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Selective regulation of ICAM-1 and RANTES gene expression after ICAM-1 ligation on human renal fibroblasts

Blaber, Robert, Stylianou, Eleni, Clayton, Aled ORCID: and Steadman, Robert ORCID: 2003. Selective regulation of ICAM-1 and RANTES gene expression after ICAM-1 ligation on human renal fibroblasts. Journal of the American Society of Nephrology 14 (1) , pp. 116-127. 10.1097/01.ASN.0000040595.35207.62

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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 β2 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-α, which were not [Ca2+]i-dependent. Electrophoretic mobility shift analysis demonstrated a time-dependent induction of both AP-1 and NF-κB 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: Lippincott, Williams & Wilkins
ISSN: 1046-6673
Last Modified: 12 Feb 2023 15:15

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