15-Deoxy-Δ12,14-prostaglandin J2 Induces Heme Oxygenase-1 Gene Expression in a Reactive Oxygen Species-dependent Manner in Human Lymphocytes

Abstract

15-Deoxy-⌬12,14 -prostaglandin J 2 (15dPGJ 2 ) has been proposed recently as a potent anti-inflammatory agent. However, the mechanisms by which 15dPGJ 2 mediates its therapeutic effects in vivo are unclear. We demonstrate that 15dPGJ 2 at micromolar (2.5-10 M) concentrations induces the expression of heme oxygenase-1 (HO-1), an anti-inflammatory enzyme, at both mRNA and protein levels in human lymphocytes. In contrast, troglitazone and ciglitazone, two thiazolidinediones that mimic several effects of 15dPGJ 2 through their binding to the peroxisome proliferator-activated receptor (PPAR)-␥, did not affect HO-1 expression, and the positive effect of 15dPGJ 2 on this process was mimicked instead by other cyclopentenone prostaglandins (PG), such as PGD 2 (the precursor of 15dPGJ 2 ) and PGA 1 and PGA 2 which do not interact with PPAR-␥. Also, 15dPGJ 2 enhanced the intracellular production of reactive oxygen species (ROS) and increased xanthine oxidase activity in vitro. Inhibition of intracellular ROS production by N-acetylcysteine, TEMPO, Me 2 SO, 1,10-phenanthroline, or allopurinol resulted in a decreased 15dPGJ 2 -dependent HO-1 expression in the cells. Furthermore, buthionine sulfoximine, an inhibitor of reduced glutathione synthesis, or Fe 2؉ /Cu 2؉ ions enhanced the positive effect of 15dPGJ 2 on HO-1 expression. On the other hand, the inhibition of phosphatidylinositol 3-kinase or p38 mitogen-activated protein kinase, or the blockade of transcription factor NF-B activation, hindered 15dPGJ 2 -elicited HO-1 expression. Collectively, the present data suggest that 15dPGJ 2 anti-inflammatory actions at pharmacological concentrations involve the induction of HO-1 gene expression through mechanisms independent of PPAR-␥ activation and dependent on ROS produced via the xanthine/xanthine oxidase system and/or through Fenton reactions. Both phosphatidylinositol 3-kinase and p38 mitogen-activated protein kinase signaling pathways also appear implicated in modulation of HO-1 expression by 15dPGJ 2 .

Up‐regulation of heme oxygenase‐1 expression through the Rac1/NADPH oxidase/ROS/p38 signaling cascade mediates the anti‐inflammatory effect of 15‐deoxy‐Δ12,14‐prostaglandin J2 in murine macrophages

“…p38 kinase acts downstream of ROS in 15dPGJ 2 signaling to HO-1 expression Recent studies have shown that signaling pathways involving mitogen-activated protein kinases (MAPKs) are ultimately responsible for on HO-1 induction by stress stimuli [14,25]. So, we tested the effects of three MAPK inhibitors on up-regulation of HO-1 expression by 15dPGJ 2 in macrophages.…”

“…HO-1 contributes to the host defense reaction against oxidative injury through the antioxidant activities of biliverdin and its metabolite, bilirubin, as well as the antiinflammatory action of CO [12,13]. A growing body of evidence revealed that 15dPGJ 2 induces HO-1 expression through mechanisms independent of PPAR-c activation and dependent on cellular redox state in various cell types [14,15]. Furthermore, the anti-inflammatory actions of 15dPGJ 2 are functionally correlated with the induction of HO-1 expression [16], suggesting an important role of HO-1 in PPAR-c-independent mechanism for anti-inflammatory action of 15dPGJ 2 .…”

Atorvastatin inhibits homocysteine-induced dysfunction and apoptosis in endothelial progenitor cells

“…However, other reports [13,14] have shown that apoptotic progenitor cells might be the result of oxidative stress. Hcy seems to promote the formation of ROS primarily by a biochemical mechanism involving endothelial nitric oxide synthase (eNOS) and NADPH oxidase (Nox) activation [15,16] . Excessive generation of ROS and reactive nitrogen species may result in cytotoxic Atorvastatin inhibits homocysteine-induced dysfunction and apoptosis in endothelial progenitor cells www.chinaphar.com Bao XM et al Acta Pharmacologica Sinica npg oxidative stress, which leads to endothelial dysfunction and plays a critical role in the progressive deterioration of vessel structure and function [17] .…”

Induction of cyclooxygenase-2 expression by allergens in lymphocytes from allergic patients

“…Human PBL were isolated as described [42]. Contaminating monocytes were depleted by a magnetic cell separation system (MACS) with anti-CD14 antibody incubation followed by the addition of anti-IgG antibody-coated magnetic beads.…”

“…RNA extraction and reverse transcription were performed as described [42]. cDNA was amplified by PCR using specific primers for COX-2 [21], IL-8 [33], glyceraldehyde-3-phosphate dehydrogenase (GAPDH) [21], and TNF-a (5 0 -AAGCCTG-TAGCCCATGTTGT-3 0 and 5 0 -CCAGATAGATGGGCTCATAC-3 0 ).…”