The 15-deoxy-δ12,14-prostaglandin J2 inhibits LPS-stimulated inflammation via enhancement of the platelet-activating factor acetylhydrolase activity in human retinal pigment epithelial cells

Abstract

A well-recognized natural ligand of PPARγ, 15-deoxy-δ(12,14)-prostaglandin J(2) (15d-PGJ(2)) possesses immunomodulatory properties. The aim of this study was to elucidate whether 15d-PGJ(2) was able to attenuate lipopolysaccharide (LPS)-induced inflammatory responses in human retinal pigment epithelial (RPE) cells, which are involved in ocular immune responses. In addition, we examined whether the platelet activating factor (PAF) is associated with the anti-inflammatory activity of 15d-PGJ(2). ARPE19 cells treated with varying concentrations of 15d-PGJ(2) and a PAF antagonist (CV3988) were used in this study. The activity of PAF-acetylhydrolase (PAF-AH) was assayed by treatment with 15d-PGJ(2) and CV3988 in the presence of LPS. 15d-PGJ(2) and CV3988 inhibited the LPS-induced mRNA expression and protein production of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and intercellular adhesion molecule-1 (ICAM-1) in ARPE19 cells. These effects resulting from 15d-PGJ(2) were not abrogated by the PPARγ antagonist, indicating that the actions were PPARγ-independent. Furthermore, 15d-PGJ(2) and CV3988 enhanced the PAF-AH activity. Additionally, 15d-PGJ(2) inhibited the phosphorylation of the extracellular signal-regulated kinase (ERK) and the activation of nuclear transcription factor-κB (NF-κB). These results demonstrated that 15d-PGJ(2) reduced LPS-stimulated inflammatory responses in ARPE19 cells by enhancing the PAH-AH activity. These results suggest that 15d-PGJ(2) may have potent anti-inflammatory activity against ocular inflammation.

The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration

“…In parallel, hyperglycemia induces microglia activation via reactive oxygen species (ROS) [ 59 ]. Generation of ROS induces nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) nuclear translocation and extracellular signal–regulated kinase (ERK) phosphorylation in microglia [ 60 , 61 , 62 , 63 ] and hence production of cytokines, such as tumor necrosis factor (TNF)α, interleukins (IL)-1β, IL-6, IL-8, vascular cell adhesion molecule (VCAM-1) and intracellular adhesion molecule 1 (ICAM-1) [ 64 , 65 , 66 ].…”

“…LPS treatment in human retinal pigment epithelial cells activated ERK signaling, which is required for cytokine gene transcription [ 143 ]. Furthermore, ERK activation is important to induce expression of IL-6, MCP-1, and ICAM-1 [ 62 ]. High glucose levels in the retina were reported to increase phosphorylation of ERK [ 144 ] and also streptozotocine-induced diabetic rats showed an increase in proliferation and ERK expression in the retinal pigment epithelium [ 145 ].…”

15-Deoxy-∆-12,14-Prostaglandin J2 (15d-PGJ2), an Endogenous Ligand of PPAR-γ: Function and Mechanism

“…Similarly, 15d-PGJ2 can protect brain endothelial cells from apoptosis induced by hypoxia by inhibiting the transcription of p22phox [48]. In human retinal pigment epithelial cells, 15d-PGJ2 also inhibits lipopolysaccharide (LPS)-stimulated inflammation by enhancing the activity of platelet-activating factor acetyl hydrolase in conjunction with PPAR- γ [49].…”

High‐Salt Enhances the Inflammatory Response by Retina Pigment Epithelium Cells following Lipopolysaccharide Stimulation

“…ARPE-19, a spontaneously arising cell line of RPE, has been extensively used in the past decades to investigate the role of this cell layer in the pathogenesis of a number of diseases including age-related macular degeneration (AMD), vitreoretinopathy, and uveitis [ 2 – 5 ]. The major inflammatory cytokines produced by ARPE-19 in response to various stimuli are interleukin-6 (IL-6), interleukin-8 (CXCL8, IL-8), and monocyte chemoattractant protein-1 (CCL2, MCP-1) [ 6 , 7 ]. IL-6 is a proinflammatory cytokine that plays an important role in intensifying the intraocular immune and inflammatory response [ 8 – 11 ].…”