title: Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-alpha-induced genes in bone cells.
abstract: 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 alpha (TNF-alpha) 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-alpha as compared with TNF-alpha 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-alpha, 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 kappaBzeta (MAIL/kappaBzeta), CCAAT/enhancer-binding protein delta (C/EBPdelta), and C/EBPbeta. We also identified the acute-phase gene lipocalin-2 (LCN2/24p3) as a novel IL-17 target, which is regulated synergistically by TNF-alpha and IL-17 at the level of its promoter. A similar but not identical pattern of genes was induced by IL-17 and TNF-alpha in ST2 bone marrow stromal cells and murine embryonic fibroblasts. This study provides a profile of genes regulated by IL-17 and TNF-alpha 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.
authors.affiliation: Department of Oral Biology, University at Buffalo, State University of New York, 36 Foster Hall, 3435 Main Street, Buffalo, NY 14214, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Shen
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Ruddy
authors.forename: Pascale
authors.initials: P
authors.lastname: Plamondon
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Gaffen
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000502:physiology*; D020869:Gene Expression Profiling; D007249:Inflammation / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010006:Osteoblasts / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha