Pharmacological Modulation of Endothelial Cell‐associated Adhesion Molecule Expression: Implications for Future Treatment of Dermatological Diseases

Abstract

Skin diseases with an inflammatory component, regardless of their etiology, are characterized at some point by the extravasation and subsequent infiltration of leukocytes into the dermal and/or epidermal compartments. This trafficking pattern is determined by a complex series of events whereby the leukocytes interact with cell adhesion molecules (CAM), particularly those induced on endothelial cells following activation with various inflammatory mediators. Vascular CAMs belonging to the selectin family (i.e., P-selectin and E-selectin) are thought to mediate early and reversible events involving leukocyte rolling and margination along the lumenal surface of microvascular cells (post-capillary venules). Certain members of the immunoglobulin supergene family (i.e., VCAM-1 and ICAM-1) regulate later and irreversible steps which lead to firm attachment and subsequent diapedesis of leukocytes. Accumulating evidence suggests that if one blocks the ligand-binding sites between leukocytes and endothelial cells, or inhibits vascular CAM expression, hematopoietic cell extravasation and progressive inflammatory events can be greatly diminished. To identify such inhibitors we developed a cell-based Elisa using the human microvascular cell line HMEC-1. As reported in the present paper, this approach yielded a naturally-occurring, low molecular weight compound which potently inhibits cytokine-induced adhesion molecule expression on cultured endothelial cells, without modulating "house-keeping" proteins.

A Proteomic Survey Indicates Sortilin as a Secondary Substrate of the ER Translocation Inhibitor Cyclotriazadisulfonamide (CADA)

“…Most of these inhibitors interfere with a specific step in the translocation process and thus affect a wide spectrum of translocon substrates, often associated with cellular toxicity (35,36). The fungal cyclic heptadepsipeptide HUN-7293 was originally identified as an inhibitor of vascular cell adhesion molecule 1 (VCAM-1) expression in endothelial cells (37,38). Derivatives of this compound also act in a SP-dependent way, similar to CADA, but the precise mechanism of action and binding sites are likely different.…”

Identification of Oncostatin M as a STAT5-Dependent Mediator of Bone Marrow Remodeling in KIT D816V-Positive Systemic Mastocytosis

“…The human microvascular endothelial cell line HMEC-1 was kindly provided by Edwin Ades (Centers for Disease Control and Prevention, Atlanta, GA). 35,36 HMEC-1 cells were cultured in MDCB131 medium with 10% FCS. hFOB 1.19 cells (ATCC, Manassas, VA) were cultured in DMEM/F12 medium without Phenol Red with 10% FCS.…”

The 3D‐structure of a natural inhibitor of cell adhesion molecule expression

“…While searching for low molecular weight inhibitors of inducible adhesion molecule expression, we identified the naturally-occurring compound HUN-7293 in a HaCaT keratinocyte-based ICAM-1 ELISA [3]. HUN-7293 also potently suppresses cytokine-induced expression of VCAM-1 on human endothelial cells [4]. The compound is a fungal product [5] and belongs to a novel class of sevenmembered cyclic peptolides that contains several uncommon constituents (i.e.…”