TNF-α stimulates monocyte adhesion to glomerular mesangial cells. The role of intercellular adhesion molecule-1 gene expression and protein kinases

Abstract

TNF-α 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-α-induced intercellular adhesion molecules-1 (ICAM-1) expression and monocyte adhesion to mesangial cells. Activation of mesangial cells with TNF-α 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-α did not inhibit ICAM-1 transcripts. Preincubation of mesangial cells with calphostin C did not affect TNF-α-induced mesangial cell ICAM-1 message, while it blocked PMA-induced ICAM-1 mRNA expression. Protein tyrosine kinase (PTK) inhibitors blocked TNF-α-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-α and dibutyrl cAMP blocked TNF-α-induced ICAM-1 message. Finally, preincubation of mesangial cells with TNF-α increased monocyte adhesion that could be blocked by anti-ICAM-1. Parallel to ICAM-1 gene expression data, TNF-α-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-α 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.