Withaferin A inhibits iNOS expression and nitric oxide production by Akt inactivation and down-regulating LPS-induced activity of NF-κB in RAW 264.7 cells

Oh, Jung Hwa; Lee, Tae-Jin; Park, Jong‐Wook; Kwon, Taeg Kyu

doi:10.1016/j.ejphar.2008.09.017

Cited by 97 publications

(69 citation statements)

References 42 publications

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“…NF-κB translocation and inhibition data conformed to the results of cytokine studies of WA in pulmonary epithelial cells (A549) and cystic fibrotic KKLEB cells [16,41]. Inactivation of protein kinase B (Akt) along with NF-κB inhibition murine macrophage cells has also been reported [42]. Effects on mitogenactivated kinases by WA were consistent with previous studies showing that, through the MAPK/ERK (MEK/ ERK) pathway, WA induces IKKβ phosphorylation with IκB phosphorylation and degradation in mouse fibrosarcoma cells [14].…”

Section: Discussionsupporting

confidence: 75%

Withaferin A inhibits pro-inflammatory cytokine-induced damage to islets in culture and following transplantation

SoRelle

Itoh²,

Han

et al. 2013

Diabetologia

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Aims/hypothesis Beta cell death triggered by pro-inflammatory cytokines plays a central role in the pathogenesis of type 1 diabetes and loss of transplanted islets. The nuclear factor κB (NF-κB) signalling pathway is a key regulator of beta cell stress response, survival and apoptosis. Withaferin A (WA), a steroidal lactone derived from Withania somnifera, has been demonstrated to be a potent, safe, anti-inflammatory molecule that can inhibit NF-κB signalling. Therefore, we evaluated the ability of WA to protect mouse and human islets from the damaging effects of pro-inflammatory cytokines in vitro and following intraportal transplantation. Methods Mouse and human islets were treated with a cytokine cocktail, and NF-κB activation was measured by immunoblots, p65 nuclear translocation and chromatin immunoprecipitation of p65-bound DNA. Intraportal transplantation of a marginal mass of syngeneic mouse islets was performed to evaluate the in vivo protective effect of WA. Results Treatment with WA substantially improved islet engraftment of syngeneic islets (83% for infusion with 200 islets + WA; 0% for 200 islets + vehicle) in a mouse model of diabetes, compared with marginal graft controls with superior islet function in WA-treated mice confirmed by glucose tolerance test. Treatment of human and mouse islets with WA prevented cytokine-induced cell death, inhibited inflammatory cytokine secretion and protected islet potency. Conclusions WA was shown to be a strong inhibitor of the inflammatory response in islets, protecting against cytokineinduced cell damage while improving survival of transplanted islets. These results suggest that WA could be incorporated as an adjunctive treatment to improve islet transplant outcome.

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Section: Discussionsupporting

confidence: 75%

Withaferin A inhibits pro-inflammatory cytokine-induced damage to islets in culture and following transplantation

SoRelle

Itoh²,

Han

et al. 2013

Diabetologia

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“…We and others 30,[33][34][35] have shown that LPS/IFN-c activates the PI3K/Akt/mTOR pathway and induces iNOS. Furthermore, we have recently shown that EGCG decreases Akt phosphorylation.…”

Section: Egcg Attenuates Inflammation In Mesangial Cells Stimulated Wmentioning

confidence: 85%

Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells

et al. 2010

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Epigallocatechin-3-gallate (EGCG), a bioactive component of green tea, has been reported to exert anti-inflammatory effects on immune cells. EGCG is also shown to activate the metabolic regulator, adenosine 5'-monophosphate-activated protein kinase (AMPK). Reports have also indicated that EGCG inhibits the immune-stimulated phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. The PI3K/Akt/mTOR pathway has been implicated in mesangial cell activation in lupus. Mesangial cells from MRL/lpr lupus-like mice are hyper-responsive to immune stimulation and overproduce nitric oxide (NO) and other inflammatory mediators when stimulated. In our current studies, we sought to determine the mechanism by which EGCG attenuates immune-induced expression of pro-inflammatory mediators. Cultured mesangial cells from MRL/lpr mice were pre-treated with various concentrations of EGCG and stimulated with lipopolysaccharide (LPS)/interferon (IFN)-c. EGCG activated AMPK and blocked LPS/ IFN-c-induced inflammatory mediator production (iNOS expression, supernatant NO and interleukin-6). Interestingly, EGCG attenuated inflammation during AMPK inhibition indicating that the anti-inflammatory effect of EGCG may be partially independent of AMPK activation. Furthermore, we found that EGCG effectively inhibited the immune-stimulated PI3K/Akt/mTOR pathway independently of AMPK, by decreasing phosphorylation of Akt, suggesting an alternate mechanism for EGCG-mediated anti-inflammatory action in mesangial cells. Taken together, these studies show that EGCG attenuated inflammation in MRL/lpr mouse mesangial cells via the PI3K/Akt/mTOR pathway. Our findings suggest a potential therapeutic role for the use of EGCG to regulate inflammation and control autoimmune disease.

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“…This enzyme catalyzes the production of high levels of NO in a wide variety of cells, including macrophages, and is regulated primarily at the transcriptional level (20, 21). Many signaling pathways and inducible transcription factors, including Akt, NF-B, JNK and p38 mitogen-activated protein kinase (p38), cAMP response element-binding protein (CREB), and CCAAT/enhancer-binding protein-␤, have been implicated in iNOS activation (22)(23)(24)(25)(26). iNOS is important for host defense against P. gingivalis infection.…”

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confidence: 99%

Signaling mechanisms involved in altered function of macrophages from diet-induced obese mice affect immune responses

Zhou

Leeman

Amar

2009

Proc. Natl. Acad. Sci. U.S.A.

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Recent research links diet-induced obesity (DIO) with impaired immunity, although the underlying mechanisms remain unclear. We find that the induction of inducible NO synthase (iNOS) and cytokines is suppressed in mice with DIO and in bone marrow macrophages (BMM⌽) from mice with DIO exposed to an oral pathogen, Porphyromonas gingivalis. BMM⌽ from lean mice pretreated with free fatty acids (FFAs) and exposed to P. gingivalis also exhibit a diminished induction of iNOS and cytokines. BMM⌽ from lean and obese mice exposed to P. gingivalis and analyzed by a phosphorylation protein array show a reduction of Akt only in BMM⌽ from mice with DIO. This reduction is responsible for diminished NF-B activation and diminished induction of iNOS and cytokines. We next observed that Toll-like receptor 2 (TLR2) is suppressed in BMM⌽ from DIO mice whereas carboxy-terminal modulator protein (CTMP), a known suppressor of Akt phosphorylation, is elevated. This elevation stems from defective TLR2 signaling. In BMM⌽ from lean mice, both FFAs and TNF-␣-via separate pathways-induce an increase in CMTP. However, in BMM⌽ from DIO mice, TLR2 can no longer inhibit the TNF-␣-induced increase in CTMP caused by P. gingivalis challenge. This defect can then be restored by transfecting WT TLR2 into BMM⌽ from DIO mice. Thus, feeding mice a high-fat diet over time elevates the CTMP intracellular pool, initially via FFAs activating TLR2 and later when the defective TLR2 is unable to inhibit TNF-␣-induced CTMP. These findings unveil a link between obesity and innate immunity.O besity has been found to lead to diminished immune response. Several epidemiological studies of obese individuals found evidence of increased susceptibility to infections, including postoperative infectious complications (1), and a positive correlation between body weight index and the incidence of nosocomial infections (2). Diet-induced obesity (DIO) interferes with the ability of the immune system to appropriately respond to Porphyromonas gingivalis infection (3) and causes a higher mortality rate in mice following infection with influenza virus (4).Obesity is known to elevate TNF-␣ levels in the plasma of obese subjects (5, 6). However, macrophage functions are impaired in obese animals, with reduced phagocytic capacity and a defective oxidative burst (7,8). The reduced cytokine expression in response to infection observed in obese mice has been linked to a dysfunction in macrophages and/or a defect in maturation of monocytes (3,4,9). Moreover, the ability of mature macrophages from an obese individual to elicit an antimicrobial and cytotoxic response may be inhibited (10). Macrophages sense the presence of microorganisms via pattern recognition receptors, especially members of the Tolllike receptor (TLR) family, and subsequently activate proinflammatory signal pathways. TLR2 is an important receptor by which macrophages recognize P. gingivalis (11)(12)(13)(14), and mediates destructive chronic inflammatory reactions or confers host protection against P. gingivalis in acut...

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Withaferin A inhibits iNOS expression and nitric oxide production by Akt inactivation and down-regulating LPS-induced activity of NF-κB in RAW 264.7 cells

Cited by 97 publications

References 42 publications

Withaferin A inhibits pro-inflammatory cytokine-induced damage to islets in culture and following transplantation

Withaferin A inhibits pro-inflammatory cytokine-induced damage to islets in culture and following transplantation

Epigallocatechin-3-gallate (EGCG) attenuates inflammation in MRL/lpr mouse mesangial cells

Signaling mechanisms involved in altered function of macrophages from diet-induced obese mice affect immune responses

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