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ABSTRACT: The role of retinoblastoma protein-interacting zinc finger 1 (RIZ1) on the cell growth of mouse and human monocytic leukemia cells was examined. RIZ1 expression was induced in response to tumor necrosis factor (TNF)-α. The expression was dependent on the nuclear factor-κB and AKT signaling. Further, RIZ1 expression led to the augmentation of p53 expression and the silencing of RIZ1 prevented it. On the other hand, a p53 inhibitor enhanced the TNF-α-induced RIZ1 expression. Silencing of RIZ1 augmented the proliferative activity of TNF-α-treated cells. Therefore, it is suggested that RIZ1 negatively regulated the cell proliferation of monocytic leukemia cells via activation of p53.
Cancer Investigation 10/2010; 28(8):806-12. · 1.85 Impact Factor
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ABSTRACT: Selective Alzheimer disease indicator-1 (seladin-1) is a broadly expressed oxidoreductase and is related to Alzheimer disease, cholesterol metabolism and carcinogenesis. The effect of lipopolysaccharide (LPS) on the expression of seladin-1 was examined using RAW 264.7 macrophage-like cells and murine peritoneal macrophages. Lipopolysaccharide induced the expression of seladin-1 protein and messenger RNA in those macrophages. The seladin-1 expression was also augmented by a series of Toll-like receptor ligands. The LPS augmented the expression of seladin-1 via reactive oxygen species generation and p38 activation. Seladin-1 inhibited LPS-induced activation of p38 but not nuclear factor-kappaB and inhibited the production of tumour necrosis factor-alpha in response to LPS. Moreover, seladin-1 inhibited LPS-induced osteoclast formation and enhanced LPS-induced alkaline phosphatase activity. Therefore, it was suggested that seladin-1 might be an LPS-responsible gene product and regulate the LPS-induced inflammatory response negatively.
Immunology 09/2010; 131(1):59-66. · 3.32 Impact Factor
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ABSTRACT: The role of retinoblastoma protein-interacting zinc finger 1 (RIZ1) in receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast formation was examined in mouse RAW 264.7 macrophage-like cells. The expression of RIZ1 was significantly augmented by RANKL-treated cells. Silencing of RIZ1 with the siRNA significantly reduced the appearance of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells as osteoclasts in RANKL-treated cells. The expression of nuclear factor of activated T cell 1 (NFATc1) as the terminal transcription factor of osteoclast formation was prevented by RIZ1 siRNA. It was suggested that that RIZ1 might participate in RANKL-induced osteoclast formation through the regulation of NFATc1 expression.
Immunology letters 07/2010; 131(2):166-9. · 2.91 Impact Factor
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ABSTRACT: The effect of a series of toll-like receptor (TLR) ligands on the production of nitric oxide (NO) in mouse B1 cells was examined by using CD5(+) IgM(+) WEHI 231 cells. The stimulation with a series of TLR ligands, which were Pam3Csk4 for TLR1/2, poly I:C for TLR3, lipopolysaccharide (LPS) for TLR4, imiquimod for TLR7 and CpG DNA for TLR9, resulted in enhanced NO production via augmented expression of an inducible type of NO synthase (iNOS). LPS was most potent for the enhancement of NO production, followed by poly I:C and Pam3Csk4. Imiquimod and CpG DNA led to slight NO production. The LPS-induced NO production was dependent on MyD88-dependent pathway consisting of nuclear factor (NF)-kappaB and a series of mitogen-activated protein kinases (MAPKs). Further, it was also dependent on the MyD88-independent pathway consisting of toll-IL-1R domain-containing adaptor-inducing IFN-beta (TRIF) and interferon regulatory factor (IRF)-3. Physiologic peritoneal B1 cells also produced NO via the iNOS expression in response to LPS. The immunological significance of TLR ligands-induced NO production in B1 cells is discussed.
Cellular Immunology 01/2010; 261(2):122-7. · 1.97 Impact Factor
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ABSTRACT: The involvement of retinoblastoma protein-interacting zinc finger 1 (RIZ1), a tumor suppressor, in lipopolysaccharide (LPS)-induced inflammatory responses was investigated by using RAW 264.7 macrophage-like cells. LPS significantly augmented the expression of RIZ1 and the augmentation was mediated by the activation of nuclear factor (NF)-kappaB and Akt. The silencing of RIZ1 with the siRNA led to the inactivation of NF-kappaB in response to LPS. Moreover, the RIZ1 silencing caused the down-regulation of p53 activation and a p53 pharmacological inhibitor attenuated the RIZ1 expression. LPS-induced tumor necrosis factor-alpha and interleukin-6 production was prevented by RIZ1 siRNA or a p53 pharmacological inhibitor. Therefore, RIZ1 was suggested to augment LPS-induced NF-kappaB activation in collaboration with p53 and enhance the production of proinflammatory cytokines in response to LPS.
Cellular Immunology 01/2010; 264(2):114-8. · 1.97 Impact Factor
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ABSTRACT: The regulatory role of tumour necrosis factor-a (TNF-a) on the expression of suppressor of cytokine signalling 3 (SOCS-3) in response to lipopolysaccharide (LPS) was examined using peritoneal macrophages from TNF-a-deficient mice. The LPS-induced SOCS-3 expression was markedly augmented in macrophages from wild-type mice whereas such augmentation was not seen in the cells from TNF-a-deficient mice. However, there was no significant difference in the level of SOCS-3 messenger RNA expression between macrophages from wild-type mice and those from TNF-a-deficient mice. The addition of exogenous TNF-a augmented the LPS-induced SOCS-3 expression in macrophages from TNF-a-deficient mice. The pulse chase analysis suggested augmented degradation of LPS-induced SOCS-3 protein in macrophages from TNF-a-deficient mice. Moreover, MG 132, a 26S proteasome inhibitor, sustained the LPS-induced SOCS-3 expression in those cells. The tyrosine phosphorylation of SOCS-3 was definitely induced in LPS-stimulated macrophages from TNF-a-deficient mice but not wild-type mice. A tyrosine phosphatase inhibitor enhanced the tyrosine phosphorylation of SOCS-3 in wild-type mice and accelerated the degradation. Therefore, it was suggested that TNF-a prevented the degradation of SOCS-3 protein via inhibition of the tyrosine phosphorylation in LPS-stimulated macrophages.
Immunology 01/2010; 129(1):97-104. · 3.32 Impact Factor
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Gantsetseg Tumurkhuu,
Naoki Koide,
Takaki Hiwasa,
Motohiro Ookoshi,
Jargalsaikhan Dagvadorj,
Abu Shadat Mohammod Noman,
Imtiaz Iftakhar-E-Khuda,
Yoshikazu Naiki,
Takayuki Komatsu,
Tomoaki Yoshida,
Takashi Yokochi
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ABSTRACT: ONO 3403, a new synthetic serine protease inhibitor, is a derivative of camostat mesilate and has a higher protease-inhibitory activity. The effect of ONO 3403 on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α and nitric oxide (NO) production in RAW 264.7 macrophage-like cells was examined. ONO 3403 significantly inhibited LPS-induced TNF-α production at a lower concentration than camostat mesilate. It also inhibited LPS-induced NO production. Their inhibition was responsible for the reduced mRNA expression of TNF-α and inducible NO synthase. In LPS-stimulated cells, ONO 3403 prevented the augmentation of MyD88 expression and inhibited the phosphorylation of IκB-α, stress-activated protein kinase (SAPK) and IRF-3, and the production of interferon-β. ONO 3403 abolished the elevation of the extracellular serine protease activity in response to LPS. Further, it reduced the circulating TNF-α level, hepatic injury and mortality in mice receiving an injection of D-galactosamine and LPS. ONO 3403 was suggested to inhibit LPS-induced inflammatory responses via inactivation of MyD88-dependent and independent pathways.
Innate Immunity 12/2009; 17(1):97-105. · 4.00 Impact Factor
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ABSTRACT: Astrocyte elevated gene-1 (AEG-1) is induced by human immunodeficiency virus 1 (HIV-1) infection and involved in tumour progression, migration and invasion as a nuclear factor-kappaB (NF-kappaB) -dependent gene. The involvement of AEG-1 on lipopolysaccharide (LPS) -induced proinflammatory cytokine production was examined. AEG-1 was induced via NF-kappaB activation in LPS-stimulated U937 human promonocytic cells. AEG-1 induced by LPS subsequently regulated NF-kappaB activation. The prevention of AEG-1 expression inhibited LPS-induced tumour necrosis factor-alpha and prostaglandin E(2) production. The AEG-1 activation was not induced by toll-like receptor ligands other than LPS. Therefore, AEG-1 was suggested to be a LPS-responsive gene and involved in LPS-induced inflammatory response.
Immunology 09/2009; 128(1 Suppl):e700-6. · 3.32 Impact Factor
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ABSTRACT: The inhibitory effect of interleukin-10 (IL-10), an anti-inflammatory cytokine, on lipopolysaccharide (LPS)-induced IL-6 production was characterized by simultaneous stimulation of RAW 264.7 cells with LPS and IL-10. The presence of IL-10 significantly inhibited LPS-induced IL-6 production at a transcriptional level. The expression of IkappaB-zeta, which promotes IL-6 production, was induced in response to LPS and it was definitely suppressed in the presence of IL-10. Further, IL-10 inhibited LPS-induced NF-kappaB activation. A pharmacological inhibitor of NF-kappaB prevented LPS-induced IkappaB-zeta expression, suggesting that IL-10 might inhibit LPS-induced IkappaB-zeta expression via the inactivation of NF-kappaB. In LPS- and IL-10-stimulated cells, the expression of Bcl-3 that inhibits NF-kappaB activation was significantly augmented. Introduction of Bcl-3 siRNA abolished IL-10-mediated IkappaB-zeta inhibition. In the presence of Bcl-3, siRNA IL-10 failed to inhibit LPS-induced IL-6 production. Therefore, it was suggested that Bcl-3 induced by IL-10 might reduce LPS-induced IkappaB-zeta activity via inactivation of NF-kappaB and that reduced IkappaB-zeta activity failed to promote LPS-induced IL-6 production.
Innate Immunity 09/2009; 15(4):217-24. · 4.00 Impact Factor
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ABSTRACT: Nystatin is known to deplete lipid rafts from mammalian cell membranes. Lipid rafts have been reported to be necessary for lipopolysaccharide signaling. In this study, it was unexpectedly found that lipopolysaccharide-induced nitric oxide production was not inhibited, but rather increased in the presence of a non-cytotoxic concentration of nystatin. Surprisingly, treatment with nystatin induced only NO production and iNOS expression in RAW264.7 cells. At the concentration used, no changes in the expression of GM1 ganglioside, a lipid raft marker on RAW264.7 cells, was seen. From studies using several kinds of inhibitors for signaling molecules, nystatin-induced NO production seems to occur via the ikappaB/NF-kappaB and the PI3 K/Akt pathway. Furthermore, because nystatin is known to activate the Na-K pump, we examined whether the Na-K pump inhibitor amiloride suppresses nystatin-induced NO production. It was found that amiloride significantly inhibited nystatin-induced NO production. The results suggest that a moderate concentration of nystatin induces NO production by Na-pump activation through the PI3 kinase/Akt/NF-kappaB pathway without affecting the condition of lipid rafts.
Microbiology and Immunology 06/2009; 53(5):295-300. · 1.30 Impact Factor
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ABSTRACT: The effect of thalidomide on lipopolysaccharide-induced nitric oxide (NO) production was studied using RAW 264.7 macrophage-like cells. Thalidomide significantly inhibited lipopolysaccharide-induced NO production via reduced expression of an inducible NO synthase. Thalidomide reduced the phosphorylation of the p65 nuclear factor-kappaB subunit, inhibitory kappaB (IkappaB) and IkappaB kinase in lipopolysaccharide-stimulated cells. However, thalidomide did not affect the expression of interferon-beta (IFN-beta) and interferon regulatory factor-1 in response to lipopolysaccharide. Further, thalidomide inhibited the MyD88 augmentation in lipopolysaccharide-stimulated cells, whereas it did not alter the expression of TIR domain-containing adaptor-inducing IFN-beta in the MyD88-independent pathway. Thalidomide significantly inhibited the NO production in response to Pam(3)Cys, CpG DNA and imiquimod as MyD88-dependent Toll-like receptor (TLR) ligands, but not polyI:C as a MyD88-independent TLR ligand. Therefore, thalidomide was suggested to inhibit lipopolysaccharide-induced NO production via downregulation of the MyD88-dependent signal pathway. The anti-inflammatory action of thalidomide might be involved in the prevention of lipopolysaccharide-mediated lethality in mice.
FEMS Immunology & Medical Microbiology 06/2009; 56(3):204-11. · 2.44 Impact Factor
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Gantsetseg Tumurkhuu,
Naoki Koide,
Jargalsaikhan Dagvadorj,
Abu Shadat Mohammod Noman,
Imtiaz Iftekar-E-Khuda,
Yoshikazu Naiki,
Takayuki Komatsu,
Tomoaki Yoshida,
Masataka Oda,
Masahiro Nagahama,
Jun Sakurai,
Takashi Yokochi
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ABSTRACT: The effect of Clostridium perfringens alpha-toxin on production of tumor necrosis factor (TNF)-alpha and nitric oxide (NO) in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells was studied. The pretreatment of wild type alpha-toxin, but not the inactive mutant, significantly decreased LPS-induced TNF-alpha and NO production. alpha-Toxin inhibited the expression of TNF-alpha and an inducible type of NO synthase protein and mRNA. Furthermore, it inhibited the phosphorylation of IkappaB-alpha and p65 NF-kappaB subunit, and the NF-kappaB luciferase reporter gene activity in LPS-stimulated cells. The pretreatment of alpha-toxin increased the level of intracellular ceramide. Taken together, Clostridium perfringens alpha-toxin pretreatment was suggested to inhibit LPS-induced TNF-alpha and NO production through the inhibition of NF-kappaB activation. The relationship between alpha-toxin-induced intracellular ceramide generation and the NF-kappaB inhibition is discussed.
International journal of medical microbiology: IJMM 06/2009; 299(8):554-62. · 2.80 Impact Factor
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ABSTRACT: The effect of thalidomide on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha production was studied by using RAW 264.7 murine macrophage-like cells. Thalidomide significantly inhibited LPS-induced TNF-alpha production. Thalidomide prevented the activation of nuclear factor (NF)-KB by down-regulating phosphorylation of inhibitory KB factor (IKB), and IKB kinase (IKK)-alpha and IKK-beta Moreover, thalidomide inhibited LPS-induced phosphorylation of AKT, p38 and stress-activated protein kinase (SAPK)/JNK. The expression of myeloid differentiation factor 88 (MyD88) protein and mRNA was markedly reduced in thalidomide-treated RAW 264.7 cells but there was no significant alteration in the expression of interleukin-1 receptor-associated kinase (IRAK) 1 and TNF receptor-associated factor (TRAF) 6 in the cells. Thalidomide did not affect the cell surface expression of Toll-like receptor (TLR) 4 and CD14, suggesting the impairment of intracellular LPS signalling in thalidomide-treated RAW 264.7 cells. Thalidomide significantly inhibited the TNF-alpha production in response to palmitoyl-Cys(RS)-2,3-di(palmitoyloxy) propyl)-Ala-Gly-OH (Pam(3)Cys) as a MyD88-dependent TLR2 ligand. Therefore, it is suggested that thalidomide might impair LPS signalling via down-regulation of MyD88 protein and mRNA and inhibit LPS-induced TNF-alpha production. The putative mechanism of thalidomide-induced MyD88 down-regulation is discussed.
Innate Immunity 03/2009; 15(1):33-41. · 4.00 Impact Factor
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ABSTRACT: The effect of toll-like receptor (TLR) 7 ligand pretreatment on the production of tumor necrosis factor (TNF)-alpha in response to TLR7 or TLR2 ligand was examined in order to establish a new TLR-mediated tolerance. RAW 264.7 macrophage-like cells were treated with imiquimod R837 as a TLR7 ligand for 18h, washed and incubated in fresh culture medium 6h. The second challenge with imiquimod R837 as a TLR7 ligand or Pam3CysSK4 as a TLR2 ligand resulted in reduced TNF-alpha production in TLR7 ligand-pretreated cells. There was impaired activation of NF-kappaB, p38 and stress-activated protein kinase (SAPK) in the tolerant cells. The expression of IRAK-M as a negative regulator of TLR signaling was markedly augmented in the tolerant cells while the interleukin-1 receptor-associated kinase (IRAK)-1 functioned normally. The involvement of IRAK-M in the TLR7-mediated tolerance is discussed.
Cellular Immunology 03/2009; 256(1-2):99-103. · 1.97 Impact Factor
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ABSTRACT: Astrocyte elevated gene-1 (AEG-1) is induced by human immunodeficiency virus 1 (HIV-1) infection and involved in tumour progression, migration and invasion as a nuclear factor-κB (NF-κB) -dependent gene. The involvement of AEG-1 on lipopolysaccharide (LPS) -induced proinflammatory cytokine production was examined. AEG-1 was induced via NF-κB activation in LPS-stimulated U937 human promonocytic cells. AEG-1 induced by LPS subsequently regulated NF-κB activation. The prevention of AEG-1 expression inhibited LPS-induced tumour necrosis factor-α and prostaglandin E2 production. The AEG-1 activation was not induced by toll-like receptor ligands other than LPS. Therefore, AEG-1 was suggested to be a LPS-responsive gene and involved in LPS-induced inflammatory response.
Immunology 02/2009; 128(1pt2):e700 - e706. · 3.32 Impact Factor
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ABSTRACT: RAW 264.7 macrophage cells differentiate into osteoclast-like cells in the presence of RANKL. Participation of M-CSF in RANKL-induced osteoclast formation of RAW 264.7 cells was examined. TRAP-positive osteoclast-like cells appeared in RAW 264.7 cells cultured in the presence of RANKL. RANKL-induced osteoclast formation was markedly inhibited by anti-M-CSF antibody. RANKL augmented M-CSF mRNA expression and M-CSF production in RAW 264.7 cells. Further, anti-M-CSF antibody inhibited the expression of RANK, c-fms, c-fos and TRAP mRNA in RANKL-stimulated RAW 264.7 cells. However, anti-M-CSF antibody did not affect the expression of DC-STAMP in the stimulated cells. Therefore, RANKL was suggested to induce osteoclast formation in RAW 264.7 cells via augmented production of M-CSF. The putative role of M-CSF in RANKL-induced osteoclast formation of RAW 264.7 cells is discussed.
Microbiology and Immunology 01/2009; 52(12):585-90. · 1.30 Impact Factor
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ABSTRACT: The susceptibility of NC/Nga mice to tumor necrosis factor (TNF)-alpha was examined by using sensitization with d-galactosamine (d-GalN). Administration of TNF-alpha and d-GalN killed none of the NC/Nga mice, whereas it killed all of the BALB/c mice. Treatment with TNF-alpha and d-GalN caused few hepatic lesions in NC/Nga mice but massive hepatocellular apoptosis in BALB/c mice. Unlike BALB/c mice, there was no elevation in caspase 3 and 8 activities in the livers of NC/Nga mice receiving TNF-alpha and d-GalN. On the other hand, administration of anti-Fas antibody definitely killed both NC/Nga and BALB/c mice via activation of caspases 3 and 8. Treatment with TNF-alpha and d-GalN led to translocation of nuclear factor (NF)-kappaB in NC/Nga and BALB/c mice. However, NF-kappaB translocation was sustained in NC/Nga mice, although it disappeared in BALB/c mice 7 h after the treatment. NF-kappaB inhibitors activated caspases 3 and 8, and enhanced TNF-alpha-mediated lethality in NC/Nga. Taken together, the low susceptibility of NC/Nga mice to TNF-alpha-mediated lethality was suggested to be responsible for the sustained NF-kappaB activation.
Clinical Immunology 11/2008; 130(2):225-32. · 4.05 Impact Factor
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ABSTRACT: The effect of thalidomide on epidermal growth factor (EGF)-induced cell growth was examined. Thalidomide inhibited EGF-induced cell growth in mouse and human monocytic leukemia cells, RAW 264.7, U937 and THP-1. Thalidomide inhibited EGF-induced phosphorylation of extracellular signal regulated kinase (ERK) 1/2, but not p38 and stress-activated protein kinase (SAPK)/JNK. The phosphorylation of MEK1/2 and Raf at Ser 338 as the upstream molecules of ERK 1/2 was also prevented by thalidomide. Further, it inhibited EGF-induced Ras activation through preventing the transition to GTP-bound active Ras. Thalidomide inhibited the Ras activation induced by lipopolysaccharide (LPS) and vascular endothelial growth factor (VEGF) as well as EGF. There was no significant difference in the expression and function of EGF receptor between thalidomide-treated and non-treated cells. Therefore, thalidomide was suggested to inhibit EGF-induced cell growth via inactivation of Ras.
Biochemical and Biophysical Research Communications 11/2008; 374(4):683-7. · 2.48 Impact Factor
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ABSTRACT: The effect of hydrogen peroxide (H(2)O(2)) on production of tumor necrosis factor (TNF)-alpha was examined in RAW 264.7 murine macrophage cells. H(2)O( 2) led to production of TNF-alpha up to 24 h after the treatment, but not nitric oxide in RAW 264.7 cells. H(2)O(2) induced TNF-alpha production in mouse peritoneal macrophages as well as RAW 264.7 cells. The H(2)O(2)induced TNF-alpha production was prevented by inhibitors of p38 and stress-activated protein kinase (SAPK/JNK), and H(2)O( 2) induced the phosphorylation of p38 and SAPK. Further, H(2)O( 2) significantly augmented the AP-1 activity, but not nuclear factor (NF)-kappaB activity in RAW 264.7 cells. A high level of intracellular reactive oxygen radicals (ROS) was detected in H(2)O(2)-exposed RAW 264.7 cells. Ebselen, a cell permeable antioxidant, prevented the H( 2)O(2)-induced TNFalpha production. H(2)O(2) significantly enhanced lipopolysaccharide (LPS)-induced TNF-alpha production. Therefore, H( 2) O(2) was suggested to induce TNF-alpha production in macrophages via activating p38 and SAPK/JNK as oxidative stress-related signal pathways.
Innate Immunity 07/2008; 14(3):190-6. · 4.00 Impact Factor
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ABSTRACT: The mechanism of interleukin (IL)-10-mediated inhibition of tumor necrosis factor (TNF)-alpha production was studied by lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells. IL-10 inhibited TNF-alpha production transiently at an early stage after LPS stimulation. IL-10 inhibited the activation of nuclear factor (NF)-kappaB, p38 and stress-activated protein kinase (SAPK) in LPS-stimulated RAW 264.7 cells. Although the level of MyD88 protein increased in response to LPS, IL-10 prevented the LPS-induced MyD88 augmentation. There was no significant difference in the MyD88 mRNA expression between the cells pretreated with or without IL-10 in response to LPS. Therefore, IL-10 was suggested to inhibit LPS-induced TNF-alpha production via reduced MyD88 expression.
Innate Immunity 05/2008; 14(2):109-15. · 4.00 Impact Factor
