were able to show that various TLR agonists tremendously differ in the way they activate the central signaling module NFkB. Differences in NFkB kinetics result in surprisingly variable biological response .
- Albrecht I, Tapmeier T, Zimmermann S, Frey M, Heeg K, and Dalpke AH (2004): Toll-like receptors differentially induce nucleosome remodeling at the IL-12p40 promoter. EMBO Reports 5 (2): 172-177
- Bode KA, Schroder K, Hume DA, Ravasi T, Heeg K, Sweet MJ, Dalpke AH (2007): Histone deacetylase inhibitors decrease Toll-like receptor-mediated activation of pro-inflammatory gene expression by impairing transcription factor recruitment. Immunology 122(4): 596-606
- Schroder K, Spille M, Pilz A, Lattin J, Bode K, Irvine KM, Burrows AD, Ravasi T, Weighardt H, Stacey KJ, Decker T, Hume DA, Dalpke AH, Sweet MJ (2007): Differential effects of CpG DNA on IFNbeta induction and STAT1 activation in murine macrophages versus dendritic cells: Identification of a novel function for STAT1 in toll-like receptor signalling. J Immunol 179(6): 3495-3503
- Theiner G, Rößner S, Dalpke A, Bode K, Berger T, Gessner A, Lutz M (2008): TLR9 cooperates with TLR4 to increase Il-12 release by murine dendritic cells. Mol Immunol 45: 244-252
- Bode KA, Schmitz F, Vargas L, Heeg K, Dalpke AH (2009):
Kinetic of RelA activation controls magnitude of Toll-like receptor mediated IL-12p40 induction. J Immunol 182(4): 2176-2184