Interleukin-6 and cyclic AMP stimulate release of cathepsin B in human osteoblasts

Immunopharmacol Immunotoxicol. 2007;29(2):155-72. doi: 10.1080/08923970701511579.

Abstract

Previous studies have suggested that cathepsin B participates in the joint destruction associated with rheumatoid arthritis (RA). This study examined the activity of cathepsin B (a lysosomal cysteine protease) in human osteoblasts along with its regulation by cyclic AMP and Interleukin-6 (IL-6). Cyclic AMP elevating agents activate cathepsin B and stimulate the secretion of cathepsin B via the secretion of IL-6, a potent mediator of RA. This study investigated the induction of cathepsin B using the proinflammatory cytokine in human osteoblasts (MG-63) in relation to p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-kappa B transcription factor. When added to MG-63 cells, IL-6 stimulated the production of cathepsin B, which was reduced significantly by the addition of SB203580, a specific p38 MAPK inhibitor. In addition, the release of IL-6 was also inhibited by either pyrrolidine dithiocarbamate (PDTC) or NF-kappaB SN50, which are potent NF-kappaB inhibitors. Both NF-kappaB inhibitors had a larger inhibitory effect on the activity of cathepsin B in the presence of SB203580. IL-6 stimulated the NF-kappaB binding affinity as well as the activation of p38 MAP kinase, leading to the release of cathepsin B. However, SB203580 had no effect on the IL-6-induced activation of NF-kappaB, and neither of the NF-kappaB inhibitors decreased the level of p38 MAPK activation in the IL-6-stimulated osteoblasts. Moreover, IL-6 increased the activity of urokinase type plasminogen activator (uPA) in MG-63 cells, which was inhibited by SB203580, PDTC and NF-kappaB SN50. This strongly suggests that p38 MAPK and NF-kappaB are essential to the IL-6-induced activation of cathepsin B or uPA and that these two IL-6-activated pathways can act independently.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Blotting, Western
  • Cathepsin B / metabolism*
  • Cell Line
  • Cyclic AMP / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Fluorometry
  • Humans
  • Imidazoles / pharmacology
  • Interleukin-6 / pharmacology*
  • NF-kappa B / metabolism
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism*
  • Pyridines / pharmacology
  • Second Messenger Systems / physiology
  • Stimulation, Chemical
  • Urokinase-Type Plasminogen Activator / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • Imidazoles
  • Interleukin-6
  • NF-kappa B
  • Pyridines
  • Cyclic AMP
  • p38 Mitogen-Activated Protein Kinases
  • Urokinase-Type Plasminogen Activator
  • Cathepsin B
  • SB 203580