The lethal effects of transplantation of<i>Socs1</i><sup>-/-</sup>bone marrow cells into irradiated adult syngeneic recipients

Metcalf, Donald; Mifsud, Sandra; Rago, Ladina Di; Alexander, Warren S.

doi:10.1073/pnas.1032925100

Cited by 14 publications

(8 citation statements)

References 24 publications

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“…SOCS1 functions as a negative regulator of signaling by various cytokines, such as IFN-γ, IL-2, IL-6, IL-7, IL-12, and IL-15, by inhibiting the Janus kinases (JAKs)/STAT in T cells and other immune cells (5, 6). Metcalf D. et al (7) reported that adoptive transfer of bone marrow (BM) cells of neonatal SOCS1-deficient ( −/− ) mice into irradiated syngeneic mice caused a pathology characteristic of graft-versus-host disease with chronic inflammatory lesions in multiple organs of the recipients, in agreement with earlier findings (6). Hanada T. et al further demonstrated that SOCS1 −/− transgenic mice in which SOCS1 expression had been restored in T and B cells on a SOCS1 −/− background developed only mild autoimmune diseases and that SOCS1 −/− DCs were hyper-responsive to LPS and IFN-γ and triggered allogeneic T cell expansion (8).…”

Section: Introductionsupporting

confidence: 77%

Human Suppressor of Cytokine Signaling 1 Controls Immunostimulatory Activity of Monocyte-Derived Dendritic Cells

Hong

Ren²,

Song³

et al. 2009

Cancer Research

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Dendritic cell (DC)-based tumor vaccines have only achieved limited clinical efficacy, underscoring the limitation of stimulatory strategies to elicit effective cytotoxic T lymphocyte (CTL) responses against self-tumor-associated antigens. Here, we investigate the role of human suppressor of cytokine signaling 1 (SOCS1), a feedback inhibitor of the Janusactivated kinase/signal transducer and activator of transcription signaling pathway, in regulating antigen presentation by human DCs (hDC). We find that human SOCS1 (hSOCS1)-silenced DCs have an enhanced stimulatory ability to prime self-antigen-specific CTLs in vitro and in a severe combined immunodeficient-hu mouse model. Human CTLs activated by SOCS1-silenced DCs, but not wild-type DCs, have an active lytic activity to natural antigen-expressing tumor cells. We further find that the capacity of hDCs to prime CTLs is likely controlled by SOCS1-restricted production and signaling of proinflammatory cytokines, such as interleukin-12. These results indicate a critical role of hSOCS1 in negatively regulating the immunostimulatory capacity of DCs and imply a translational potential of this alternative SOCS1 silencing strategy to develop effective DC vaccines. [Cancer Res 2009;69(20):8076-84]

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Section: Introductionsupporting

confidence: 77%

Human Suppressor of Cytokine Signaling 1 Controls Immunostimulatory Activity of Monocyte-Derived Dendritic Cells

Hong

Ren²,

Song³

et al. 2009

Cancer Research

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“…However, unlike GMRβc, SOCS-1 did not negatively regulate the expression level of EPOR. This is consistent with previous findings showing that JAK2-mediated degradation of EPOR is dependent on another E3 ligase containing the F-box protein β-TrCP [21],[22] and that progenitor cells from SOCS-1 −/− mice are hypersensitive towards GM-CSF but not to other cytokines such as M-CSF or G-CSF [23], [24]. It is at present unclear why the recruitment of SOCS-1 to certain activated cytokine receptors leads to the degradation of only JAK2 via SOCS-1 while the receptor itself is targeted by another E3 ubiquitin ligase, such as in the case for the EPOR, whereas SOCS-1 recruitment to activated GMR results in the degradation of both JAK2 and GMRβc via SOCS-1.…”

Section: Discussionsupporting

confidence: 93%

SOCS-1 Mediates Ubiquitylation and Degradation of GM-CSF Receptor

et al. 2013

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) and the related cytokines interleukin (IL)-3 and IL-5 regulate the production and functional activation of hematopoietic cells. GM-CSF acts on monocytes/macrophages and granulocytes, and several chronic inflammatory diseases and a number of haematological malignancies such as Juvenile myelomonocytic leukaemia (JMML) are associated with deregulated GM-CSF receptor (GMR) signaling. The downregulation of GMR downstream signaling is mediated in part by the clearance of activated GMR via the proteasome, which is dependent on the ubiquitylation of βc signaling subunit of GMR via an unknown E3 ubiquitin ligase. Here, we show that suppressor of cytokine signaling 1 (SOCS-1), best known for its ability to promote ubiquitin-mediated degradation of the non-receptor tyrosine kinase Janus kinase 2 (JAK2), also targets GMRβc for ubiquitin-mediated degradation and attenuates GM-CSF-induced downstream signaling.

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“…Despite the prominent role of SOCS-1 for IFN-␥ signaling it has also been shown that hematopoetic progenitor cells of SOCS-1 knockout mice have an increased sensitivity to GM-CSF but not to M-CSF. 18,19 It is noteworthy that the CSF-1 receptor belongs to the receptor-tyrosine kinase family, which in general is not a reported target of SOCS proteins. This could explain why TLR stimulation results in inhibition of GM-CSFmediated DC formation but has no effects on the generation of a more macrophage-like phenotype, which possibly is due to effects of intrinsic CSF as a kind of default pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, SOCS-1 knockout mice, in spite of a lethal phenotype due to hypersensitivity 16,17 toward IFN-␥, also exhibit hyperresponsiveness to GM-CSF. 18,19 We and others have shown that TLR stimulation in innate immune cells results in the induction of various SOCS members, thereby regulating the responsiveness to cytokine stimulation as shown in detail for IFN-␥. [20][21][22] We now tested the hypothesis that by means of induction of SOCS proteins, TLR-dependent signals influence differentiation of DCs from precursor cells.…”

Section: Introductionmentioning

confidence: 98%

Involvement of suppressors of cytokine signaling in toll-like receptor–mediated block of dendritic cell differentiation

Bartz

Avalos

Baetz

et al. 2006

Blood

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IntroductionInnate immunity represents the first line of defense against invading pathogens. Tissue-resident immune cells, including macrophages and dendritic cells (DCs), are the first immune cells to encounter infectious agents. Recognition of infecting pathogens within these cells is performed by now well-known pattern recognition receptors responding to conserved microbial structures. 1 Among these receptors, toll-like receptors (TLRs) have been identified as playing a pivotal role and indeed, both macrophages and dendritic cells express TLRs. [2][3][4] In macrophages, TLR stimulation activates the antimicrobial weaponry, including increased phagocytosis 5 ; in dendritic cells, migration into lymph nodes, antigen presentation, cytokine secretion, and subsequent activation of adaptive immunity 6 are enhanced. Interestingly, both of these primary pathogen-encountering cells can develop from monocytes, which thus serve as common progenitors. Differentiation is regulated by cytokines from the environment and immune cells among which macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophagecolony-stimulating factor (GM-CSF) are of ultimate importance.Although it is well accepted that TLR stimulation activates macrophages and dendritic cells, there is only limited information as to a role of TLRs during differentiation processes. Thus, it is largely unknown whether TLR stimulation affects the replenishment of tissue-resident macrophages and dendritic cells from monocytes. This question is of significance as it might suggest a role for infectious stimuli to influence and guide the cellular composition of inflammatory responses.It has been reported that migration of dendritic cells from local tissue to lymph nodes can be inhibited by intradermal administration of either whole Salmonella typhimurium or simply by LPS in a TLR-4-dependent manner. 7 Another study showed that administration of LPS during the early stage of differentiation of human monocytes to DCs diminished the generation of CD1a ϩ DCs. 8 This was confirmed by another group demonstrating that this blocking effect of LPS depends on activation of mitogen-activated protein kinase p38. 9 However, the exact mechanisms of these inhibitory effects still remain to be identified. Secreted cytokines such as IL-10 9 have been suggested but seem to play only a minor role. 7 Myeloid dendritic cell differentiation depends on the activity of GM-CSF, a cytokine that signals through Janus kinases (JAKs) and signal transducers and activators of transcription (STATs), especially JAK2 and STAT5. 10 Suppressor of cytokine signaling proteins (SOCS) have been identified as intracellular feedback inhibitors of JAK/STAT signaling. 11-13 Furthermore, SOCS-1 has been shown to negatively regulate JAK2 and GM-CSF signaling by inhibiting phosphorylation 14 as well as proteasomal targeting 15 of JAK2. Accordingly, SOCS-1 knockout mice, in spite of a lethal phenotype due to hypersensitivity 16,17 toward IFN-␥, also exhibit hyperresponsiveness to GM-CSF. 18,19 We and othe...

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The lethal effects of transplantation ofSocs1^-/-bone marrow cells into irradiated adult syngeneic recipients

Cited by 14 publications

References 24 publications

Human Suppressor of Cytokine Signaling 1 Controls Immunostimulatory Activity of Monocyte-Derived Dendritic Cells

Human Suppressor of Cytokine Signaling 1 Controls Immunostimulatory Activity of Monocyte-Derived Dendritic Cells

SOCS-1 Mediates Ubiquitylation and Degradation of GM-CSF Receptor

Involvement of suppressors of cytokine signaling in toll-like receptor–mediated block of dendritic cell differentiation

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The lethal effects of transplantation ofSocs1-/-bone marrow cells into irradiated adult syngeneic recipients

Cited by 14 publications

References 24 publications

Human Suppressor of Cytokine Signaling 1 Controls Immunostimulatory Activity of Monocyte-Derived Dendritic Cells

Human Suppressor of Cytokine Signaling 1 Controls Immunostimulatory Activity of Monocyte-Derived Dendritic Cells

SOCS-1 Mediates Ubiquitylation and Degradation of GM-CSF Receptor

Involvement of suppressors of cytokine signaling in toll-like receptor–mediated block of dendritic cell differentiation

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The lethal effects of transplantation ofSocs1^-/-bone marrow cells into irradiated adult syngeneic recipients