TY - JOUR
T1 - PPARγ regulates the function of human dendritic cells primarily by altering lipid metabolism
AU - Szatmari, Istvan
AU - Töröcsik, Daniel
AU - Agostini, Maura
AU - Nagy, Tibor
AU - Gurnell, Mark
AU - Barta, Endre
AU - Chatterjee, Krishna
AU - Nagy, Laszlo
PY - 2007/11/1
Y1 - 2007/11/1
N2 - Activation of the lipid-regulated nuclear receptor peroxisome proliferatoractivated receptor gamma (PPARγ) modifies the immunophenotype of monocytederived dendritic cells (DCs). However it has not been analyzed in a systematic manner how lipid metabolism and immune regulation are connected at the transcriptional level via this receptor. Here we present the genome-wide expression analyses of PPARγ-instructed human DCs. Receptor activation was achieved by exogenous, synthetic as well as endogenous, natural means. More than 1000 transcripts are regulated during DC development by activation of PPARγ; half of the changes are positive effects. These changes appear to enhance and modulate the robust gene expression alterations associated with monocyte to DC transition. Strikingly, only genes related to lipid metabolism are overrepresented among early induced genes. As a net consequence, lipid accumulation appears to be diminished in these cells. In contrast, genes related to immune response are regulated after 24 hours, implying the existence of indirect mechanisms of modulation. Receptor dependence was established by using DCs of patients harboring a dominant-negative mutation of PPARγ. Our data show that PPARγ acts as a mostly positive transcriptional regulator in human developing DCs, acting primarily through controlling genes involved in lipid metabolism and via this, indirectly modifying the immune phenotype.
AB - Activation of the lipid-regulated nuclear receptor peroxisome proliferatoractivated receptor gamma (PPARγ) modifies the immunophenotype of monocytederived dendritic cells (DCs). However it has not been analyzed in a systematic manner how lipid metabolism and immune regulation are connected at the transcriptional level via this receptor. Here we present the genome-wide expression analyses of PPARγ-instructed human DCs. Receptor activation was achieved by exogenous, synthetic as well as endogenous, natural means. More than 1000 transcripts are regulated during DC development by activation of PPARγ; half of the changes are positive effects. These changes appear to enhance and modulate the robust gene expression alterations associated with monocyte to DC transition. Strikingly, only genes related to lipid metabolism are overrepresented among early induced genes. As a net consequence, lipid accumulation appears to be diminished in these cells. In contrast, genes related to immune response are regulated after 24 hours, implying the existence of indirect mechanisms of modulation. Receptor dependence was established by using DCs of patients harboring a dominant-negative mutation of PPARγ. Our data show that PPARγ acts as a mostly positive transcriptional regulator in human developing DCs, acting primarily through controlling genes involved in lipid metabolism and via this, indirectly modifying the immune phenotype.
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U2 - 10.1182/blood-2007-06-096222
DO - 10.1182/blood-2007-06-096222
M3 - Article
C2 - 17664351
AN - SCOPUS:36148982257
SN - 0006-4971
VL - 110
SP - 3271
EP - 3280
JO - Blood
JF - Blood
IS - 9
ER -