Involvement of Rho-kinase in tumor necrosis factor-alpha-induced interleukin-6 release from C6 glioma cells

Neurochem Int. 2009 Nov;55(6):438-45. doi: 10.1016/j.neuint.2009.04.016. Epub 2009 May 7.

Abstract

Tumor necrosis factor (TNF)-alpha stimulated interleukin (IL)-6 release and induced the phosphorylation of myosin phosphatase targeting subunit (MYPT)-1, a Rho-kinase substrate. The IL-6 release was significantly suppressed by Y-27632 and fasudil, Rho-kinase inhibitors. Although IkappaB inhibitor suppressed the TNF-alpha-induced IL-6 release, the Rho-kinase inhibitors did not affect the TNF-alpha-induced IkappaB phosphorylation. TNF-alpha induced the phosphorylation of p38 mitogen-activated protein (MAP) kinase, stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), and p44/p42 MAP kinase. The TNF-alpha-induced IL-6 release was suppressed by SB203580, a p38 MAPK inhibitor, or SP600125, a SAPK/JNK inhibitor, but not by PD98059, a MAP kinase/extracellular signal-regulated kinase kinase inhibitor. The Rho-kinase inhibitors attenuated the TNF-alpha-induced phosphorylation of both p38 MAP kinase and SAPK/JNK. Rho-kinase, which has been used for the clinical treatment of cerebral vasospasms, may be involved in other central nervous system (CNS) disorders such as traumatic injury, stroke, neurodegenerative disease and neuropathic pain. TNF-alpha, a proinflammatory cytokine that affects the CNS through cytokines, such as IL-6, release from neurons, astrocytes and microglia. Therefore, we investigated the involvement of Rho-kinase in the TNF-alpha-induced IL-6 release from rat C6 glioma cells. These results strongly suggest that Rho-kinase regulates the TNF-alpha-induced IL-6 release at a point upstream from p38 MAPK and SAPK/JNK in C6 glioma cells. Therefore, Rho-kinase inhibitor may be considered to be a new clinical candidate for the treatment of CNS disorders in addition to cerebral vasospasms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / therapeutic use
  • Amides / pharmacology
  • Amides / therapeutic use
  • Animals
  • Brain / drug effects
  • Brain / immunology
  • Brain / metabolism
  • Cell Line, Tumor
  • Encephalitis / drug therapy*
  • Encephalitis / enzymology*
  • Encephalitis / immunology
  • I-kappa B Proteins / drug effects
  • I-kappa B Proteins / metabolism
  • Interleukin-6 / metabolism
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Neurons / drug effects
  • Neurons / immunology
  • Neurons / metabolism
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Rats
  • Signal Transduction / drug effects
  • Signal Transduction / immunology
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / metabolism*

Substances

  • Amides
  • I-kappa B Proteins
  • Interleukin-6
  • Protein Kinase Inhibitors
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • Y 27632
  • 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
  • rho-Associated Kinases
  • fasudil