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* Laboratory of Cancer Biology and Genetics,
Experimental Immunology Branch, and
Antibody and Protein Purification Unit, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892;
Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Center for Cancer Research, and
¶ Science Applications International Corp. Frederick, Division of Basic Sciences and Cellular Immunology, National Cancer Institute, Frederick, MD 21702; and
|| X-ray Crystallography Facility, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
Human S100A7 (psoriasin) is overexpressed in inflammatory diseases. The recently discovered, co-evolved hS100A15 is almost identical in sequence and up-regulated with hS100A7 during cutaneous inflammation. The functional role of these closely related proteins for inflammation remains undefined. By generating specific Abs, we demonstrate that hS100A7 and hS100A15 proteins are differentially expressed by specific cell types in the skin. Although highly homologous, both proteins are chemoattractants with distinct chemotactic activity for leukocyte subsets. We define RAGE (receptor for advanced glycation end products) as the hS100A7 receptor, whereas hS100A15 functions through a Gi protein-coupled receptor. hS100A7-RAGE binding, signaling, and chemotaxis are zinc-dependent in vitro, reflecting the previously reported zinc-mediated changes in the hS100A7 dimer structure. When combined, hS100A7 and hS100A15 potentiate inflammation in vivo. Thus, proinflammatory synergism in disease may be driven by the diverse biology of these almost identical proteins that have just recently evolved. The identified S100A7 interaction with RAGE may provide a novel therapeutic target for inflammation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 R.W. is supported by the German Research Foundation, Emmy-Noether Program (Wo 843/2-1). This work was supported in part by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, and of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health.
2 Address correspondence and reprint requests to Dr. Stuart H. Yuspa, Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Drive, MSC-4255, Building 37, Room 4068A, Bethesda, MD 20892. E-mail address: yuspas{at}mail.nih.gov
3 Abbreviations used in this paper: MBP, myelin basic protein; CHO, Chinese hamster ovary; GiPCR, Gi protein-coupled receptor; RAGE, receptor for advanced glycation end products.
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