BACKGROUND AND PURPOSE We previously reported that 3‐(benzo[d]‐1,3‐dioxol‐5‐yl)‐4‐phenylfuran‐2,5‐dione (BPD) showed strong inhibitory effects on PGE2 production. However, the exact mechanism for the anti‐inflammatory effect of BPD is not completely understood. In this study, we investigated the molecular mechanism involved in the effects of BPD on inflammatory mediators in LPS‐stimulated macrophages and animal models of inflammation. EXPERIMENTAL APPROACH The expressions of COX‐2, inducible NOS (iNOS), TNF‐α, IL‐6 and IL‐1β, in LPS‐stimulated RAW 264.7 cells and murine peritoneal macrophages, were determined by Western blot and/or qRT‐PCR, respectively. NF‐κB activation was investigated by EMSA, reporter gene assay and Western blotting. Anti‐inflammatory effects of BPD were evaluated in vivo in carrageenan‐induced paw oedema in rats and LPS‐induced septic shock in mice. KEY RESULTS BPD not only inhibited COX‐2 activity but also reduced the expression of COX‐2. In addition, BPD inhibited the expression of iNOS, TNF‐α, IL‐6 and IL‐1β at the transcriptional level. BPD attenuated LPS‐induced DNA‐binding activity and the transcription activity of NF‐κB; this was associated with a decrease in the phosphorylation level of inhibitory κB‐α (IκB‐α) and reduced nuclear translocation of NF‐κB. Furthermore, BPD suppressed the formation of TGF‐β‐activated kinase‐1 (TAK1)/TAK‐binding protein1 (TAB1), which was accompanied by a parallel reduction of phosphorylation of TAK1 and IκB kinase (IKK). Pretreatment with BPD inhibited carrageenan‐induced paw oedema and LPS‐induced septic death. CONCLUSION AND IMPLICATIONS Taken together, our data indicate that BPD is involved in the dual inhibition of COX‐2 activity and TAK1‐NF‐κB pathway, providing a molecular basis for the anti‐inflammatory properties of BPD.
As an attempt to search for bioactive natural products exerting anti-inflammatory activity, we have evaluated the anti-inflammatory effects of euscaphic acid (19α-hydroxyursane-type triterpenoids, EA) isolated from roots of Rosa rugosa and its underlying molecular mechanisms in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. EA concentration-dependently reduced the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) induced by LPS in RAW 264.7 macgophages. Consistent with these data, expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein and iNOS, COX-2, TNF-α, and IL-1β mRNA were inhibited by EA in a concentration-dependent manner. In addition, EA attenuated LPS-induced DNA binding and transcriptional activity of nuclear factor-kappa B (NF-κB), which was accompanied by a parallel reduction of degradation and phosphorylation of inhibitory kappa Bα (IκBα) and consequently by decreased nuclear translocation of p65 subunit of NF-κB. Pretreatment with EA significantly inhibited the LPS-induced phosphorylation of IκB kinase β (IKKβ), p38, and JNK, whereas the phosphorylation of ERK1/2 was unaffected. Furthermore, EA interfered with the LPS-induced clustering of TNF receptor-associated factor 6 (TRAF6) with interleukin receptor associated kinase 1 (IRAK1) and transforming growth factor-β-activated kinase 1 (TAK1). Taken together, these results suggest that EA inhibits LPS-induced inflammatory responses by interference with the clustering of TRAF6 with IRAK1 and TAK1, resulting in blocking the activation of IKK and MAPKs signal transduction to downregulate NF-κB activations.
Since inhibition of angiotensin II type 1 (AT1) receptor reduces chronic inflammation associated with hypertension, we evaluated the anti-inflammatory potential and the underlying mechanism of fimasartan, a Korean Food and Drug Administration approved anti-hypertension drug, in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Fimasartan suppressed the expressions of inducible nitric oxide synthase (iNOS) by down-regulating its transcription, and subsequently inhibited the productions of nitric oxide (NO). In addition, fimasartan attenuated LPS-induced transcriptional and DNA-binding activities of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). These reductions were accompanied by parallel reductions in the nuclear translocation of NF-κB and AP-1. Taken together, our data suggest that fimasartan down-regulates the expression of the iNOS in macrophages via NF-κB and AP-1 inactivation.Key words fimasartan; inflammation; nitric oxide; nuclear factor-kappa B; activator protein-1 Inflammatory processes are important participants in the pathophysiology of hypertension and cardiovascular disease. Hypertension patients have impaired functions of the endothelium, in which inflammation plays a key role.1) Angiotensin II is recognized as an important vascular pro-inflammatory factor in hypertension. Angiotensin II-driven vascular inflammation is considered the result of direct modulates on cytokine release and pro-inflammatory transcription factor including nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1), and angiotehsin II receptor blockers (ARBs) reduce the peripheral and cerebrovascular inflammation associated with this disease. 2,3)Anti-inflammatory effects of ARBs, first established in the peripheral vasculature, 4) were later demonstrated in the cerebral vasculature 5) and in stress-induced gastric ulcerations. 6)These observations suggest that ARBs may exert general antiinflammatory effects beyond those associated with cardiovascular and metabolic disease. 7) Thus, apart from being a major vasopressor effector of the renin-angiotensin system, ARBs are probably good candidate drugs for inflammation. 8)Since the important role of macrophages in inflammation, many investigations about ARBs (e.g., candesartan, losartan, telmisartan and valsartan) were performed in lipopolysaccharide (LPS)-induced macrophages.9-11) In fact, there are several physiological roles of angiotensin II type 1 (AT1) receptor in macrophages, such as positive regulation of peroxide production 12) and shift M1/M2 polarization balance. 13) However, in macrophages AT1a receptor expression level is reportedly low and AT1b receptor is not detected at all 14) and the most important feature of macrophages is that macrophages are widely distributed in the body and provide an immediate defense against foreign agents, such as lipopolysaccharide (LPS).15) Nitric oxide (NO), a potent pro-inflammatory mediator, is mainly produced by macrophages and acts as a cytotoxic agent during immune and inflammatory responses, which is...
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