Proinflammatory cytokines, IL-1β and TNF-α, induce expression of interleukin-34 mRNA via JNK- and p44/42 MAPK-NF-κB pathway but not p38 pathway in osteoblasts

Rheumatol Int. 2011 Nov;31(11):1525-30. doi: 10.1007/s00296-010-1688-7. Epub 2010 Dec 23.

Abstract

The aim of this study is to investigate the induction of interleukin-34 (IL-34) and macrophage colony-stimulating factor (M-CSF) mRNA by inflammatory cytokines and the involvement of mitogen-activated protein kinases (MAPKs) in this signaling pathway in human osteoblasts as both IL-34 and M-CSF bind to the same receptor c-FMS. Among four inflammatory cytokines [(IL-1β, IL-6, IL-17, and tumor necrosis factor-α (TNF-α)], IL-34 mRNA expression level was dramatically induced by IL-1β (17-fold) and TNF-α (74-fold). IL-1β and TNF-α activated the intracellular mitogen-activated protein kinases (MAPKs): p44/42 MAPK, p38, and c-Jun N-terminal kinase (JNK) as well as nuclear factor-κB (NF-κB) in osteoblasts. IL-1β- and TNF-α-mediated induction of IL-34 mRNA expression was decreased by JNK inhibitor. Interestingly, although treatment of MEK-1/2 inhibitor showed no reduction in the increase of IL-34 mRNA expression by cytokines, combination of MEK-1/2 inhibitor and JNK inhibitor significantly inhibited IL-1β- and TNF-α-mediated IL-34 mRNA expression level compared to those by each inhibitor alone. On the other hand, M-CSF mRNA expression level was significantly induced by both IL-1β and TNF-α by up to 7- and 11-fold, respectively. IL-1β- and TNF-α-mediated induction of M-CSF mRNA was not affected by p38, JNK, and MEK-1/2 inhibitors. However, NF-κB inhibitor completely inhibited the elevation of M-CSF mRNA expression by these cytokines. These results showed that proinflammatory cytokines, IL-1β and TNF-α, induced the expression of IL-34 mRNA via JNK and p44/42 MAPK but not p38 in human osteoblasts while p38, JNK, and p44/42 MAPK were not involved in the induction of M-CSF mRNA expression by these cytokines.

MeSH terms

  • Cells, Cultured
  • Cytokines / genetics
  • Cytokines / pharmacology
  • Cytokines / physiology*
  • Enzyme Inhibitors / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Interleukin-1beta / pharmacology
  • Interleukin-1beta / physiology
  • Interleukins / genetics
  • Interleukins / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • MAP Kinase Signaling System / physiology
  • Macrophage Colony-Stimulating Factor / genetics
  • Macrophage Colony-Stimulating Factor / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • NF-kappa B / metabolism*
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism*
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factor-alpha / physiology

Substances

  • Cytokines
  • Enzyme Inhibitors
  • Interleukin-1beta
  • Interleukins
  • NF-kappa B
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • interleukin-34, human
  • Macrophage Colony-Stimulating Factor
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases