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Article ; Online: Epigenetic reactivation of tumor suppressor genes with CRISPRa technologies as precision therapy for hepatocellular carcinoma.

Sgro, Agustin / Cursons, Joseph / Waryah, Charlene / Woodward, Eleanor A / Foroutan, Momeneh / Lyu, Ruqian / Yeoh, George C T / Leedman, Peter J / Blancafort, Pilar

Clinical epigenetics

2023 Volume 15, Issue 1, Page(s) 73

Abstract: Background: Epigenetic silencing of tumor suppressor genes (TSGs) is a key feature of oncogenesis in hepatocellular carcinoma (HCC). Liver-targeted delivery of CRISPR-activation (CRISPRa) systems makes it possible to exploit chromatin plasticity, by ... ...

Abstract	Background: Epigenetic silencing of tumor suppressor genes (TSGs) is a key feature of oncogenesis in hepatocellular carcinoma (HCC). Liver-targeted delivery of CRISPR-activation (CRISPRa) systems makes it possible to exploit chromatin plasticity, by reprogramming transcriptional dysregulation. Results: Using The Cancer Genome Atlas HCC data, we identify 12 putative TSGs with negative associations between promoter DNA methylation and transcript abundance, with limited genetic alterations. All HCC samples harbor at least one silenced TSG, suggesting that combining a specific panel of genomic targets could maximize efficacy, and potentially improve outcomes as a personalized treatment strategy for HCC patients. Unlike epigenetic modifying drugs lacking locus selectivity, CRISPRa systems enable potent and precise reactivation of at least 4 TSGs tailored to representative HCC lines. Concerted reactivation of HHIP, MT1M, PZP, and TTC36 in Hep3B cells inhibits multiple facets of HCC pathogenesis, such as cell viability, proliferation, and migration. Conclusions: By combining multiple effector domains, we demonstrate the utility of a CRISPRa toolbox of epigenetic effectors and gRNAs for patient-specific treatment of aggressive HCC.
MeSH term(s)	Humans ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Liver Neoplasms/genetics ; Liver Neoplasms/pathology ; Clustered Regularly Interspaced Short Palindromic Repeats ; DNA Methylation ; Epigenesis, Genetic ; Genes, Tumor Suppressor ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic
Language	English
Publishing date	2023-04-29
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553921-8
ISSN	1868-7083 ; 1868-7075
ISSN (online)	1868-7083
ISSN	1868-7075
DOI	10.1186/s13148-023-01482-0
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer.

Gopal Krishnan, Priya D / Golden, Emily / Woodward, Eleanor A / Pavlos, Nathan J / Blancafort, Pilar

Cancers

2020 Volume 12, Issue 2

Abstract: The Rab GTPase family of proteins are mediators of membrane trafficking, conferring identity to the cell membranes. Recently, Rab and Rab-associated factors have been recognized as major regulators of the intracellular positioning and activity of ... ...

Abstract	The Rab GTPase family of proteins are mediators of membrane trafficking, conferring identity to the cell membranes. Recently, Rab and Rab-associated factors have been recognized as major regulators of the intracellular positioning and activity of signaling pathways regulating cell growth, survival and programmed cell death or apoptosis. Membrane trafficking mediated by Rab proteins is controlled by intracellular localization of Rab proteins, Rab-membrane interactions and GTP-activation processes. Aberrant expression of Rab proteins has been reported in multiple cancers such as lung, brain and breast malignancies. Mutations in Rab-coding genes and/or post-translational modifications in their protein products disrupt the cellular vesicle trafficking network modulating tumorigenic potential, cellular migration and metastatic behavior. Conversely, Rabs also act as tumor suppressive factors inducing apoptosis and inhibiting angiogenesis. Deconstructing the signaling mechanisms modulated by Rab proteins during apoptosis could unveil underlying molecular mechanisms that may be exploited therapeutically to selectively target malignant cells.
Language	English
Publishing date	2020-01-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12020259
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Article ; Online: The anti-inflammatory actions of IL-4 in human monocytes are not mediated by IL-10, RP105 or the kinase activity of RIPK2.

Woodward, Eleanor A / Kolesnik, Tatiana B / Nicholson, Sandra E / Prêle, Cecilia M / Hart, Prue H

Cytokine

2012 Volume 58, Issue 3, Page(s) 415–423

Abstract: The anti-inflammatory actions of IL-4 in activated human monocytes may reflect transcriptional regulation of genes involved in TLR signaling pathways. Tailored gene arrays were conducted to profile the expression of 84 genes central to TLR-mediated ... ...

Abstract	The anti-inflammatory actions of IL-4 in activated human monocytes may reflect transcriptional regulation of genes involved in TLR signaling pathways. Tailored gene arrays were conducted to profile the expression of 84 genes central to TLR-mediated signal transduction in human monocytes treated with the TLR4 ligand, LPS, with or without IL-4. In the first 3h, IL-4 down-regulated mRNA levels of LPS-induced inflammatory cytokines and chemokines, without altering mRNA levels of TLRs, TLR-related signaling molecules or multiple transcription factors. The down-regulation of inflammatory genes by IL-4 was preceded by an early up-regulation of IL-10 mRNA and protein and mRNA for receptor-interacting serine-threonine kinase 2 (RIPK2), the TLR homolog, RP105, and c-Maf, a transcription factor required for IL-10 gene expression. However, IL-4 still suppressed LPS-induced TNFα production in bone-marrow derived macrophages from IL10(-/-) mice, and in the presence of a neutralizing antibody to IL-10 in human monocytes. The up-regulation of RIPK2 and RP105 mRNA by IL-4 occurred independently of IL-10. IL-4 maintained the ability to suppress LPS-induced TNFα and enhance IL-10 production in the presence of RIPK2 kinase inhibitors. Further, IL-4 failed to up-regulate expression of RP105 at the cell surface. In conclusion, the anti-inflammatory actions of IL-4 occur independently of IL-10, RP105, and the kinase activity of RIPK2.
MeSH term(s)	Animals ; Antigens, CD/physiology ; Base Sequence ; DNA Primers ; Flow Cytometry ; Humans ; Inflammation/prevention & control ; Interleukin-10/genetics ; Interleukin-10/physiology ; Interleukin-4/physiology ; Mice ; Monocytes/physiology ; Real-Time Polymerase Chain Reaction ; Receptor-Interacting Protein Serine-Threonine Kinase 2/physiology
Chemical Substances	Antigens, CD ; CD180 protein, human ; DNA Primers ; Interleukin-10 (130068-27-8) ; Interleukin-4 (207137-56-2) ; RIPK2 protein, human (EC 2.7.11.1) ; Receptor-Interacting Protein Serine-Threonine Kinase 2 (EC 2.7.11.1)
Language	English
Publishing date	2012-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1018055-2
ISSN	1096-0023 ; 1043-4666
ISSN (online)	1096-0023
ISSN	1043-4666
DOI	10.1016/j.cyto.2012.03.009
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Article: The anti-inflammatory actions of IL-4 in human monocytes are not mediated by IL-10, RP105 or the kinase activity of RIPK2

Woodward, Eleanor A / Kolesnik, Tatiana B / Nicholson, Sandra E / Prêle, Cecilia M / Hart, Prue H

Cytokine. 2012 June, v. 58, no. 3

2012

Abstract	The anti-inflammatory actions of IL-4 in activated human monocytes may reflect transcriptional regulation of genes involved in TLR signaling pathways. Tailored gene arrays were conducted to profile the expression of 84 genes central to TLR-mediated signal transduction in human monocytes treated with the TLR4 ligand, LPS, with or without IL-4. In the first 3h, IL-4 down-regulated mRNA levels of LPS-induced inflammatory cytokines and chemokines, without altering mRNA levels of TLRs, TLR-related signaling molecules or multiple transcription factors. The down-regulation of inflammatory genes by IL-4 was preceded by an early up-regulation of IL-10 mRNA and protein and mRNA for receptor-interacting serine–threonine kinase 2 (RIPK2), the TLR homolog, RP105, and c-Maf, a transcription factor required for IL-10 gene expression. However, IL-4 still suppressed LPS-induced TNFα production in bone-marrow derived macrophages from IL10⁻/⁻ mice, and in the presence of a neutralizing antibody to IL-10 in human monocytes. The up-regulation of RIPK2 and RP105 mRNA by IL-4 occurred independently of IL-10. IL-4 maintained the ability to suppress LPS-induced TNFα and enhance IL-10 production in the presence of RIPK2 kinase inhibitors. Further, IL-4 failed to up-regulate expression of RP105 at the cell surface. In conclusion, the anti-inflammatory actions of IL-4 occur independently of IL-10, RP105, and the kinase activity of RIPK2.
Keywords	bone marrow ; chemokines ; gene expression ; gene expression regulation ; genes ; humans ; interleukin-10 ; interleukin-4 ; macrophages ; mice ; monocytes ; neutralizing antibodies ; signal transduction ; transcription (genetics) ; transcription factors
Language	English
Dates of publication	2012-06
Size	p. 415-423.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1018055-2
ISSN	1096-0023 ; 1043-4666
ISSN (online)	1096-0023
ISSN	1043-4666
DOI	10.1016/j.cyto.2012.03.009
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Article ; Online: The anti-inflammatory effects of interleukin-4 are not mediated by suppressor of cytokine signalling-1 (SOCS1).

Woodward, Eleanor A / Prêle, Cecilia M / Nicholson, Sandra E / Kolesnik, Tatiana B / Hart, Prue H

Immunology

2010 Volume 131, Issue 1, Page(s) 118–127

Abstract: While it is known that the anti-inflammatory effects of interleukin (IL)-4 require new protein synthesis, the exact mechanisms by which IL-4 suppresses the production of pro-inflammatory cytokines by human monocytes and macrophages is unclear. IL-4 ... ...

Abstract	While it is known that the anti-inflammatory effects of interleukin (IL)-4 require new protein synthesis, the exact mechanisms by which IL-4 suppresses the production of pro-inflammatory cytokines by human monocytes and macrophages is unclear. IL-4 rapidly induced suppressor of cytokine signalling-1 (SOCS1) mRNA and protein, which peaked at 60 min, much earlier than lipopolysaccharide (LPS)-induced SOCS1 mRNA and protein which were consistently maximal 4 hr post-exposure. SOCS1 is a molecule generally considered to be induced for negative feedback of inflammatory processes. We investigated whether the early induction of SOCS1 by IL-4 was responsible for the suppression of LPS-induced tumour necrosis factor (TNF)-alpha production by IL-4. IL-4 suppressed LPS-induced TNF-alpha in freshly isolated monocytes at the level of transcription but acted by a different, possibly translational, mechanism in monocytes cultured overnight in macrophage colony-stimulating factor (M-CSF). Despite different modes of regulation by IL-4, the kinetics and magnitude of induction of SOCS1 mRNA and protein by IL-4 in the two cell types were identical. There was no significant difference in the suppression by IL-4 of LPS-induced TNF-alpha production by bone-marrow derived macrophages from wild-type mice, Ifngamma(-/-) mice and mice lacking SOCS1 (Socs1(-/-)Ifngamma(-/-)). These data suggest that SOCS1 is not involved in the suppression of LPS-induced TNF-alpha production by IL-4.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/metabolism ; Anti-Inflammatory Agents/pharmacology ; Cells, Cultured ; Humans ; Interferon-gamma/pharmacology ; Interleukin-4/metabolism ; Interleukin-4/pharmacology ; Lipopolysaccharides/immunology ; Lipopolysaccharides/pharmacology ; Macrophages/drug effects ; Macrophages/immunology ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Monocytes/drug effects ; Monocytes/immunology ; Monocytes/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Signal Transduction ; Suppressor of Cytokine Signaling 1 Protein ; Suppressor of Cytokine Signaling Proteins/drug effects ; Suppressor of Cytokine Signaling Proteins/genetics ; Suppressor of Cytokine Signaling Proteins/metabolism ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	Anti-Inflammatory Agents ; Lipopolysaccharides ; RNA, Messenger ; SOCS1 protein, human ; Suppressor of Cytokine Signaling 1 Protein ; Suppressor of Cytokine Signaling Proteins ; Tumor Necrosis Factor-alpha ; Interleukin-4 (207137-56-2) ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2010-04-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/j.1365-2567.2010.03281.x
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Article ; Online: The oncogene AAMDC links PI3K-AKT-mTOR signaling with metabolic reprograming in estrogen receptor-positive breast cancer.

Golden, Emily / Rashwan, Rabab / Woodward, Eleanor A / Sgro, Agustin / Wang, Edina / Sorolla, Anabel / Waryah, Charlene / Tie, Wan Jun / Cuyàs, Elisabet / Ratajska, Magdalena / Kardaś, Iwona / Kozlowski, Piotr / Johnstone, Elizabeth K M / See, Heng B / Duffy, Ciara / Parry, Jeremy / Lagerborg, Kim A / Czapiewski, Piotr / Menendez, Javier A /

Gorczyński, Adam / Wasag, Bartosz / Pfleger, Kevin D G / Curtis, Christina / Lee, Bum-Kyu / Kim, Jonghwan / Cursons, Joseph / Pavlos, Nathan J / Biernat, Wojciech / Jain, Mohit / Woo, Andrew J / Redfern, Andrew / Blancafort, Pilar

Nature communications

2021 Volume 12, Issue 1, Page(s) 1920

Abstract: Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the ...

Abstract	Adipogenesis associated Mth938 domain containing (AAMDC) represents an uncharacterized oncogene amplified in aggressive estrogen receptor-positive breast cancers. We uncover that AAMDC regulates the expression of several metabolic enzymes involved in the one-carbon folate and methionine cycles, and lipid metabolism. We show that AAMDC controls PI3K-AKT-mTOR signaling, regulating the translation of ATF4 and MYC and modulating the transcriptional activity of AAMDC-dependent promoters. High AAMDC expression is associated with sensitization to dactolisib and everolimus, and these PI3K-mTOR inhibitors exhibit synergistic interactions with anti-estrogens in IntClust2 models. Ectopic AAMDC expression is sufficient to activate AKT signaling, resulting in estrogen-independent tumor growth. Thus, AAMDC-overexpressing tumors may be sensitive to PI3K-mTORC1 blockers in combination with anti-estrogens. Lastly, we provide evidence that AAMDC can interact with the RabGTPase-activating protein RabGAP1L, and that AAMDC, RabGAP1L, and Rab7a colocalize in endolysosomes. The discovery of the RabGAP1L-AAMDC assembly platform provides insights for the design of selective blockers to target malignancies having the AAMDC amplification.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Everolimus/pharmacology ; Female ; GTPase-Activating Proteins/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Imidazoles/pharmacology ; Nerve Tissue Proteins/metabolism ; Oncogenes/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Protein Binding ; Proto-Oncogene Proteins c-akt/metabolism ; Quinolines/pharmacology ; Receptors, Estrogen/metabolism ; Signal Transduction/drug effects ; TOR Serine-Threonine Kinases/metabolism
Chemical Substances	AAMDC protein, human ; Antineoplastic Agents ; Cell Cycle Proteins ; GTPase-Activating Proteins ; Imidazoles ; Nerve Tissue Proteins ; Quinolines ; RABGAP1L protein, human ; Receptors, Estrogen ; Everolimus (9HW64Q8G6G) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; dactolisib (RUJ6Z9Y0DT)
Language	English
Publishing date	2021-03-26
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-021-22101-7
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Article: The anti-inflammatory effects of interleukin-4 are not mediated by suppressor of cytokine signalling-1 (SOCS1)

Woodward, Eleanor A / Prêle, Cecilia M / Nicholson, Sandra E / Kolesnik, Tatiana B / Hart, Prue H

Immunology. 2010 Sept., v. 131, no. 1

2010

Abstract	While it is known that the anti-inflammatory effects of interleukin (IL)-4 require new protein synthesis, the exact mechanisms by which IL-4 suppresses the production of pro-inflammatory cytokines by human monocytes and macrophages is unclear. IL-4 rapidly induced suppressor of cytokine signalling-1 (SOCS1) mRNA and protein, which peaked at 60 min, much earlier than lipopolysaccharide (LPS)-induced SOCS1 mRNA and protein which were consistently maximal 4 hr post-exposure. SOCS1 is a molecule generally considered to be induced for negative feedback of inflammatory processes. We investigated whether the early induction of SOCS1 by IL-4 was responsible for the suppression of LPS-induced tumour necrosis factor (TNF)-α production by IL-4. IL-4 suppressed LPS-induced TNF-α in freshly isolated monocytes at the level of transcription but acted by a different, possibly translational, mechanism in monocytes cultured overnight in macrophage colony-stimulating factor (M-CSF). Despite different modes of regulation by IL-4, the kinetics and magnitude of induction of SOCS1 mRNA and protein by IL-4 in the two cell types were identical. There was no significant difference in the suppression by IL-4 of LPS-induced TNF-α production by bone-marrow derived macrophages from wild-type mice, Ifnγ⁻/⁻ mice and mice lacking SOCS1 (Socs1⁻/⁻Ifnγ⁻/⁻). These data suggest that SOCS1 is not involved in the suppression of LPS-induced TNF-α production by IL-4.
Keywords	inflammation
Language	English
Dates of publication	2010-09
Size	p. 118-127.
Publisher	Blackwell Publishing Ltd
Publishing place	Oxford, UK
Document type	Article
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/j.1365-2567.2010.03281.x
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Article: The receptor for cis-urocanic acid remains elusive.

Woodward, Eleanor A / Prêle, Cecilia M / Finlay-Jones, John J / Hart, Prue H

The Journal of investigative dermatology

2006 Volume 126, Issue 5, Page(s) 1191–1193

MeSH term(s)	Dinoprostone/biosynthesis ; Humans ; Lipopolysaccharides/pharmacology ; Receptors, Cell Surface/metabolism ; Serotonin/metabolism ; Tumor Necrosis Factor-alpha/biosynthesis ; Ultraviolet Rays ; Urocanic Acid/metabolism ; Urocanic Acid/pharmacology
Chemical Substances	Lipopolysaccharides ; Receptors, Cell Surface ; Tumor Necrosis Factor-alpha ; Serotonin (333DO1RDJY) ; Urocanic Acid (G8D26XJJ3B) ; Dinoprostone (K7Q1JQR04M)
Language	English
Publishing date	2006-05
Publishing country	United States
Document type	Letter
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1038/sj.jid.5700249
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Article ; Online: SOCS1 regulates the IFN but not NFkappaB pathway in TLR-stimulated human monocytes and macrophages.

Prêle, Cecilia M / Woodward, Eleanor A / Bisley, Jacqueline / Keith-Magee, April / Nicholson, Sandra E / Hart, Prue H

Journal of immunology (Baltimore, Md. : 1950)

2008 Volume 181, Issue 11, Page(s) 8018–8026

Abstract: SOCS1 can regulate TLR-mediated signal transduction, yet mechanistic studies in murine macrophages have been confusing and contradictory. This study has used an adenoviral transfection system to determine the role of SOCS1 in the regulation of TNF-alpha ... ...

Abstract	SOCS1 can regulate TLR-mediated signal transduction, yet mechanistic studies in murine macrophages have been confusing and contradictory. This study has used an adenoviral transfection system to determine the role of SOCS1 in the regulation of TNF-alpha production by activated human monocytes. Monocytes were infected with AdV-SOCS1 or with an empty vector control, AdV-GFP, for 24 h before activation with the TLR4 ligand, LPS. SOCS1 did not regulate TNF-alpha mRNA or protein production within the first two hours of TLR4 activation. However, SOCS1 suppressed the sustained production of TNF-alpha by primary human monocytes and synovial fluid macrophages ex vivo. In addition, SOCS1 regulated the production of IL-6, but not IL-10, by monocytes. Analysis of the early signaling pathway downstream of TLR4 demonstrated that SOCS1 had no regulatory effect on the activation or on the DNA binding capacity of NFkappaB. The late effects of LPS are mediated in part through the MyD88-independent pathway activating IRF3 and initiating the production of IFN-beta. In response to adenoviral infection and before LPS exposure, monocytes expressed enhanced levels of IFN-beta and Myxovirus A mRNA, an anti-viral molecule characterizing IFN-beta activity. These two genes were reduced in AdV-SOCS1-infected cells. Further, SOCS1 regulated IFN-dependent pathways in LPS-activated cells as evidenced by reduced IFN-beta production and STAT1 phosphorylation. Using AdV-infection to dissect SOCS1 control of IFN-dependent pathways, this study suggests that SOCS1-regulation of the IFN-dependent component of the LPS-induced TLR4 signaling pathway may contribute to the down-regulation of inflammatory cytokine production by AdV-SOCS1-infected human monocytes.
MeSH term(s)	Adenoviridae ; Animals ; Cell Line ; Humans ; Interferon Regulatory Factor-3/genetics ; Interferon Regulatory Factor-3/immunology ; Interferon Regulatory Factor-3/metabolism ; Interferon-beta/genetics ; Interferon-beta/immunology ; Interferon-beta/metabolism ; Lipopolysaccharides/pharmacology ; Macrophage Activation/drug effects ; Macrophage Activation/genetics ; Macrophage Activation/immunology ; Macrophages/immunology ; Macrophages/metabolism ; Mice ; Monocytes/immunology ; Monocytes/metabolism ; Myeloid Differentiation Factor 88/genetics ; Myeloid Differentiation Factor 88/immunology ; Myeloid Differentiation Factor 88/metabolism ; NF-kappa B/genetics ; NF-kappa B/immunology ; NF-kappa B/metabolism ; Orthomyxoviridae/immunology ; Orthomyxoviridae/metabolism ; RNA, Viral/immunology ; RNA, Viral/metabolism ; STAT1 Transcription Factor/genetics ; STAT1 Transcription Factor/immunology ; STAT1 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Signal Transduction/genetics ; Signal Transduction/immunology ; Suppressor of Cytokine Signaling 1 Protein ; Suppressor of Cytokine Signaling Proteins/genetics ; Suppressor of Cytokine Signaling Proteins/immunology ; Suppressor of Cytokine Signaling Proteins/metabolism ; Synovial Fluid/immunology ; Synovial Fluid/metabolism ; Time Factors ; Toll-Like Receptor 4/genetics ; Toll-Like Receptor 4/immunology ; Toll-Like Receptor 4/metabolism ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/immunology ; Tumor Necrosis Factor-alpha/metabolism
Chemical Substances	IRF3 protein, human ; Interferon Regulatory Factor-3 ; Lipopolysaccharides ; MYD88 protein, human ; Myeloid Differentiation Factor 88 ; NF-kappa B ; RNA, Viral ; SOCS1 protein, human ; STAT1 Transcription Factor ; STAT1 protein, human ; Suppressor of Cytokine Signaling 1 Protein ; Suppressor of Cytokine Signaling Proteins ; TLR4 protein, human ; Toll-Like Receptor 4 ; Tumor Necrosis Factor-alpha ; Interferon-beta (77238-31-4)
Language	English
Publishing date	2008-11-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.181.11.8018
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Article: anti-inflammatory actions of IL-4 in human monocytes are not mediated by IL-10, RP105 or the kinase activity of RIPK2

Woodward, Eleanor A. / Kolesnik, Tatiana B. / Nicholson, Sandra E. / Prêle, Cecilia M. / Hart, Prue H.

Cytokine

Volume v. 58,, Issue no. 3

Abstract	The anti-inflammatory actions of IL-4 in activated human monocytes may reflect transcriptional regulation of genes involved in TLR signaling pathways. Tailored gene arrays were conducted to profile the expression of 84 genes central to TLR-mediated signal transduction in human monocytes treated with the TLR4 ligand, LPS, with or without IL-4. In the first 3h, IL-4 down-regulated mRNA levels of LPS-induced inflammatory cytokines and chemokines, without altering mRNA levels of TLRs, TLR-related signaling molecules or multiple transcription factors. The down-regulation of inflammatory genes by IL-4 was preceded by an early up-regulation of IL-10 mRNA and protein and mRNA for receptor-interacting serine–threonine kinase 2 (RIPK2), the TLR homolog, RP105, and c-Maf, a transcription factor required for IL-10 gene expression. However, IL-4 still suppressed LPS-induced TNFα production in bone-marrow derived macrophages from IL10⁻/⁻ mice, and in the presence of a neutralizing antibody to IL-10 in human monocytes. The up-regulation of RIPK2 and RP105 mRNA by IL-4 occurred independently of IL-10. IL-4 maintained the ability to suppress LPS-induced TNFα and enhance IL-10 production in the presence of RIPK2 kinase inhibitors. Further, IL-4 failed to up-regulate expression of RP105 at the cell surface. In conclusion, the anti-inflammatory actions of IL-4 occur independently of IL-10, RP105, and the kinase activity of RIPK2.
Keywords	neutralizing antibodies ; interleukin-4 ; genes ; transcription factors ; humans ; signal transduction ; transcription (genetics) ; gene expression regulation ; bone marrow ; mice ; interleukin-10 ; gene expression ; chemokines ; macrophages ; monocytes
Language	English
Document type	Article
ISSN	1043-4666
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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