Selective regulation of ICAM-1 and RANTES gene expression after ICAM-1 ligation on human renal fibroblasts.
Leukocyte infiltration of the cortico-interstitium is characteristic of many forms of progressive renal disease. The principal adhesion molecule expressed on resident interstitial cells and recognized by leukocytes is intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is an inducible transmembrane receptor, which forms the counter-receptor for the leukocyte beta 2 integrins. ICAM-1-dependent binding induces the synthesis of the chemokine RANTES and of ICAM-1 itself. This study examines some of the signaling pathways involved in this induction. After ICAM-1 cross-linking on fibroblasts, the mRNA and protein for both RANTES and ICAM-1 were induced. This induction was calcium-dependent and inhibited by BAPTA-AM. The p38, ERK1, and ERK2 MAP kinases were activated in a [Ca2+]i-dependent manner, with a maximum phosphorylation at approximately 3 min after cross-linking. Through the use of selective inhibitors of p38 MAP kinase (SB203580) or MEKK (PD98059), p38 but not ERK activation was shown to be essential for the induction of ICAM-1. Neither was involved in RANTES activation, however. These mechanisms differed from those initiated by TNF-alpha, which were not [Ca2+]i-dependent. Electrophoretic mobility shift analysis demonstrated a time-dependent induction of both AP-1 and NF-kappaB binding activity in nuclear extracts, maximal at approximately 15 min after ICAM-1 cross-linking. Only AP-1 activation, however, was calcium-dependent, suggesting the central involvement of this transcription factor in ICAM-1 and RANTES induction after the ligation of ICAM-1. This study suggests an independent mechanism of inflammatory amplification, which may be characteristic of a persistent leukocytic involvement in areas of chronic inflammation rather than in cytokine-induced acute inflammation.
Blaber
Robert
R
Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff, Wales, UK.
Stylianou
Eleni
E
Clayton
Aled
A
Steadman
Robert
R
D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics*; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D007668:Kidney / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009994:Osmolar Concentration; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000502:physiology
D018946:Chemokine CCL5; D003432:Cross-Linking Reagents; D007074:Immunoglobulin G; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D018799:Intercellular Adhesion Molecule-1; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium