Activation of mesangial cells with TNF-alpha stimulates M-CSF gene expression and monocyte proliferation: evidence for involvement of protein kinase C and protein tyrosine kinase

Biochim Biophys Acta. 1996 Aug 28;1313(2):161-72. doi: 10.1016/0167-4889(96)00064-x.

Abstract

In this study, we examined the effect of TNF-alpha on mesangial cell gene expression of M-CSF, a colony-stimulating factor associated with monocyte differentiation into macrophages and proliferation. Incubation of mesangial cells with TNF-alpha-stimulated mRNA expression and protein synthesis of M-CSF. Mesangial cell activation with PMA, a PKC activator, stimulated M-CSF mRNA expression while PKC depletion decreased M-CSF mRNA expression to control levels. Stimulation of PKC-depleted mesangial cells with either PMA or TNF-alpha inhibited M-CSF mRNA transcripts. Preincubation of mesangial cells with calphostin C, a PKC inhibitor, reduced both PMA- and TNF-alpha-induced M-CSF mRNA transcripts. Specific protein tyrosine kinase inhibitors blocked TNF-alpha-induced mesangial cell M-CSF mRNA expression. Additional studies showed that pertussis toxin, isoproterenol, and dibutyryl (db)cAMP did not induce mesangial cell M-CSF gene expression. However, coincubation of mesangial cells with TNF-alpha and either dbcAMP, forskolin, or pertussis toxin inhibited TNF-alpha-induced M-CSF gene expression. Finally, TNF-alpha-activated mesangial cell conditioned media stimulated monocyte/macrophage proliferation dose-dependently and was prevented by using anti-M-CSF. These data suggested that M-CSF can regulate monocyte differentiation into macrophages and proliferation within the mesangium induced by proinflammatory cytokines such as TNF-alpha. These cellular events appeared to be modulated by signal transduction pathways mediated by PKC and PTK.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Cyclic AMP / physiology
  • Cycloheximide / pharmacology
  • Gene Expression / drug effects
  • Glomerular Mesangium / metabolism*
  • Macrophage Colony-Stimulating Factor / genetics*
  • Mice
  • Monocytes / metabolism
  • Protein Kinase C / physiology*
  • Protein Synthesis Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / physiology*
  • RNA, Messenger / genetics
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Macrophage Colony-Stimulating Factor
  • Cycloheximide
  • Cyclic AMP
  • Protein-Tyrosine Kinases
  • Protein Kinase C