IntroductionInterleukin-17 (IL-17), originally identified by Rouvier et al 1 as cytolytic T-lymphocyte (CTL)-associated antigen 8, is a T-cellderived cytokine with homology to Herpesvirus saimiri. [1][2] It is expressed mainly by activated CD4 ϩ CD45RO ϩ memory T cells. [3][4] CD4 T cells can be classified into T-helper (Th) 1 cells, which secrete interferon (IFN) ␥, IL-2, and tumor necrosis factor (TNF) ; Th2 cells, which produce IL-4, IL-5, IL-6, IL-10, and IL-13; and Th0 cells, a common precursor with the ability to release both IFN␥ and IL-4. Thirty percent of Th0/Th1 clones have been shown to produce IL-17, whereas Th2 clones never express IL-17. 5 IL-2 and IL-15 were found to increase IL-17 production by human peripheral blood (PB) mononuclear cells. 6 IL-17 is considered to be a proinflammatory cytokine because it increases IL-6 and IL-8 production by macrophages, fibroblasts, keratinocytes, and synovial cells 2,3,[7][8][9] and nitric oxide production by human osteoarthritic cartilage. 10,11 IL-17 also induces secretion of IL-1 and TNF-␣ by human macrophages and endothelial cells. 7,12 IL-17 activates the nuclear factor B and activator protein 1 transcription factors, which may explain its proinflammatory properties. 10,13 In addition, IL-17 induces production of granulocyte colony-stimulating factor and CXC chemokines that stimulate granulopoiesis and recruitment of neutrophils into tissues. [14][15][16] The IL-17 receptor is a type I transmembrane protein that is expressed in virtually all cells and tissues, in contrast to the restricted expression of IL-17, which is confined to T cells. 2,17 This receptor has no sequence similarity with any other known cytokine receptor. It interacts with the adapter molecule TNF receptorassociated factor 6, which is required for IL-17 signaling. 18 The exact role of IL-17 in disease is unknown. IL-17 has been found to promote cartilage destruction in various forms of arthritis. 19,20 Overproduction of IL-17 has been observed in the synovium of patients with rheumatoid arthritis 21 and in PB lymphocytes from patients with systemic sclerosis. 22 In a previous study, we found that IL-17 promotes tumorigenicity of human cervical tumors in nude mice. 23 Because this paradoxical tumor-promoting activity of IL-17 in the absence of T cells was unexpected, we conducted the current study to analyze the effect of IL-17 on the growth of syngeneic tumors in immunocompetent mice. We found that IL-17 inhibits the growth of 2 hematopoietic tumors, mastocytoma P815 and plasmocytoma Materials and methods Mice and tumor cell linesFemale Balb/c, DBA/2, and athymic nude/nude mice 6 to 8 weeks of age (Iffa Credo L'Arbresle, France) were used in this study. The mouse plasmocytoma J558L and mastocytoma P815 cell lines were obtained from the American Type Culture Collection (Manassas, VA). The mouse squamous cell carcinoma KLN 205 was purchased from the European Collection of Cell Culture (Salisbury, Wiltshire, United Kingdom). The cell lines were cultured in RPMI supplemented with 10% fet...
Osteoporosis, which results from excessive bone resorption by osteoclasts, is the major cause of morbidity for elder people. Identification of clinically relevant regulators is needed to develop novel therapeutic strategies. Rho GTPases have essential functions in osteoclasts by regulating actin dynamics. This is of particular importance because actin cytoskeleton is essential to generate the sealing zone, an osteoclast-specific structure ultimately mediating bone resorption. Here we report that the atypical Rac1 exchange factor Dock5 is necessary for osteoclast function both in vitro and in vivo. We discovered that establishment of the sealing zone and consequently osteoclast resorbing activity in vitro require Dock5. Mechanistically, our results suggest that osteoclasts lacking Dock5 have impaired adhesion that can be explained by perturbed Rac1 and p130Cas activities. Consistent with these functional assays, we identified a novel small-molecule inhibitor of Dock5 capable of hindering osteoclast resorbing activity. To investigate the in vivo relevance of these findings, we studied Dock5 -/-mice and found that they have increased trabecular bone mass with normal osteoclast numbers, confirming that Dock5 is essential for bone resorption but not for osteoclast differentiation. Taken together, our findings characterize Dock5 as a regulator of osteoclast function and as a potential novel target to develop antiosteoporotic treatments. ß
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