Selective Regulation of ICAM-1 and RANTES Gene Expression after ICAM-1 Ligation on Human Renal Fibroblasts

Abstract

Abstract. 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 ␤ 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 [Ca 2ϩ ] i -dependent manner, with a maximum phosphorylation at approximately 3 min after crosslinking. 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-␣, which were not [Ca 2ϩ ] i -dependent. Electrophoretic mobility shift analysis demonstrated a time-dependent induction of both AP-1 and NF-B binding activity in nuclear extracts, maximal at approximately 15 min after ICAM-1 cross-linking. Only AP-1 activation, however, was calciumdependent, 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. steadmanr@cf.ac.uk An influx of leukocytes, particularly macrophages and lymphocytes, into the glomerulus and subsequently into the cortical interstitium is characteristic of most forms of progressive renal disease [see reference 1 for review and references 2-11). The initial interaction of the infiltrating cells is with the endothelial lining of the vessels. After migration through the endothelium, however, the principal interaction of leukocytes is with cortical fibroblasts, which, under inflammatory conditions, have the phenotypic appearance of myofibroblasts (8,(12)(13)(14)(15)(16). This interaction is mediated through the increased expression of intercellular adhesion molecule-1 (ICAM-1) (17-22) on the surface of the myofibroblasts and is central to the progression of inflammatory renal disease (2-11).ICAM-1 is a heavily glycosylated, single-chain transmembrane receptor induced by inflammatory cytokines at sites of inflammation, where it forms the counter-receptor for the leukocyte ␤ 2 integrins (23-25). We have recently demonstrated, for the first time, that leukocyte adherence to primary cultures of human renal fibroblasts was a stimulus for ICAM-1 induction (26). This induction was initiated as a result of the ICAM-1/␤ 2 integrin ...

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