p38 Mitogen‐activated protein kinase modulates expression of tumor necrosis factor‐related apoptosis‐inducing ligand induced by interferon‐γ in fetal brain astrocytes

Lee, J.; Shin, Jeon Soo; Park, J. Y.; Kwon, Daeho; Choi, Sukjin; Kim, S. J.; Choi, In Hong

doi:10.1002/jnr.10815

Cited by 30 publications

(17 citation statements)

References 32 publications

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“…In contrast, p38 and ERK1/2 MAPK were in part activated also by IFN-␥ or TNF-␣. This has also been demonstrated by others in various cell models (73)(74)(75)(76)(77)(78). These seemingly incongruous effects may be attributable to the kinetics and extent of activation of the MAPK system by guanosine, which overcame the stimulation caused by the two cytokines, when administered to the cultures in combination with IFN-␥ or TNF-␣ (Fig.…”

Section: Discussionsupporting

confidence: 63%

Guanosine Inhibits CD40 Receptor Expression and Function Induced by Cytokines and β Amyloid in Mouse Microglia Cells

D’Alimonte

Flati

D’Auro

et al. 2007

The Journal of Immunology

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Growing evidence implicates CD40, a member of the TNFR superfamily, as contributing to the pathogenesis of many neurodegenerative diseases. Thus, strategies to suppress its expression may be of benefit in those disorders. To this aim, we investigated the effect of guanosine, a purine nucleoside that exerts neurotrophic and neuroprotective effects. CD40 expression and function are increased by exposure of mouse microglia cultures or the N9 microglia cell line to IFN-γ (10 ng/ml) plus TNF-α (50 ng/ml) or β amyloid (Aβ) peptide (Aβ1–42; 500 nM). Culture pretreatment with guanosine (10–300 μM), starting 1 h before cytokine or Aβ addition, dose-dependently inhibited the CD40-induced expression as well as functional CD40 signaling by suppressing IL-6 production promoted by IFN-γ/TNF-α challenge in the presence of CD40 cross-linking. Moreover, guanosine abrogated IFN-γ-induced phosphorylation on Ser727 and translocation of STAT-1α to the nucleus as well as TNF-α-/Aβ-induced IκBα and NF-κB p65/RelA subunit phosphorylation, thus inhibiting NF-κB-induced nuclear translocation. Guanosine effects were mediated by an increased phosphorylation of Akt, a PI3K downstream effector, as well as of ERK1/2 and p38 in the MAPK system, because culture pretreatment with selective ERK1/2, p38 MAPK, and PI3K antagonists (U0126, SB203580, or LY294002, respectively) counteracted guanosine inhibition on IFN-γ/TNF-α-induced CD40 expression and function as well as on STAT-1α or NF-κB nuclear translocation. These findings suggest a role for guanosine as a potential drug in the experimental therapy of neuroinflammatory/neurodegenerative diseases, particularly Alzheimer’s disease.

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Section: Discussionsupporting

confidence: 63%

Guanosine Inhibits CD40 Receptor Expression and Function Induced by Cytokines and β Amyloid in Mouse Microglia Cells

D’Alimonte

Flati

D’Auro

et al. 2007

The Journal of Immunology

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“…Therefore, regardless of the mechanisms by which these 2 FA proteins modulate TLR-dependent p38 MAPK activation and whether these mechanisms are shared with other FA complementation groups, the control of p38 MAPK and MK2 with small molecules has substantial appeal. In light of the capacity of p38 inhibition to suppress IFN␥ and TNF␣ responsiveness, 20,25,54 and because inhibition of MK2 suppresses inducible production of MIP-1␣, TNF␣, and IFN␥, 26,27 p38 MAPK and MK2 play a central role in the FA hematologic phenotype, at least in 2 of the most common FA complementation groups, A and C. Preclinical studies of new-generation p38 MAPK inhibitors are clearly warranted and should be designed in a way that tests their capacity in murine models of FA to safely correct the aberrant hematopoietic phenotype (both cytokine overproduction and hypersensitivity) without enhancing the evolution of neoplastic clones. For personal use only.…”

Section: Discussionmentioning

confidence: 99%

“…Transcription of TNF␣ relies both on phosphorylation (Ser536) 24 and acetylation (Lys310) 25 of p65. Both posttranslational modifications are overrepresented in R848-exposed T-shFC cells, but only BIRB 796 suppressed p65 acetylation and phosphorylation ( Figure 4A) and only dasatinib suppressed c-Jun activation ( Figure 4B).…”

Section: P38 Mapk Inhibition Suppresses Tlrmentioning

confidence: 99%

“…We also determined that both agents functioned to suppress TNF␣ gene expression posttranscriptionally by inhibiting p38 MAPK activation of MAPKAPK2 (MK2). Others have demonstrated that short-term p38 MAPK inhibition enhances the repopulating capacity of Fancc-deficient HSCs, 24 that p38 MAPK modulates responses to IFN␥ in some cell types, 25 and that MK2 controls expression of not only TNF␣, but also IFN␥ and MIP-1␣ production. 26,27 Therefore, preclinical evaluation of p38 MAPK inhibitors is clearly warranted using murine models of FA.…”

Section: Introductionmentioning

confidence: 99%

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p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes

Anur

Yates

Garbati

et al. 2012

Blood

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Fanconi anemia, complementation group C (FANCC)-deficient hematopoietic stem and progenitor cells are hypersensitive to a variety of inhibitory cytokines, one of which, TNF␣, can induce BM failure and clonal evolution in Fancc-deficient mice. FANCC-deficient macrophages are also hypersensitive to TLR activation and produce TNF␣ in an unrestrained fashion. Reasoning that suppression of inhibitory cytokine production might enhance hematopoiesis, we screened small molecules using TLR agonist-stimulated FANCCand Fanconi anemia, complementation IntroductionBM failure is a nearly universal complication of Fanconi anemia (FA), an inherited disease caused by biallelic inactivating mutations of any one of 15 genes. [1][2][3][4] FA gene products collectively facilitate responses to DNA damage, 1 and therefore it is often presumed (notwithstanding a lack of direct evidence supporting the idea) that hematopoietic defects simply reflect attrition of hematopoietic stem cells (HSCs) that have specifically suffered excessive DNA damage. An alternative explanation is that the FA proteins are multifunctional and play a direct role in stem cell maintenance, and therefore, DNA damage in FA HSCs is not necessarily required to suppress their function. [5][6][7][8][9] In normal cells, for example, Fanconi anemia, complementation group C (FANCC) modulates the hematopoietic inhibitory effects of TNF␣, IFN␥, and MIP-1␣, each of which normally function to suppress hematopoiesis. 6,10-12 FANCC influences TNF␣ responsiveness at least in part by modulating the activation state of the IFN-inducible double-stranded RNA activated protein kinase. 13 FANCC also suppresses the activation potential of certain TLR pathways in normal mononuclear phagocytes. 14 Therefore, in hematopoietic tissues, FANCC deficiency results in a TLR-dependent overproduction of TNF␣, one of the cytokines to which the stem-cell pool is uniquely intolerant. 10,[15][16][17][18][19] These abnormalities are important elements in the pathogenesis of BM failure. 6,20 There is also experimental evidence that this TNF␣-inhibitory loop is a selective pressure that enhances the ultimate emergence of TNF-resistant leukemic and preleukemic clones. [21][22][23] Therefore, interdiction of TNF␣-induced BM failure, particularly in ways that might have an additional favorable influence on IFN␥-and MIP-1␣-activated signaling pathways, may improve BM function and reduce the likelihood of clonal evolution by improving the fitness landscape and altering the coefficient of selection. 21 Seeking small molecules with these attributes, in the present study we exploited the TLR-hypersensitive phenotype as a screening tool to identify therapeutic agents that might suppress that pathway in FA cells. Using a TLR8-hypersensitive, FANCCdeficient mononuclear phagocyte cell line that we described previously, 14 we screened 75 small molecules, approximately 50 of which were kinase inhibitors. We identified 2 inhibitors, BIRB 796 and dasatinib, that functioned to suppress the TLR-dependent overproduction...

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“…5E). Activated IFN-g binding receptor in the plasma membrane after binding IFN-g activates JAK2, which phosphorylates the Tyr701 residue of STAT1 and ERK1/2 to phosphorylates the Ser727 residue of STAT1 (Huang et al, 2004;Lee et al, 2003;Song et al, 2002;Zhang et al, 2004). These phosphorylated STAT1 proteins translocate to the nucleus after forming homo-or hetero-dimmer then bind to the response element (TTCCTCTAA) within the BACE1 promoter region to modulate BACE1 gene transcription in astrocytes.…”

Section: Discussionmentioning

confidence: 99%

IFN‐γ‐induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes

Cho

Kim

Jin

et al. 2006

Glia

102

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b-Site APP cleaving enzyme 1 (BACE1) is an essential enzyme for the production of b amyloid. Since we found that injection of interferon-g (IFN-g) into young mouse brains increased BACE1 expression in astrocytes, we investigated molecular mechanisms underlying this process by cloning a putative BACE1 promoter. BACE1 promoter activity was differentially regulated by IFN-g in a region specific manner and down-regulated by an inhibitor of Janus kinase 2 (JAK2). A dominant negative mutant of signal transducer and activator of transcription 1 (STAT1) expression suppressed BACE1 promoter activity, and this was rescued by transfecting wild type STAT1. Electrophoretic mobility shift assay and promoter activity assays indicated that STAT1 binds directly to the putative STAT1 binding sequence of BACE1 promoter. Because IFN-g treatment induced STAT1 phosphorylation, we examined whether the expression of a suppressor of cytokine signaling (SOCS), negative regulator of JAK2, suppresses BACE1 promoter activity. The results show that SOCS1 or SOCS3 expression suppressed BACE1 promoter by blocking phosphorylation of Tyr701 residue in STAT1. Also, because IFN-g treatment specifically potentiated extracellular signal regulated MAP kinase (ERK) 1/2 activation, pretreatment of mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, PD98059, significantly attenuated IFN-g-induced BACE1 promoter activity and protein expression through blocking phosphorylation of Ser727 residue in STAT1, suggesting that ERK1/2 is associated with IFN-g-induced STAT1 signaling cascade. Taken together, our results suggest that IFN-g activates JAK2 and ERK1/2 and then phosphorylated STAT1 binds to the putative STAT1 binding sequences in BACE1 promoter region to modulate BACE1 protein expression in astrocytes. V V C 2006 Wiley-Liss, Inc.

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p38 Mitogen‐activated protein kinase modulates expression of tumor necrosis factor‐related apoptosis‐inducing ligand induced by interferon‐γ in fetal brain astrocytes

Cited by 30 publications

References 32 publications

Guanosine Inhibits CD40 Receptor Expression and Function Induced by Cytokines and β Amyloid in Mouse Microglia Cells

Guanosine Inhibits CD40 Receptor Expression and Function Induced by Cytokines and β Amyloid in Mouse Microglia Cells

p38 MAPK inhibition suppresses the TLR-hypersensitive phenotype in FANCC- and FANCA-deficient mononuclear phagocytes

IFN‐γ‐induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes

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