IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling.
Interleukin-17 (IL-17) is a cytokine secreted primarily by T(H)-17 cells. Although IL-17 is primarily associated with the induction of tissue inflammation, the other biological roles of IL-17, including non-immune functions, have yet to be thoroughly explored. Here, we report that T-cell-produced IL-17 can induce proliferation of human bone marrow-derived mesenchymal stem cells (hMSCs) in a manner dependent on the generation of reactive oxygen species (ROS). Rac1 GTPase and NADPH oxidase 1 (Nox1) are activated by IL-17 to produce ROS, which in turn stimulates hMSC proliferation. The activation of the MEK-ERK pathway is also crucial for IL-17-dependent hMSC proliferation. TRAF6 and Act1 are required to activate Nox 1 and to phosphorylate MEK on IL-17 stimulation. Interestingly, IL-17 not only accelerates the proliferation of hMSCs, but also induces their migration, motility, and osteoblastic differentiation. Furthermore, IL-17 induces the expression of M-CSF and receptor activator of NF-kappaB ligand (RANKL) on hMSCs, thereby supporting osteoclastogenesis both in vivo and in vitro. On the basis of these results, we suggest that IL-17 can function as a signal to induce extensive bone turnover by regulating hMSC recruitment, proliferation, motility, and differentiation.
Huang
H
H
Department of Cell and Developmental Biology, BK21 and DRI, Seoul National University School of Dentistry, Seoul 110-749, Korea.
Kim
H J
HJ
Chang
E-J
EJ
Lee
Z H
ZH
Hwang
S J
SJ
Kim
H-M
HM
Lee
Y
Y
Kim
H-H
HH
D001374:Azacitidine / Q000494:pharmacology; D016723:Bone Remodeling; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism
C541130:ACT1 protein; D018031:Connexin 43; D050659:Core Binding Factor Alpha 1 Subunit; D020381:Interleukin-17; D010446:Peptide Fragments; D053245:RANK Ligand; D034741:RNA, Small Interfering; C493709:RUNX2 protein, human; D017382:Reactive Oxygen Species; D048029:TNF Receptor-Associated Factor 6; C505688:TNFSF11 protein, human; D016173:Macrophage Colony-Stimulating Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; D001374:Azacitidine