SOCS1 Is a Critical Inhibitor of Interferon γ Signaling and Prevents the Potentially Fatal Neonatal Actions of this Cytokine

Alexander, Warren S.; Starr, Robyn; Fenner, Jennifer Eve; Scott, Clare L.; Handman, Emanuela; Sprigg, Naomi S.; Corbin, Jason; Cornish, Ann L.; Darwiche, Rima; Owczarek, Catherine M.; Kay, Thomas; Nicola, Nicos A.; Hertzog, Paul J.; Metcalf, Donald; Hilton, Douglas J.

doi:10.1016/s0092-8674(00)80047-1

Cited by 706 publications

(627 citation statements)

References 62 publications

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“…Interestingly, the signaling events that culminate in Stat1 activation and transcription of IFNresponsive genes follow the well established pathway involving the transcription factor IRF3 and the type I IFN receptor but independent of MyD88. The increased IFN signaling in MyD88 Ϫ/Ϫ cells may be explained by reduced expression of the inhibitor of IFN signaling SOCS1 (75). SOCS1 expression is known to be dependent on p38 MAPK (76), which we show in our study to be strongly reduced in GAS-infected MyD88 Ϫ/Ϫ cells.…”

Section: Discussionsupporting

confidence: 50%

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

Gratz

Siller

Schaljo

et al. 2008

Journal of Biological Chemistry

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Bacterial pathogens are recognized by the innate immune system through pattern recognition receptors, such as Toll-like receptors (TLRs). Engagement of TLRs triggers signaling cascades that launch innate immune responses. Activation ofMAPKs and NF-B, elements of the major signaling pathways induced by TLRs, depends in most cases on the adaptor molecule MyD88. In addition, Gram-negative or intracellular bacteria elicit MyD88-independent signaling that results in production of type I interferon (IFN). Here we show that in mouse macrophages, the activation of MyD88-dependent signaling by the extracellular Gram-positive human pathogen group A streptococcus (GAS; Streptococcus pyogenes) does not require TLR2, a receptor implicated in sensing of Gram-positive bacteria, or TLR4 and TLR9. Redundant engagement of either of these TLR molecules was excluded by using TLR2/4/9 triple-deficient macrophages. We further demonstrate that infection of macrophages by GAS causes IRF3 (interferon-regulatory factor 3)-dependent, MyD88-independent production of IFN. Surprisingly, IFN is induced also by GAS lacking slo and sagA, the genes encoding cytolysins that were shown to be required for IFN production in response to other Gram-positive bacteria. Our data indicate that (i) GAS is recognized by a MyD88-dependent receptor other than any of those typically used by bacteria, and (ii) GAS as well as GAS mutants lacking cytolysin genes induce type I IFN production by similar mechanisms as bacteria requiring cytoplasmic escape and the function of cytolysins.Group A streptococcus (GAS 4 ; Streptococcus pyogenes) is an important human Gram-positive pathogen responsible for a wide spectrum of infections, ranging from mild diseases (e.g. tonsillitis) to serious illness (e.g. necrotizing fasciitis, sepsis, or severe poststreptococcal sequelae) (1). The persistence of GAS in the human population and the severity of some GAS diseases are the result of activities of a number of virulence factors that enable the pathogen to escape immune surveillance or, on contrary, induce an overreaction of the immune system (2, 3). Although GAS is generally regarded as an extracellular pathogen, recent findings suggest that GAS can survive (although not multiply) within various host cells, such as neutrophils, macrophages, epithelial cells, and fibroblasts (4 -7). The surviving bacteria may serve as a reservoir for recurrent GAS diseases.Immune responses to bacteria are initiated by recognition of bacterial components called pathogen-associated molecular patterns through host cell-encoded pattern recognition receptors (PRRs) (8, 9). Typically, pathogen-associated molecular patterns are components of the bacterial cell wall (e.g. lipopolysaccharide and lipoteichoic acid), but they may also be derived from the inside of bacteria (e.g. DNA). The primary function of PRRs is to trigger signaling cascades that activate antimicrobial defense programs. The best studied class of PRRs is the Toll-like receptor (TLR) family, which consists of 13 transmembrane glycoprote...

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Section: Discussionsupporting

confidence: 50%

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

Gratz

Siller

Schaljo

et al. 2008

Journal of Biological Chemistry

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“…In the presence of the inhibitor, STAT1 and STAT5 activation by the TEL-PDGFR is abolished. Additionally, Jak inhibitors are involved in repressing Jak activation after cytokine stimulation and are inducibly expressed in normal cells (Alexander et al, 1999;Marine et al, 1999). These genes or proteins could conceivably be introduced into leukemic cells to abrogate Jak-mediated STAT activation.…”

Section: Targeting Stats For Anti-leukemic Therapymentioning

confidence: 99%

STAT signaling in the pathogenesis and treatment of leukemias

2000

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“…As a negative regulator of cytokine signaling, SOCS-1 is a candidate gene for inactivating mutations that will favor the development of hematopoietic malignancies. SOCS-1 de®cient mice die within 3 weeks after birth from a myeloproliferative disorder resulting from unbridled IFN-g and TNF-a signaling Starr et al, 1998;Alexander et al, 1999;Marine et al, 1999b;Morita et al, 2000). Deletion of SOCS-3, the most similar SOCS-family member to SOCS-1, results in polycythemia, a premalignant form of erythroid leukemia (Marine et al, 1999a).…”

Section: Introductionmentioning

confidence: 99%

The tumor suppressor activity of SOCS-1

et al. 2002

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SOCS-1 is an inducible SH2-containing inhibitor of Jak kinases and as such can potently suppress cytokine signaling. SOCS-1 de®cient mice die within the ®rst three weeks of life from a myeloproliferative disorder driven by excessive interferon signaling. We report here that SOCS-1 inhibits proliferation signals induced by a variety of oncogenes active within the hematopoietic system. Ectopic expression of SOCS-1 abolished proliferation mediated by a constitutively active form of the KIT receptor, TEL-JAK2, and v-ABL, and reduced metastasis from BCR-ABL transformed cells. SOCS-1, however, did not interfere with v-SRC or RASV12 mediated cellular transformation. A mutant form of SOCS-1 unable to bind through its SH2 domain to tyrosine phosphorylated proteins could still inhibit KIT, but not TEL-JAK2, indicating multiple mechanisms for SOCS-1-mediated tumor suppression. We show that the steady state levels of TEL-JAK2 and to a greater extent v-ABL are diminished in the presence of SOCS-1. Lastly, we show that SOCS-1 7/7 ®broblasts are more sensitive than wild type ®broblasts to either spontaneous or oncogene-induced transformation. These data suggest that loss-of-function of SOCS-1 may collaborate with a variety of hematopoietic oncogenes to facilitate tumor progression.

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SOCS1 Is a Critical Inhibitor of Interferon γ Signaling and Prevents the Potentially Fatal Neonatal Actions of this Cytokine

Cited by 706 publications

References 62 publications

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

Group A Streptococcus Activates Type I Interferon Production and MyD88-dependent Signaling without Involvement of TLR2, TLR4, and TLR9

STAT signaling in the pathogenesis and treatment of leukemias

The tumor suppressor activity of SOCS-1

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