Suppressive effect of simvastatin on interferon-β-induced expression of CC chemokine ligand 5 in microglia

Nakamichi, Kazuo; Saiki, Megumi; Kitani, Hiroshi; Kuboyama, Yuki; Morimoto, Kanehisa; Takayama-Ito, Mutsuyo; Kurane, Ichiro

doi:10.1016/j.neulet.2006.08.044

Cited by 58 publications

(44 citation statements)

References 28 publications

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“…Indeed, our results also demonstrate that SS induces TNF-␣ expression modestly, as well as enhances that induced by IFN-␥ (data not shown). Several recent reports have documented that SS does not influence TNF-␣-induced NF-B activation in microglia [28] and actually enhances TNF-␣ secretion by microglia [29]. In addition, statins enhance the secretion of proinflammatory cytokines such as IL-6, IL-18, IL-1, IL-12, and TNF-␣ from monocytes and dendritic cells [53,61].…”

Section: Discussionmentioning

confidence: 98%

Simvastatin inhibits IFN-γ-induced CD40 gene expression by suppressing STAT-1α

Lee

Qin

Benveniste

2007

Journal of Leukocyte Biology

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CD40, a member of the TNF receptor superfamily, is critical for productive immune responses. Macrophages constitutively express CD40 at low levels, which are enhanced by IFN-gamma. IFN-gamma-induced CD40 expression involves activation of STAT-1alpha as well as NF-kappaB activation through an autocrine response to IFN-gamma-induced TNF-alpha production. Statins are 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, which exert anti-inflammatory effects independent of their cholesterol-lowering actions. Herein, we describe that simvastatin (SS) inhibits IFN-gamma-induced CD40 expression via the suppression of STAT-1alpha expression. This results in diminished STAT-1alpha recruitment to the CD40 promoter upon IFN-gamma treatment, in addition to reduced RNA Polymerase II recruitment and diminished levels of H3 and H4 histone acetylation. SS-mediated inhibition of STAT-1alpha occurs through suppression of constitutive STAT-1alpha mRNA and protein expression. The inhibitory effect of SS on CD40 and STAT-1alpha is dependent on HMG-CoA reductase activity, as the addition of mevalonate reverses the inhibitory effect. In addition, CD40 and/or STAT-1alpha expression is inhibited by GGTI-298 or Clostridium difficile Toxin A, a specific inhibitor of Rho family protein prenylation, indicating the involvement of small GTP-binding proteins in this process. Collectively, these data indicate that SS inhibits IFN-gamma-induced CD40 expression by suppression of STAT-1alpha, and altering transcriptional events at the CD40 promoter.

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Section: Discussionmentioning

confidence: 98%

Simvastatin inhibits IFN-γ-induced CD40 gene expression by suppressing STAT-1α

Lee

Qin

Benveniste

2007

Journal of Leukocyte Biology

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“…The c-myc-immortalized mouse microglial cell line, MG6 (KIREN Cell Bank), was maintained in DMEM containing 10% fetal bovine serum (ICN Biomedicals) supplemented with 100 M ␣-mercaptoethanol, 10 g/ml insulin, 100 g/ml streptomycin, and 100 U/ml penicillin (BD Falcon) (Takenouchi et al, 2005;Nakamichi et al, 2006). Primary cultured microglia were isolated from the mixed primary cell cultures from the cerebral cortex of 3-d-old wild-type or CatBϪ/Ϫ mice according to the previously described methods (Sastradipura et al, 1998;Terada et al, 2010).…”

Section: Methodsmentioning

confidence: 99%

Microglial Cathepsin B Contributes to the Initiation of Peripheral Inflammation-Induced Chronic Pain

Sun

Hayashi

et al. 2012

J. Neurosci.

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Interleukin (IL)-1␤ and IL-18 play critical roles in the induction of chronic pain hypersensitivity. Their inactive forms are activated by caspase-1. However, little is known about the mechanism underlying the activation of pro-caspase-1. There is increasing evidence that cathepsin B (CatB), a typical lysosomal cysteine protease, is involved in the pro-caspase-1 activation and the subsequent maturation of IL-1␤ and IL-18. In this context, CatB is considered to be an important molecular target to control chronic pain. However, no information is currently available about the role of CatB in chronic pain hypersensitivity. We herein show that CatB deficiency or the intrathecal administration of CA-074Me, a specific CatB inhibitor, significantly inhibited the induction of complete Freund's adjuvant-induced tactile allodynia in mice without affecting peripheral inflammation. In contrast, CatB deficiency did not affect the nerve injury-induced tactile allodynia. Furthermore, CatB deficiency or CA-074Me treatment significantly inhibited the maturation and secretion of IL-1␤ and IL-18 by cultured microglia following treatment with the neuroactive glycoprotein chromogranin A (CGA), but not with ATP. Moreover, the IL-1␤ expression in spinal microglia and the induction of tactile allodynia following the intrathecal administration of CGA depended on CatB, whereas those induced by the intrathecal administration of ATP or lysophosphatidic acid were CatB independent. These results strongly suggest that CatB is an essential enzyme for the induction of chronic inflammatory pain through its activation of pro-caspase-1, which subsequently induces the maturation and secretion of IL-1␤ and IL-18 by spinal microglia. Therefore, CatB-specific inhibitors may represent a useful new strategy for treating inflammation-associated pain.

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“…A c-myc-immortalized mouse microglial cell line, MG6 (a kind gift from Dr. H. Kitani, Transgenic Animal Research Center, National Institute of Agrobiological Science, Tsukuba, Japan) (Takenouchi et al, 2005;Nakamichi et al, 2006), was maintained in a growth medium composed of DMEM containing 10% fetal bovine serum (MP Biomedicals) supplemented with 100 M ␤-mercaptoethanol, 10 g/ml insulin, 100 g/ml streptomycin, and 100 U/ml penicillin in 100 mm Petri dishes (Falcon; BD Biosciences Discovery Labware). Primary cultured microglia were prepared according to previous methods (Tsuda et al, 2003;Hayashi et al, 2006a) and maintained for 10 -14 d in Eagle's MEM medium with fetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

Microglial Ca²⁺-Activated K⁺Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

Hayashi¹,

Kawaji²,

Sun³

et al. 2011

J. Neurosci.

110

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Ketamine is an important analgesia clinically used for both acute and chronic pain. The acute analgesic effects of ketamine are generally believed to be mediated by the inhibition of NMDA receptors in nociceptive neurons. However, the inhibition of neuronal NMDA receptors cannot fully account for its potent analgesic effects on chronic pain because there is a significant discrepancy between their potencies. The possible effect of ketamine on spinal microglia was first examined because hyperactivation of spinal microglia after nerve injury contributes to neuropathic pain. Optically pure S-ketamine preferentially suppressed the nerve injury-induced development of tactile allodynia and hyperactivation of spinal microglia. S-Ketamine also preferentially inhibited hyperactivation of cultured microglia after treatment with lipopolysaccharide, ATP, or lysophosphatidic acid. We next focused our attention on the Ca 2ϩ -activated K ϩ (K Ca ) currents in microglia, which are known to induce their hyperactivation and migration. S-Ketamine suppressed both nerve injury-induced large-conductance K Ca (BK) currents and 1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one (NS1619)-induced BK currents in spinal microglia. Furthermore, the intrathecal administration of charybdotoxin, a K Ca channel blocker, significantly inhibited the nerve injury-induced tactile allodynia, the expression of P2X 4 receptors, and the synthesis of brainderived neurotrophic factor in spinal microglia. In contrast, NS1619-induced tactile allodynia was completely inhibited by S-ketamine. These observations strongly suggest that S-ketamine preferentially suppresses the nerve injury-induced hyperactivation and migration of spinal microglia through the blockade of BK channels. Therefore, the preferential inhibition of microglial BK channels in addition to neuronal NMDA receptors may account for the preferential and potent analgesic effects of S-ketamine on neuropathic pain.

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Suppressive effect of simvastatin on interferon-β-induced expression of CC chemokine ligand 5 in microglia

Cited by 58 publications

References 28 publications

Simvastatin inhibits IFN-γ-induced CD40 gene expression by suppressing STAT-1α

Simvastatin inhibits IFN-γ-induced CD40 gene expression by suppressing STAT-1α

Microglial Cathepsin B Contributes to the Initiation of Peripheral Inflammation-Induced Chronic Pain

Microglial Ca²⁺-Activated K⁺Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

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Suppressive effect of simvastatin on interferon-β-induced expression of CC chemokine ligand 5 in microglia

Cited by 58 publications

References 28 publications

Simvastatin inhibits IFN-γ-induced CD40 gene expression by suppressing STAT-1α

Simvastatin inhibits IFN-γ-induced CD40 gene expression by suppressing STAT-1α

Microglial Cathepsin B Contributes to the Initiation of Peripheral Inflammation-Induced Chronic Pain

Microglial Ca2+-Activated K+Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain

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Microglial Ca²⁺-Activated K⁺Channels Are Possible Molecular Targets for the Analgesic Effects ofS-Ketamine on Neuropathic Pain