IL-17 stimulates the proliferation and differentiation of human mesenchymal stem cells: implications for bone remodeling

Cell Death Differ. 2009 Oct;16(10):1332-43. doi: 10.1038/cdd.2009.74. Epub 2009 Jun 19.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Azacitidine / pharmacology
  • Bone Remodeling*
  • Cell Differentiation*
  • Cell Movement
  • Cell Proliferation*
  • Connexin 43 / genetics
  • Connexin 43 / metabolism
  • Core Binding Factor Alpha 1 Subunit / metabolism
  • Cyclooxygenase 2 / metabolism
  • Humans
  • Interleukin-17 / metabolism*
  • Macrophage Colony-Stimulating Factor / metabolism
  • Mesenchymal Stem Cells / cytology*
  • Mesenchymal Stem Cells / metabolism
  • NADPH Oxidase 1
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism
  • RANK Ligand / metabolism
  • RNA, Small Interfering / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism

Substances

  • ACT1 protein
  • Connexin 43
  • Core Binding Factor Alpha 1 Subunit
  • Interleukin-17
  • Peptide Fragments
  • RANK Ligand
  • RNA, Small Interfering
  • RUNX2 protein, human
  • Reactive Oxygen Species
  • TNF Receptor-Associated Factor 6
  • TNFSF11 protein, human
  • Macrophage Colony-Stimulating Factor
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • NADPH Oxidase 1
  • NADPH Oxidases
  • NOX1 protein, human
  • Azacitidine