期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2001
卷号：98
期号：5
页码：2443-2448
DOI：10.1073/pnas.041493198
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：IL-4 is a pleiotropic immune cytokine secreted by activated TH2 cells that inhibits bone resorption both in vitro and in vivo. The cellular targets of IL-4 action as well as its intracellular mechanism of action remain to be determined. We show here that IL-4 inhibits receptor activator of NF-{kappa}B ligand-induced osteoclast differentiation through an action on osteoclast precursors that is independent of stromal cells. Interestingly, this inhibitory effect can be mimicked by both natural as well as synthetic peroxisome proliferator-activated receptor {gamma}1 (PPAR{gamma}1) ligands and can be blocked by the irreversible PPAR{gamma} antagonist GW 9662. These findings suggest that the actions of IL-4 on osteoclast differentiation are mediated by PPAR{gamma}1, an interpretation strengthened by the observation that IL-4 can activate a PPAR{gamma}1-sensitive luciferase reporter gene in RAW264.7 cells. We also show that inhibitors of enzymes such as 12/15-lipoxygenase and the cyclooxygenases that produce known PPAR{gamma}1 ligands do not abrogate the IL-4 effect. These findings, together with the observation that bone marrow cells from 12/15-lipoxygenase-deficient mice retain sensitivity to IL-4, suggest that the cytokine may induce novel PPAR{gamma}1 ligands. Our results reveal that PPAR{gamma}1 plays an important role in the suppression of osteoclast formation by IL-4 and may explain the beneficial effects of the thiazolidinedione class of PPAR{gamma}1 ligands on bone loss in diabetic patients.
