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Blood, 15 June 2006, Vol. 107, No. 12, pp. 4763-4769.
Prepublished online as a Blood First Edition Paper on March 9, 2006; DOI 10.1182/blood-2005-04-1501.
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Submitted April 14, 2005
Accepted January 12, 2006
Adaptive functional differentiation of dendritic cells - integrating the network of extra- and intracellular signals
Thomas Luft, Elena Rodionova, Eugene Maraskovsky*, Michael Kirsch, Michael Hess, Christian Buchholtz, Martin Goerner, Max Schnurr, Radek Skoda, and Anthony D Ho
Dept. of Molecular Oncology/Hematology, German Cancer Research Center, Heidelberg, Germany; Medizinische Klinik und Poliklinik V, University of Heidelberg, Heidelberg, Germany
Dept. of Molecular Oncology/Hematology, German Cancer Research Center, Heidelberg, Germany
CSL Limited, Melbourne, VIC, Australia; The Ludwig Institute for Cancer Research, Melbourne, VIC, Australia
Medizinische Klinik und Poliklinik V, University of Heidelberg, Heidelberg, Germany
Department of Internal Medicine, Division of Gastroenterology, University of Munich, Munich, Germany
* Corresponding author; email: eugene_maraskovsky{at}csl.com.au.
Phenotypic maturation, cytokine secretion and migration are distinct functional characteristics of dendritic cells (DCs). These functions are independently regulated by a number of extracellular variables, such as type, strength and persistence of an array of soluble and membrane-bound mediators. Since the exact composition of these variables in response to infection may differ between individuals, the intracellular signalling pathways activated by these extracellular networks may more closely correlate with DC function and predict the course of adaptive immunity. This study demonstrates that activation of p38K, ERK1/2 and PC-PLC enhanced cytokine secretion, whereas p38K, cAMP and PC-PLC enhanced migration. In contrast, PI3K/Akt-1 and cAMP inhibited cytokine secretion whilst ERK1/2 inhibited migration. Migration and cytokine secretion further differed in their sensitivity to inhibition over time. However, although DCs could be manipulated to express migration, cytokine secretion or both, the level of activation or persistence of intracellular pathway signalling was not predictive. Our results suggest a modular organization of function. We hypothesize that the expression of specific DC functions integrates a large variety of activating and inhibitory variables, and is represented by the formation of a functional unit of molecular networks - the signal response module (SRM). The combined activities of these modules define the functional outcome of DC activation.
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