Published online before print November 2, 2006, doi: 10.1161/01.ATV.0000251608.09329.9a
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© 2007 American Heart Association, Inc.
Vascular Biology |
Role of the Toll-like Receptor 4/NF-
B Pathway in Saturated Fatty Acid–Induced Inflammatory Changes in the Interaction Between Adipocytes and Macrophages
From the Department of Molecular Medicine and Metabolism (T.S., K.T.-K., J.N., M.I., X.Y., Y.K., Y.O.) and the Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone (Y.O.), Medical Research Institute, Tokyo Medical and Dental University; the Tsukuba Research Institute (S.M., H.K.), Banyu Pharmaceutical Co Ltd; the Department of Molecular Virology (S.Y.), Graduate School of Medicine, Tokyo Medical and Dental University; the Division of Infectious Genetics (K.M.), The Institute of Medical Science, The University of Tokyo; and the Department of Home Economics (S.A.), Otsuma Womens University, Tokyo, Japan.
Correspondence to Yoshihiro Ogawa, MD, PhD, Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. E-mail ogawa.mmm{at}mri.tmd.ac.jp
Objective— Previous studies demonstrated that obese adipose tissue is characterized by increased infiltration of macrophages, suggesting that they might represent an important source of inflammation. Using an in vitro coculture system composed of 3T3-L1 adipocytes and RAW264 macrophages, we previously demonstrated that saturated fatty acids (FAs) and tumor necrosis factor (TNF)-
derived from adipocytes and macrophages, respectively, play a major role in the coculture-induced inflammatory changes.
Methods and Results— Coculture of adipocytes and macrophages resulted in the activation of nuclear factor-
B (NF-B), a primary regulator of inflammatory responses, in both cell types. Pharmacological inhibition of NF-B markedly suppressed the coculture-induced production of proinflammatory cytokines and adipocyte lipolysis. Peritoneal macrophages obtained from Toll-like receptor 4 (TLR4) mutant mice exhibited marked attenuation of TNF production in response to saturated FAs. Notably, coculture of hypertrophied adipocytes and TLR4-mutant macrophages resulted in marked inhibition of proinflammatory cytokine production and adipocyte lipolysis. We also observed that endogenous FAs, which are released from adipocytes via the ß3-adrenergic stimulation, resulted in the activation of the TLR4/NF-B pathway.
Conclusion— These findings suggest that saturated FAs, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for TLR4, thereby inducing the inflammatory changes in both adipocytes and macrophages through NF-B activation.
Using an in vitro coculture system composed of adipocytes and macrophages, we demonstrate that saturated FAs, which are released in large quantities from hypertrophied adipocytes via the macrophage-induced adipocyte lipolysis, serve as a naturally occurring ligand for TLR4, thereby inducing the inflammatory changes in both adipocytes and macrophages through NF-B activation.
Key Words: adipocytes • fatty acids • macrophages • nuclear factor-B • Toll-like receptor
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