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Regulatory Effects of Interleukin (IL)-1, Interferon-ß, and IL-4 on the Production of IL-1 Receptor Antagonist by Human Adipose Tissue

Endocrine Unit, Division of Endocrinology, Diabetes and Nutrition, Department of Internal Medicine (C.E.J.-A., E.S., A.P., C.A.M.); Hans Wilsdorf Laboratory, Division of Immunology and Allergy, Department of Internal Medicine (R.C., D.B., J.-M.D.); and Plastic Reconstructive Surgery Unit, Division of Reconstructive Surgery, Department of Surgery (B.C.-P.), University Hospital, CH-1211 Geneva 14, Switzerland; La Tour Hospital (P.Q.), CH-1217 Meyrin, Switzerland; and Division of Endocrinology, Diabetology and Metabolism, Department of Medicine (V.G.), University Hospital, CH-1011 Lausanne, Switzerland

Address all correspondence and requests for reprints to: Dr. Christoph A. Meier, Endocrine Unit, University Hospital Geneva, 24, rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. E-mail: Christoph.Meier{at}medecine.unige.ch.

Adipose tissue is the source of production and site of action of several pro- and antiinflammatory cytokines. We have recently shown that white adipose tissue (WAT) is a major producer of the antiinflammatory IL-1 receptor antagonist (IL-1Ra). Because IL-1Ra serum levels are elevated 7-fold in human obesity and an excess of this protein has been implicated in the acquired resistance to leptin and insulin, we investigated the regulation of IL-1Ra in human WAT.

We demonstrate that IL-1Ra is mainly produced by adipocytes, rather than the stromal fraction of WAT, and that IL-1 and ß, as well as interferon-ß (IFN-ß), strongly up-regulate the expression and secretion of IL-1Ra in WAT. Moreover, human WAT expresses the receptors and proteins known to be required for the action of IL-1 (IL-1 receptor type I, IL-1 receptor accessory protein) and IFN-ß (IFN-/ß receptor subunits 1 and 2). Finally, human WAT actively secretes these regulatory cytokines, suggesting that they up-regulate IL-1Ra through a local autocrine/paracrine action, which is hypothesized to play a regulatory role in adipogenesis and metabolism.

This work was supported by the Swiss National Science Foundation Grants 3200-064078 0.01 (to C.A.M.) and 32-68286.02 (to J.-M.D.), as well as by a grant from the Hans Wilsdorf Foundation (to D.B. and C.A.M.).

C.E.J.-A. and E.S. contributed equally to this work.

Abbreviations: BMI, Body mass index; FBS, fetal bovine serum; IFN, interferon; IFNAR1 and IFNAR2, IFN- and -ß receptor subunit 1 and 2; IL-1Ra, IL-1 receptor antagonist; IL-1RAcP, IL-1 receptor-associated protein; IL-1RI and II, IL-1 receptor type I and II; LPS, lipopolysaccharide; PMA, phorbol myristate acetate; WAT, white adipose tissue.

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