The peroxisome proliferator activated receptor δ is required for the differentiation of THP-1 monocytic cells by phorbol ester.
BACKGROUND
PPARδ (NR1C2) promotes lipid accumulation in human macrophagesin vitroand has been implicated in the response of macrophages to vLDL. We have investigated the role of PPARδ in PMA-stimulated macrophage differentiation. The THP-1 monocytic cell line which displays macrophage like differentiation in response to phorbol esters was used as a model system. We manipulated the response to PMA using a potent synthetic agonist of PPARδ , compound F. THP-1 sub-lines that either over-expressed PPARδ protein, or expressed PPARδ anti-sense RNA were generated. We then explored the effects of these genetic modulations on the differentiation process.


RESULTS
The PPARδ agonist, compound F, stimulated differentiation in the presence of sub-nanomolar concentrations of phorbol ester. Several markers of differentiation were induced by compound F in a synergistic fashion with phorbol ester, including CD68 and IL8. Over-expression of PPARδ also sensitised THP-1 cells to phorbol ester and correspondingly, inhibition of PPARδ by anti-sense RNA completely abolished this response.


CONCLUSIONS
These data collectively demonstrate that PPARδ plays a fundamental role in mediating a subset of cellular effects of phorbol ester and supports observations from mouse knockout models that PPARδ is involved in macrophage-mediated inflammatory responses.
Vosper
Helen
H
Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee. DD1 9SY, UK.
Khoudoli
Guennadi A
GA
Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee. DD1 9SY, UK.|Medical Sciences Institute, University of Dundee, Nethergate, Dundee. DD1 4HN, UK.
Palmer
Colin Na
CN
Biomedical Research Centre, University of Dundee, Ninewells Hospital and Medical School, Dundee. DD1 9SY, UK.