Endothelin-1 (ET-1), is implicated in the pathogenesis of fibrotic and inflammatory diseases including scleroderma, modulates extracellular matrix turnover and up-regulates cell surface adhesion molecules such as ICAM-1. Signal transduction under normal conditions has not been fully investigated, but is of interest as basal expression of ICAM-1 increases in cells from fibrotic lesions in scleroderma, and sensitivity to ET-1 is significantly reduced yet enhanced in response to Interleukin-1β(IL-1β). In normal human dermal fibroblasts (HDF) ET-1 increased ICAM-1 mRNA after 1h, with protein expression increasing after 4h. Antagonists against ET-1 receptors ET_A (JKC-301, 10μM) and ET_B (BQ788, 10μM) inhibited ICAM-1 protein expression by 47±13% and 46±11%, respectively (mean±SD, n=4), whilst the dual antagonist Bosentan (10μM) abolished the ET-1 response, indicating that ET-1 signalling occurs via both receptor subtypes. We previously reported that the signalling pathway involved in ET-1-induced ICAM-1 expression involves the activation of MEK, NFκB and PKCε(1). Involvement of PKCε was further confirmed by failure of the PKCδ-specific inhibitor Rottlerin (6μM) to prevent ET-1 induced increases in ICAM-1 mRNA. MEK and NFκB, along with PKCε, are involved in the direct effect of ET-1 on ICAM-1 expression. This was shown by rapid ET-1-induced phosphorylation of p42/p44 MAP kinase at 1min (seen via western blot), nuclear translocation of NFκB at 30 mins (NFκB EMSA/Supershift), and inhibition of ET-1-induced ICAM-1 mRNA and protein at 1h and 5h respectively by U0126 and PG490. IL-1β signalling involves activation of NFκB and C/EBPβ in dermal microvascular endothelium, yet unknown in fibroblasts. In HDF, PG490 and PD98059 (MEK inhibitor) significantly reduced IL-1β induced protein expression, abolishing it when combined. NFκB activation (confirmed by EMSA/supershift), and ERK1/2 phosphorylation (western blot), indicates that IL-1β signalling is identical in fibroblasts vs. endothelium. The direct contribution of NFκB and ERK1/2 to IL-1-induced ICAM-1 was seen by inhibition of mRNA and protein expression by PD98059 and PG490 – as with ET-1. An unexpected similarity in ET-1 and IL-1β-mediated ICAM-1 regulation was observed in HDF by transient transfection using a series of deleted ICAM-1 promoter constructs; ET-1 and IL-1β utilized the NFκB binding site at -180bp. Due to the convergence of the signaling pathways, we hypothesize that the changes in sensitivity to ET-1 and IL-1β in scleroderma may be due to alterations in PKC expression and the regulation of NFκB activation.