Upregulation of IL-6, IL-8, CXCL1, and CXCL2 Dominates Gene Expression in Human Fibroblast Cells Exposed to Loxosceles reclusa Sphingomyelinase D: Insights into Spider Venom Dermonecrosis

Phospholipase D from Loxosceles laeta Spider Venom Induces IL-6, IL-8, CXCL1/GRO-α, and CCL2/MCP-1 Production in Human Skin Fibroblasts and Stimulates Monocytes Migration

“…Despite the many unknowns, the effect of PLD of Loxosceles venom on the production of inflammatory mediators and activation of NF-κB has been documented in different cell types, such as endothelial cells and fibroblasts. In this latter cell type, it has been demonstrated that human foreskin fibroblast cell line Hs68 treated with recombinant SMD from L. reclusa not only over-expresses IL-6, IL-8, CXCL1, and CXCL2, but also IL-1β, CCL5 (RANTES), and the transcriptional factor NF-κB [22]. The results presented in this study were consistent with the above description.…”

“…These are known to be produced by the action of PLD from Loxosceles venom [9,11,17,18]. C1P has been suggested to be the inducing agent in the expression of IL-6, IL-8, CXCL1, and CXCL2 present in fibroblasts treated with recombinant L. reclusa PLD [22,23]. This hypothesis was challenged by van Meeteren et al [23], who proposed that LPA rather than C1P was responsible for the induction of cytokines and chemokines expression by activating LPA receptor-mediated signaling pathways.…”

“…Then, the neutrophils migrate to the bite site and are subsequently activated and degranulate, resulting in inflammation and necrosis [15]. Additionally, dermis fibroblasts, together with the endothelia, have been suggested to be involved in the deregulated leukocyte activation, since up-regulated expression of IL-6, IL-8, CXCL1, and CXCL2 has been reported in human foreskin fibroblast Hs68 cells exposed to recombinant L. reclusa PLD [22]. Thus, the product of sphingomyelin hydrolysis (C1P [22]) or the product of lysophosphatidylcholine (LPC) hydrolysis (LPA [23]) could reportedly be triggering the expression of these inflammatory mediators and neutrophil infiltration.…”

“…Additionally, dermis fibroblasts, together with the endothelia, have been suggested to be involved in the deregulated leukocyte activation, since up-regulated expression of IL-6, IL-8, CXCL1, and CXCL2 has been reported in human foreskin fibroblast Hs68 cells exposed to recombinant L. reclusa PLD [22]. Thus, the product of sphingomyelin hydrolysis (C1P [22]) or the product of lysophosphatidylcholine (LPC) hydrolysis (LPA [23]) could reportedly be triggering the expression of these inflammatory mediators and neutrophil infiltration. Some recent results support this mechanism, including implications that LPA produced by LPC from L. similis venom or L. intermedia SMD could mediate the cytokine and chemokine release in fibroblasts, and that this effect is mediated by an LPA receptor [24].…”

Sphingomyelinase D Activity in Model Membranes: Structural Effects of in situ Generation of Ceramide-1-Phosphate

“…van Meeteren et al have argued that the lysophospholipase activity of the enzyme on circulating lysophospholipids underlies the inflammatory and dermonecrotic effects of the venom [12] and find a role for the sphingomyelinase D activity unlikely [13]. Dragulev et al, however, have shown that recombinant SMD by itself can elicit production of proinflammatory factors in the absence of any source of exogenous lysophospholipids [14]. The latter favor the idea that the sphingomyelinase D activity of the enzyme is important in its overall toxicity with the implication that ceramide-1-phosphate plays a key role in the cellular response that leads to the clinical manifestations.…”