Anti-ALOX15 monoclonal antibody, clone 4E9

Inflammation dysregulation in placenta is implicated in the pathogenesis of numerous pregnancy complications. Glucocorticoids (GCs), universally considered anti-inflammatory, can also exert proinflammatory actions under some conditions, whereas whether and how GCs promote placental inflammation have not been intensively investigated. In this paper we report the opposing regulation of rat placental inflammation by synthetic GC dexamethasone (Dex). When Dex was subcutaneously injected 1 h after we administered an intraperitoneal lipopolysaccharide (LPS) challenge, neutrophil infiltration and proinflammatory Il1b, Il6, and Tnfa expression in rat placenta were significantly reduced. In contrast, Dex pretreatment for 24 h potentiated rat placental proinflammatory response to LPS and delayed inflammation resolution, which involved MAPKs and NF-kappaB activation. Mechanically, Dex pretreatment promoted 5-lipoxygenase (ALOX5) activation and increased leukotriene B-4 production, whereas it inhibited the anti-inflammatory and proresolving lipid mediator lipoxin A(4) (LXA(4)) biosynthesis in rat placenta via downregulating ALOX15 and ALOX15B expression. Moreover, LXA(4) supplementation dampened Dex-potentiated placental inflammation and suppressed Dex-mediated ALOX5 activation in vivo and in vitro. Taken together, these findings suggest that GCs exposure could promote placental inflammation initiation and delay resolution via disrupting LXA(4) biosynthesis.

We have shown that Alox15, the gene encoding for 12/15-lipoxygenase (12/15-LO), is markedly up-regulated in livers from apolipoprotein E-deficient (ApoE(-/-)) mice, which spontaneously develop nonalcoholic fatty liver disease secondary to hyperlipidemia. In the current study, we used ApoE(-/-) mice with a targeted disruption of the Alox15 gene to assess the role of 12/15-LO in the development and progression of hepatic steatosis and inflammation Compared with ApoE(-/-) mice, which exhibited extensive hepatic lipid accumulation and exacerbated inflammatory injury, ApoE/12/15-LO double-knockout (ApoE(-/-)/12/15-LO-/-) mice showed reduced serum alanine aminotransferase levels, decreased hepatic steatosis, inflammation, and macrophage infiltration, and decreased fatty acid synthase, tumor necrosis factor alpha (TNF alpha), monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-18, and HA expression Remarkably, disruption of Alox15 attenuated glucose intolerance and high-fat diet-induced insulin resistance, up-regulated insulin receptor substrate-2, and exerted opposite effects on hepatic c-Jun amino-terminal kinase and adenosine monophosphate-activated protein kinase phosphorylation, known negative and positive regulators of insulin signaling, respectively In adipose tissue, the absence of Alox15 induced significant reductions in the expression of the proinflammatory and insulin-resistant adipokines MCP-1, TNF alpha, and resistin while increasing the expression of glucose transporter-4 Interestingly, compared with ApoE(-/-) mice, which exhibited increased hepatic caspase-3 staining, ApoE(-/-)/12/15-LO-/- mice showed attenuated hepatocellular injury Consistent with this finding, hepatocytes Isolated from ApoE(-/-) mice were more vulnerable to TNE alpha-induced programmed cell death, an effect that was not observed in hepatocytes carrying a targeted disruption of the Alox15 gene. Conclusion. Collectively, our data suggest a potentially relevant mechanism Inking 12/15-LO to the promotion of hepatic steatosis, insulin resistance, and inflammation in experimental liver disease of metabolic origin (HEPATOLOGY 2010,52 1980-1991)