Distinct signaling pathways for induction of type II NOS by IFNγ and LPS in BV-2 microglial cells

Shen, Siming; Yu, Shiguang; Binek, Joshua; Chalimoniuk, Małgorzata; Zhang, Xiaolin; Lo, S.-C.B.; Hannink, Mark; Wu, Jinmei; Fritsche, Kevin L.; Donato, Rosario; Sun, Grace Y.

doi:10.1016/j.neuint.2005.03.007

Cited by 71 publications

(74 citation statements)

References 37 publications

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“…Although the exact intracellular signal pathways of microglial activation by LPS have not been clearly defined, LPS has been reported to induce iNOS and TNF expression in microglial cells through signal pathways, including ERK1/2, p38 MAPK, and NF-κB (Bhat et al, 1998;Shen et al, 2005). Thus, inhibition of these signaling pathways may explain the potent activity of celastrol as a suppressor of inflammatory mediators.…”

Section: Discussionmentioning

confidence: 99%

Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-κB in LPS-stimulated BV-2 microglial cells

Jung

Chung²,

Kim³

et al. 2007

Exp Mol Med

118

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Excessive production of nitric oxide (NO) and proinflammatory cytokines from activated microglia play an important role in human neurodegenerative disorders. Here, we investigated whether celastrol, which has been used as a potent anti-inflammatory and anti-oxidative agent in Chinese medicine, attenuates excessive production of NO and proinflammatory cytokines such as TNF-α and IL-1β in LPS-stimulated BV-2 cells, a mouse microglial cell line. We report here that the LPS-elicited excessive production of NO, TNF-α , and IL-1β in BV-2 cells was largely inhibited in the presence of celastrol, and the attenuation of inducible iNOS and these cytokines resulted from the reduced expression of mRNAs of iNOS and these cytokines, respectively. The molecular mechanisms that underlie celastrol-mediated attenuation were the inhibition of LPS-induced phosphorylation of MAPK/ERK1/2 and the DNA binding activity of NF-κ B in BV-2 cells. The results indicate that celastrol effectively attenuated NO and proinflammatory cytokine production via the inhibition of ERK1/2 phosphorylation and NF-κ B activation in LPS-activated microglia. Thus, celastrol may be an effective therapeutic candidate for use in the treatment of neurodegenerative human brain disorders.

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Section: Discussionmentioning

confidence: 99%

Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-κB in LPS-stimulated BV-2 microglial cells

Jung

Chung²,

Kim³

et al. 2007

Exp Mol Med

118

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“…In addition, although ERK is not stress-induced, it appears to participate, at least partly, in the production of inflammatory cytokines (Toledo-Pereyra et al, 2004), whereas thrombin-induced NO release is inhibited by p38 (SB203580) and ERK (PD98059) inhibitors (Ryu et al, 2000). However, SB203580 has no effect by itself on IFN-␥-mediated NO release and needed the addition of PD98059 to reach a significant inhibitory effect in microglia (Han et al, 2002;Shen et al, 2005). On the other hand, PI3K has a very potent effect on IFN-␥-induced NO production and iNOS gene in microglia, an effect that is likely mediated by signal transducer and activator of transcription 1 and partly by nuclear factor-B (Hwang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Thrombin-Induced Neuroinflammation in BV-2 Microglia by Carbon Monoxide-Releasing Molecule 3

Banihani

Greenstein²,

Mann³

et al. 2006

J Pharmacol Exp Ther

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Carbon monoxide-releasing molecules are emerging as a new class of pharmacological agents that regulate important cellular function by liberating CO in biological systems. Here, we examined the role of carbon monoxide-releasing molecule 3 (CORM-3) in modulating neuroinflammatory responses in BV-2 microglial cells, considering its practical application as a novel therapeutic alternative in the treatment of stroke. BV-2 microglia cells were incubated for 24 h in normoxic conditions with thrombin alone or in combination with interferon-␥ to simulate the inflammatory response. Cells were also subjected to 12 h of hypoxia and reoxygenated for 24 h in the presence of thrombin and interferon-␥. In both set of experiments, the anti-inflammatory action of CORM-3 was evaluated by assessing its effect on nitric oxide production (nitrite levels) and tumor necrosis factor (TNF)-␣ release. CORM-3 (75 M) did not show any cytotoxicity and markedly attenuated the inflammatory response to thrombin and interferon-␥ in normoxia and to a lesser extent in hypoxia as evidenced by a reduction in nitrite levels and TNF-␣ production. Inactive CORM-3, which does not liberate CO and is used as a negative control, failed to prevent the increase in inflammatory mediators. Blockade of endogenous CO production by tin protoporphyrin-IX did not change the anti-inflammatory activity of CORM-3, suggesting that CO liberated from the compound is responsible for the observed effects. In addition, inhibition of the mitogen-activated protein kinases phosphatidyl inositol 3 kinase and extracellular signal-regulated kinase amplified the anti-inflammatory effect of CORM-3. These results suggest that the anti-inflammatory activity of CORM-3 could be exploited to mitigate microglia activity in stroke and other neuroinflammatory diseases.Stroke is the major cause of disabilities in adults, leaving more than half of the survivors dependent on others for everyday activities (Wolfe et al., 2000). It is also a major cause of dementia, depression, epilepsy, and falls (Rothwell et al., 2004). This pathological event is characterized by blockade of blood supply to the brain and consequently oxygen and glucose deprivation, which lead to necrotic cell death and tissue infarct. Rescuing the surrounding partially ischemic penumbra depends on the severity of brain edema, subsequent neuroinflammation, and production of free radicals.Microglia are the main inflammatory-reacting cells in the brain after ischemia (Suk, 2004). They act through redoxsensitive inflammatory enzymes such as inducible nitric oxide synthase (iNOS) and NAD(P)H oxidase, which produce NO, superoxide, peroxynitrite, and other reactive oxygen species (ROS) that mediate their phagocytic ability. Free radicals generated during the inflammatory process can directly damage neurons by interacting with their lipid-rich membranes or by increasing ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptor susceptibility to the toxic effects of glutamate (Zhao et al., 2004).Another important ...

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“…As discussed above, microglia undergo marked morphologic alterations during ontogeny, so that primary microglia from the fetal/neonatal and adult brain cannot be considered as phenotypically equivalent. Indeed, although microglial cell lines (Shen et al, 2005), microglia purified from mixed glial cultures (Roy et al, 2006) and acutely isolated neonatal microglia (Brannan and Roberts, 2004) are capable of robust nitric oxide responses when stimulated in vitro, we have previously reported that microglia from adult mouse brain are relatively inefficient producers of nitric oxide in response to a wide variety of stimuli in vitro (Brannan and Roberts, 2004).…”

Section: Introductionmentioning

confidence: 99%

Differential ex vivo nitric oxide production by acutely isolated neonatal and adult microglia

Schell

Crane

Smith

et al. 2007

Journal of Neuroimmunology

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Microglia are the macrophage population residing in the parenchyma of the central nervous system (CNS), and are thought to play critical roles in CNS development, homeostasis and defense against pathogens. Microglia are capable of rapidly responding to microbial pathogens through engagement of their Toll-like receptors (TLRs). We first compared the efficiency of these responses in primary microglia acutely isolated from adult and neonatal mice. While the cytokine and chemokine responses of adult microglia were generally higher than those of neonatal cells stimulated ex vivo through TLRs, the nitric oxide response of neonatal microglia was markedly enhanced relative to the adult cells. We then went on to identify culture conditions such as exposure to M-SCF or GM-CSF that markedly enhanced the nitric oxide response of microglia, particularly those from the adult CNS. Finally, we demonstrate that the differential nitric oxide response of neonatal and adult microglia is not limited to the mouse, but also extends to rat microglia.

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Distinct signaling pathways for induction of type II NOS by IFNγ and LPS in BV-2 microglial cells

Cited by 71 publications

References 37 publications

Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-κB in LPS-stimulated BV-2 microglial cells

Celastrol inhibits production of nitric oxide and proinflammatory cytokines through MAPK signal transduction and NF-κB in LPS-stimulated BV-2 microglial cells

Modulation of Thrombin-Induced Neuroinflammation in BV-2 Microglia by Carbon Monoxide-Releasing Molecule 3

Differential ex vivo nitric oxide production by acutely isolated neonatal and adult microglia

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