We have recently shown that leptin strongly induces the expression and secretion of the interleukin-1 receptor antagonist (IL-1Ra) [Gabay, Dreyer, Pellegrinelli, Chicheportiche and Meier (2001) J. Clin. Endocrinol. Metab. 86, 783—791] in monocytes. However, the intracellular signalling mechanisms involved remained unknown. We now demonstrate that the activation of the IL-1Ra promoter by leptin is strictly dependent on the presence of the long form of the leptin receptor (OB-Rb), and that it also requires the activation of the p42/44 mitogen-activated protein kinases (MAPKs) as well as the presence of a nuclear factor κB (NF-κB)/PU.1 composite site at position −80 of the IL-1Ra promoter. Although leptin is capable of activating a NF-κB reporter element in transient transfection experiments, the protein complex binding to the NF-κB/PU.1 site of the IL-1Ra promoter is not composed of the p65/p50 subunits of NF-κB, as is evident in electrophoretic gel mobility-shift experiments. In contrast, a protein complex which does not contain PU.1 binds to this composite element in a leptin-dependent manner. In summary, we characterize the signalling pathway for leptin and OB-Rb involved in the induction of IL-1Ra, involving p42/44 MAPK, and a yet uncharacterized complex of transcription factor(s) binding to a NF-κB/PU.1 composite element of the IL-1Ra promoter.
Secretory Interleukin-1 Receptor Antagonist Gene Expression Requires both a PU.1 and a Novel Composite NF-κB/PU.1/ GA-binding Protein Binding Site
