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.
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.
Kamanna
V S
VS
Nephrology Section, Department of Veterans Affairs Medical Center, Long Beach, CA 90822, USA.
Pai
R
R
Bassa
B
B
Kirschenbaum
M A
MA
D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D003513:Cycloheximide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics*; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D003513:Cycloheximide; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C