Leptin activates the promoter of the interleukin-1 receptor antagonist through p42/44 mitogen-activated protein kinase and a composite nuclear factor kappa B/PU.1 binding site.
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 kappaB (NF-kappa B)/PU.1 composite site at position -80 of the IL-1Ra promoter. Although leptin is capable of activating a NF-kappa B reporter element in transient transfection experiments, the protein complex binding to the NF-kappa B/PU.1 site of the IL-1Ra promoter is not composed of the p65/p50 subunits of NF-kappa B, 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-kappa B/PU.1 composite element of the IL-1Ra promoter.
Dreyer
Magali G
MG
Endocrine Unit, Division of Endocrinology, Diabetes and Nutrition, University Hospital Geneva, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland.
Juge-Aubry
Cristiana E
CE
Gabay
Cem
C
Lang
Ursula
U
Rohner-Jeanrenaud
Françoise
F
Dayer
Jean-Michel
JM
Meier
Christoph A
CA
D001665:Binding Sites; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D020738:Leptin / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
D053590:Interleukin 1 Receptor Antagonist Protein; D020738:Leptin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D012795:Sialoglycoproteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C507763:IL1RN protein, human