Interleukin-17 regulates expression of the CXC chemokine LIX/CXCL5 in osteoblasts: implications for inflammation and neutrophil recruitment

Abstract

Interleukin (IL)-17 is the founding member of an emerging family of inflammatory cytokines whose functions remain poorly defined. IL-17 has been linked to the pathogenesis of rheumatoid arthritis, and numerous studies implicate this cytokine in inflammation-induced bone loss. It is clear that a major function of IL-17 is to amplify the immune response by triggering production of chemokines, cytokines, and cell-surface markers, ultimately leading to neutrophil chemotaxis and inflammation. As an IL-17 signaling deficiency in mice causes a dramatic reduction in neutrophil chemotaxis and a consequent increased susceptibility to bacterial infection, it is important to define gene targets involved in IL-17-mediated neutrophil trafficking. Here, we demonstrate that IL-17 and tumor necrosis factor alpha (TNF-alpha) cooperatively induce the lipopolysaccharide-inducible CXC chemokine (LIX; a.k.a., CXC chemokine ligand 5, Scya5, or murine granulocyte chemotactic protein-2) in the preosteoblast cell line MC3T3. LIX is induced rapidly at the mRNA and protein levels, likely through the activation of new gene transcription. Conditioned media from MC3T3 cells treated with IL-17 and/or TNF-alpha stimulates neutrophil mobility potently, and LIX is a significant contributing factor to this process. In addition, IL-17 cooperates with bacterial components involved in periodontal disease to up-regulate LIX expression. This study is the first demonstration of LIX expression in bone cells and has implications for inflammatory bone diseases such as arthritis and periodontal disease.

Prostaglandin mediates IL-23/IL-17-induced neutrophil migration in inflammation by inhibiting IL-12 and IFNγ production

“…Recent studies demonstrated that IL-17 induces the release by joint structural and resident cells (e.g., chondrocytes, synovial fibroblasts, and macrophages) of several inflammatory mediators, including cytokines (e.g., TNF␣) and chemokines (e.g., CXCL1 and CXCL5), which may recruit neutrophils (42,43). Here we identify the mediators downstream of IL-17 participating in the neutrophil migration to the joint cavities in AIA.…”

Identification of Common Transcriptional Regulatory Elements in Interleukin-17 Target Genes

“…This may be particularly important in light of IL-17 and TNF␣ synergy. Nearly all IL-17-induced genes that we have examined exhibit additive or synergistic induction when combined with TNF␣ (6,19,53). Several mechanisms of cooperative activity have been proposed, such as cooperative enhancement of mRNA stability and/or activation of the p38 MAPK pathway (37, 38, 40, 54 -56).…”

Structure–function relationships in the IL-17 receptor: Implications for signal transduction and therapy

“…For example, IL-17 together with TNFα stabilizes IL-6 mRNA [71,[76][77][78]. Similarly, IL-17 serves to enhance mRNA stability of transcripts encoding G-CSF [79], GM-CSF [80], CXCL1/KC/Groα [81], CXCL5/LIX [82,83], IL-8 [77], IκBζ [84] and COX-2 [85,86]. Considerable data implicate MAPK pathways in mRNA stabilization effects.…”