The necrotic venom of the brown recluse spider induces dysregulated endothelial cell-dependent neutrophil activation. Differential induction of GM-CSF, IL-8, and E-selectin expression

• Published in: The Journal of clinical investigation Vol. 94; no. 2; pp. 631 - 642
• Main Authors: Patel, K D, Modur, V, Zimmerman, G A, Prescott, S M, McIntyre, T M
• Format: Journal Article
• Language: English
• Published: United States 01-08-1994
• Subjects: Animals; Base Sequence; Cell Adhesion Molecules - biosynthesis; Cell Communication - drug effects; Cells, Cultured; E-Selectin; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Interleukin-8 - biosynthesis; Molecular Sequence Data; Neutrophils - drug effects; Neutrophils - physiology; Spider Venoms - pharmacology; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0021-9738
• DOI: 10.1172/JCI117379

Brown recluse spider (Loxosceles reclusa) venom induces severe dermonecrotic lesions. The mechanism for this is unknown but presents an interesting paradox: necrosis is completely dependent on the victim's neutrophils, yet neutrophils are not activated by the venom. We show Loxosceles venom is a potent, but disjointed, endothelial cell agonist. It weakly induced E-selectin expression, but not intercellular adhesion molecule-1 or IL-6 expression, yet significantly stimulated release of IL-8 and large amounts of GM-CSF by 4 h. In contrast, TNF strongly induced all of these, except for GM-CSF. PMN bound to E-selectin on venom-activated endothelial cells, apparently via counterreceptors different from those that bind E-selectin on TNF alpha-activated monolayers. Notably, PMN bound venom-activated monolayers only at intercellular junctions, did not polarize, and completely failed to migrate beneath the monolayer. Despite this, bound PMN demonstrated increased intracellular Ca2+ levels and secreted primary and secondary granule markers. The latter event was suppressed by sulfones used to treat envenomation. We have defined a new endothelial cell agonist, Loxosceles venom, that differentially stimulates the inflammatory response of endothelial cells. This, in turn, leads to a dysregulated PMN response where adhesion and degranulation are completely dissociated from shape change and transmigration.