title: TNF-alpha stimulates monocyte adhesion to glomerular mesangial cells. The role of intercellular adhesion molecule-1 gene expression and protein kinases.
abstract: TNF-alpha has been implicated in glomerular cell activation to produce adhesion molecules and monocyte chemoattractants associated with glomerular monocyte infiltration. This study examined the regulatory role of protein kinases and cAMP on TNF-alpha-induced intercellular adhesion molecules-1 (ICAM-1) expression and monocyte adhesion to mesangial cells. Activation of mesangial cells with TNF-alpha induced ICAM-1 mRNA and protein expression. Mesangial cells preincubated with phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator, stimulated both the gene and protein expression of ICAM-1. Mesangial cell PKC depletion abolished ICAM-1 mRNA message, while activation with TNF-alpha did not inhibit ICAM-1 transcripts. Preincubation of mesangial cells with calphostin C did not affect TNF-alpha-induced mesangial cell ICAM-1 message, while it blocked PMA-induced ICAM-1 mRNA expression. Protein tyrosine kinase (PTK) inhibitors blocked TNF-alpha-mediated mesangial cell ICAM-1 transcripts. cAMP-generating substances (e.g., pertussis toxin, isoproterenol, or dibutyryl cAMP) did not induce mesangial cell ICAM-1 gene expression. However, incubation of mesangial cells with TNF-alpha and dibutyrl cAMP blocked TNF-alpha-induced ICAM-1 message. Finally, preincubation of mesangial cells with TNF-alpha increased monocyte adhesion that could be blocked by anti-ICAM-1. Parallel to ICAM-1 gene expression data, TNF-alpha-induced monocyte-mesangial cell adhesion was inhibited by PTK inhibitors, but was not regulated through either PKC or intracellular cAMP-associated pathways. These results suggest that increased ICAM-1 expression by TNF-alpha activation of mesangial cells is one of the major pathways involved in monocyte adhesion to the mesangium, a phenomenon presumably regulated by signal-transduction pathways dependent on PTK, but not PKC or cAMP.
authors.affiliation: Nephrology Section, Department of Veterans Affairs Medical Center, Long Beach, CA 90822, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pai
authors.forename: B
authors.initials: B
authors.lastname: Bassa
authors.forename: M A
authors.initials: MA
authors.lastname: Kirschenbaum
authors.forename: V S
authors.initials: VS
authors.lastname: Kamanna
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects*; D002461:Cell Line, Transformed; D003513:Cycloheximide / Q000494:pharmacology; D015870:Gene Expression; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D005921:Glomerulonephritis / Q000209:etiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D051379:Mice; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013539:Simian virus 40; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D003513:Cycloheximide; D011494:Protein Kinases