Abstract
As a regulator of cellular inflammation and proliferation, cytosolic phospholipase A2 α (cPLA2α) is a promising therapeutic target for psoriasis; indeed, the cPLA2α inhibitor AVX001 has shown efficacy against plaque psoriasis in a phase I/IIa clinical trial. To improve our understanding of the anti-psoriatic properties of AVX001, we sought to determine how the compound modulates inflammation and keratinocyte hyperproliferation, key characteristics of the psoriatic epidermis. We measured eicosanoid release from human peripheral blood mononuclear cells (PBMC) and immortalized keratinocytes (HaCaT) and studied proliferation in HaCaT grown as monolayers and stratified cultures. We demonstrated that inhibition of cPLA2α using AVX001 produced a balanced reduction of prostaglandins and leukotrienes; significantly limited prostaglandin E2 (PGE2) release from both PBMC and HaCaT in response to pro-inflammatory stimuli; attenuated growth factor-induced arachidonic acid and PGE2 release from HaCaT; and inhibited keratinocyte proliferation in the absence and presence of exogenous growth factors, as well as in stratified cultures. These data suggest that the anti-psoriatic properties of AVX001 could result from a combination of anti-inflammatory and anti-proliferative effects, probably due to reduced local eicosanoid availability.
Highlights
The phospholipase A2 (PLA2) superfamily of enzymes cleave phospholipids at the sn-2 position to release free fatty acids and lysophospholipids
Several eicosanoids including prostaglandin E2 (PGE2), prostaglandin F2 (PGF2), leukotriene B4 (LTB4), and 12S-hydroxyeicosatetraenoic acids (HETEs) are known to be elevated in psoriatic lesions [20,21,22,23,49], and their direct roles in disease progression are supported by animal models of inflammatory skin disease [24,31,50,51]
To test whether the Cytosolic phospholipase A2 α (cPLA2α) inhibitor AVX001 can normalize a broader range of eicosanoids than known COXand LOX inhibitors, we treated peripheral blood mononuclear cells (PBMC) with AVX001, the non-specific lipo-oxygenase (LOX) inhibitor nordihydroguaiaretic acid (NDGA), the cyclooxygenase (COX)-2 selective inhibitor celecoxib, or the dual COX1/COX2 inhibitor naproxen, and stimulated the mixture with the Ca++ ionophore A23178
Summary
The phospholipase A2 (PLA2) superfamily of enzymes cleave phospholipids at the sn-2 position to release free fatty acids and lysophospholipids These are the precursors to a multitude of lipid signaling molecules including the eicosanoids, which are metabolites of arachidonic acid (AA) and have important roles in inflammation and inflammatory diseases. When activated by extracellular stimuli, cPLA2α undergoes Ca++-dependent translocation from the cytoplasm to intracellular membranes and becomes predominantly localized to the peri-nuclear region of the cell [2,3,4] This is where metabolism of AA by the cyclo-oxygenase (COX) and lipo-oxygenase (LOX) pathways typically occurs, producing prostaglandins and thromboxane A2 (TxA2), or leukotrienes, hydroxyeicosatetraenoic acids (HETEs), and hydroperoxyeicosatetraenoic acids (HPETEs), respectively.
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