Fatty acid–binding protein 5 controls microsomal prostaglandin E synthase 1 (mPGES-1) induction during inflammation

Abstract

Fatty acid binding proteins (FABPs) are intracellular lipid carriers that regulate inflammation, and pharmacological inhibition of FABP5 reduces inflammation and pain. The mechanism(s) underlying the anti-inflammatory effects associated with FABP5 inhibition are poorly understood. Herein, we identify a novel mechanism through which FABP5 modulates inflammation. In mice, intraplantar injection of carrageenan induces acute inflammation that is accompanied by edema, enhanced pain sensitivity, and elevations in pro-inflammatory cytokines and prostaglandin E2 (PGE2). Inhibition of FABP5 reduced pain, edema, cytokine, and PGE2 levels. PGE2 is a major eicosanoid that enhances pain in the setting of inflammation and we focused upon the mechanism(s) through which FABP5 modulates PGE2 production. Cyclooxygenase-2 and microsomal prostaglandin E synthase-1 (mPGES-1) are enzymes upregulated at the site of inflammation and account for the bulk of PGE2 biosynthesis. Pharmacological or genetic FABP5 inhibition suppressed the induction of mPGES-1 but not COX-2 in carrageenan-injected paws, which occurred predominantly in macrophages.The cytokine interleukin 1β (IL-1β) is a major inducer of mPGES-1 during inflammation. Using A549 cells that express FABP5, IL-1β stimulation upregulated mPGES-1 expression, and mPGES-1 induction was attenuated in A549 cells bearing a knockdown of FABP5. IL-1β upregulates mPGES-1 via NF-kB, which activates the mPGES-1 promoter. Knockdown of FABP5 reduced the activation and nuclear translocation of NF-kB, and attenuated mPGES-1 promoter activity. Deletion of NF-kB binding sites within the mPGES-1 promoter abrogated the ability of FABP5 to inhibit mPGES-1 promoter activation. Collectively, these results position FABP5 as a novel regulator of mPGES-1 induction and PGE2 biosynthesis during inflammation. ________________________________________ Pain is a frequent reason for seeking medical care and approximately thirty percent of older adults experience chronic pain (1-3). Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are mainstay treatments for chronic pain. However, chronic NSAID use is associated with gastrointestinal hemorrhage and even acute NSAID use increases the incidence of myocardial FABP5 regulates mPGES-1 during inflammation2 infarctions (4,5). Chronic opioid use is associated with significant addiction and overdose liability (6)(7)(8). Consequently, there is a need to develop novel efficacious non-opioid analgesics.Fatty acid binding proteins (FABPs) are intracellular carriers for fatty acids and related bioactive lipids such as the endocannabinoid anandamide (9-11). In addition to the cytosolic transport of lipids, FABPs deliver ligands to the nucleus wherein they activate nuclear receptors (10,(12)(13)(14). There are ten FABP isoforms expressed in mammals and we previously demonstrated that pharmacological inhibition of FABP5 produces analgesic effects by enhancing endocannabinoid signaling (15)(16)(17)(18). We also demonstrated that FABP5 is expressed in nociceptors, p...

SAR studies on truxillic acid mono esters as a new class of antinociceptive agents targeting fatty acid binding proteins

“…Recent work indicates that FABP4 can modulate inflammation [34] and its inhibition could contribute to the antinociceptive effects of our FABP inhibitors. However, this is unlikely because FABP4 KO mice display normal pain responses [35] and inhibitors that produce antinociceptive effects (e.g., 3f , 4b and 4j ) do not appreciably inhibit FABP4 (see Fig. S5).…”

Discovery and Development of a Novel mPGES-1/5-LOX Dual Inhibitor LFA-9 for Prevention and Treatment of Chronic Inflammatory Diseases

“…LFA-9 showed maximum edema inhibition at 3 hours after carrageenan injection, which is referred to as the second phase of acute inflammation, in which CD68-positive inflammatory cells are accumulated, pro-inflammatory enzymes of arachidonic acid pathways and TNF-α are over-expressed. 29 , 38 , 50 Results also demonstrate that LFA-9 inhibited inflammatory response by inhibiting pro-inflammatory PGE 2 and chemotactic LTB 4 levels and thereby, preventing the infiltration of CD68 positive macrophages and granular neutrophils along with TNF-α expression ( Figure 5G ).…”

Treatment of Microglia with Anti-PrP Antibodies Induces Neuronal Allergenicity

“…Ge et al showed that FABP4 is involved in the regulation of eosinophil recruitment and plays a proin ammatory role during allergic asthma development [108]. Of note, FABP5 is an intracellular lipid carrier protein involved in the regulation of in ammation and its inhibition decreases levels of prostaglandin E 2 and proin ammatory cytokines [109]. PCDH11X and PCDH1 are cell adhesion molecules and belong to the cadherin protein family that are highly expressed within the CNS [110][111][112].…”