Licofelone Inhibits Interleukin‐18‐Induced Pro‐Inflammatory Cytokine Release and Cellular Proliferation in Human Mesangial Cells

Abstract

Licofelone, a novel dual anti‐inflammatory drug that inhibits 5‐lipoxygenase (5‐LOX) and cyclooxygenase (COX), has recently been defined to have therapeutic effects in osteoarthritis. Both 5‐LOX and COX play functional roles in the pathogenesis of glomerulonephritis in children as well. Interleukin‐18 is a pro‐inflammatory cytokine. It remains unclear whether licofelone can ameliorate inflammatory response of human mesangial cells (HMC) exposed to interleukin‐18. In this study, HMC were cultured and exposed to interleukin‐18 with or without pre‐treatment of licofelone. COX‐2 and 5‐LOX enzyme activities in mesangial cells were determined with chromometry or high‐performance liquid chromatography. Prostaglandin E2, cysteinyl leukotriene, monocyte chemotactic protein‐1 and interferon‐γ concentrations in culture medium were measured using an enzyme‐linked immunosorbent assay. Western blotting was employed to detect phosphorylated mitogen‐activated protein kinases ERK1/2, p38 and JNK1/2 in HMC. It was found that licofelone attenuated interleukin‐18‐induced COX‐2 enzyme activity in HMC and prostaglandin E2 release in a dose‐dependent manner. Similarly, licofelone inhibited interleukin‐18‐induced 5‐LOX enzyme activity and leukotriene release. Licofelone reduced interleukin‐18‐induced phosphorylation of p38 mitogen–activated protein kinase and suppressed monocyte chemotactic protein‐1 and interferon‐γ synthesis. Moreover, licofelone inhibited IL‐18‐induced proliferation of mesangial cells. We conclude that licofelone inhibits interleukin‐18‐induced pro‐inflammatory cytokine release and cellular proliferation in HMC, which may represent a really interesting therapeutic approach for glomerulonephritis in children.

Arachidonic Acid Metabolism and Kidney Inflammation

“…In addition, licofelone blocked IL-18-induced phosphorylation of p38 proliferation protein kinase, inhibited the expression of monocyte chemoattractant protein 1 and interferon-γ. Licofelone also suppressed mesangial cell proliferation caused by IL-18 [201]. These results indicate that licofelone alleviates human glomerular inflammation by inhibiting IL-18-induced proinflammatory cytokine release and cell proliferation.…”

“…Licofelone is a novel dual anti-inflammatory drug that inhibits both COX and 5-LOX. A study has indicated that licofelone improved inflammation in human mesangial cells (HMCs) exposed to IL-18 in a dose-dependent manner, through inhibiting COX-2 enzyme activity and reducing PGE 2 release in HMCs [201]. Similarly, licofelone inhibited IL-18-induced 5-LOX enzyme activity and thereby reduces leukotriene release.…”

Licofelone Modulates Neuroinflammation and Attenuates Mechanical Hypersensitivity in the Chronic Phase of Spinal Cord Injury

“…3), are elevated in the chronic spinal cord lesion site. Licofelone is a dual COX/5-LOX inhibitor that possesses potent anti-inflammatory properties (Singh et al, 2005, 2006; Wu et al, 2012). We therefore examined the ability of licofelone treatment to combat inflammation and oxidative stress in the chronically-injured spinal cord.…”

Genetic Variants in Interleukin Genes and Susceptibility to IgA Nephropathy: A Meta-Analysis

“…In addition, ILs are an important group of soluble mediators that exert diverse effects on multiple cell types but little is known of the signal transduction mechanisms that convey information from activated IL receptors to the cell interior (KurowskaStolarska et al, 2011). A number of studies have showed that ILs have the capability to stimulate glomerular mesangial cell proliferation and release various inflammatory mediators (Wang et al, 2007;Wu et al, 2012). Moreover, ILs contributed to the expression of adhesion glycoproteins by stimulating endothelial cells (Alexander et al, 2012;Kim et al, 2013).…”