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Published online before print December 10, 2004
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-induced genes in bone cells
,1,2
* Department of Oral Biology, School of Dental Medicine, and
Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York
2 Correspondence: Department of Oral Biology, University at Buffalo, SUNY, 36 Foster Hall, 3435 Main Street, Buffalo, NY 14214. E-mail: sgaffen{at}buffalo.edu
The novel cytokine interleukin (IL)-17 has been implicated in many infectious and autoimmune settings, especially rheumatoid arthritis. Consistent with its proinflammatory effects on bone, osteoblast cells are highly responsive to IL-17, particularly in combination with other inflammatory cytokines. To better understand the spectrum of activities controlled by IL-17, we globally profiled genes regulated by IL-17 and tumor necrosis factor 
(TNF-) in the preosteoblast cell line MC3T3-E1. Using Affymetrix microarrays, 80–90 genes were up-regulated, and 19–50 genes were down-regulated with IL-17 and TNF- as compared with TNF- alone. These included proinflammatory chemokines and cytokines, inflammatory genes, transcriptional regulators, bone-remodeling genes, signal transducers, cytoskeletal genes, genes involved in apoptosis, and several unknown or unclassified genes. The CXC family chemokines were most dramatically induced by IL-17 and TNF-, confirming the role of IL-17 as a potent mediator of inflammation and neutrophil recruitment. Several transcription factor-related genes involved in inflammatory gene expression were also enhanced, including molecule possessing ankyrin repeats induced by lipopolysaccharide/inhibitor of 
B
(MAIL/B), CCAAT/enhancer-binding protein 
(C/EBP), and C/EBPß. We also identified the acute-phase gene lipocalin-2 (LCN2/24p3) as a novel IL-17 target, which is regulated synergistically by TNF- and IL-17 at the level of its promoter. A similar but not identical pattern of genes was induced by IL-17 and TNF- in ST2 bone marrow stromal cells and murine embryonic fibroblasts. This study provides a profile of genes regulated by IL-17 and TNF- in osteoblasts and suggests that in bone, the major function of IL-17 is to cooperate and/or synergize with other cytokines to amplify inflammation.
Key Words: synergy • chemokine • lipocalin
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