Lyn-Deficient Mice Develop Severe, Persistent Asthma: Lyn Is a Critical Negative Regulator of Th2 Immunity

Beavitt, Sarah-Jane E; Harder, Kenneth W.; Kemp, Joanna; Jones, Juli E.; Quilici, Cathy; Casagranda, Franca; Lam, Ellen; Turner, Debra J.; Brennan, Siobhain; Sly, Peter D.; Tarlinton, David M.; Anderson, Gary P.; Hibbs, Margaret L.

doi:10.4049/jimmunol.175.3.1867

Cited by 74 publications

(79 citation statements)

References 64 publications

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“…Dendritic cells from Lyndeficient mice had decreased phosphorylation of SHIP-1, suggesting that SHIP-1 might participate in regulating dendritic cell (DC) activation in response to allergen. 21 SHIP-1 knockout mice exhibited a general myeloproliferative response that affects several tissues and organs. Some SHIP-1-null mice had a spontaneous inflammatory response in the lung, indicating that SHIP-1 is an important regulator in the lung.…”

Section: Discussionmentioning

confidence: 99%

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung

Zheng

Bailey

et al. 2007

Journal of Allergy and Clinical Immunology

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Background-Src homology 2 domain-containing inositol 5-phosphatase 1 (SHIP-1) controls the intracellular level of the phosphoinositide 3-kinase product phosphotidylinositol-3,4,5-trisphosphate and functions as a negative regulator of cytokine and immune receptor signaling. Emerging evidence suggests that the phosphoinositide 3-kinase pathway might be involved in allergic inflammation in the lung. However, the functional relevance of SHIP-1 in the T H 2 activation pathway has not been established. SHIP-1 −/− mice have spontaneous myeloproliferative inflammation in the lung, the nature of which has not been elucidated. We hypothesized that SHIP-1 plays an important role as a regulator in pulmonary allergic inflammation and in maintaining lung homeostasis.

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Section: Discussionmentioning

confidence: 99%

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung

Zheng

Bailey

et al. 2007

Journal of Allergy and Clinical Immunology

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“…In fact, Fc RI-dependent stimulation of IL-4 production was demonstrated to be defective in Fyn-deficient BMMC but not in Lyn deficiency (23)(24)(25) To determine whether Lyn and/or Fyn might be required for H 2 O 2 -induced IL-4 production, we analyzed IL-4 mRNA up-regulation using BMMC from Lyn Ϫ/Ϫ , Fyn Ϫ/Ϫ , and PI3K Ϫ/Ϫ mice. BMMC from wild type, Lyn-, Fyn-, and PI3K-null mice were treated with 10 nM H 2 O 2 for 3 h and then analyzed together with untreated samples for IL-4 mRNA production.…”

Section: H 2 O 2 -Induced Il-4 Up-regulation Requires Fynmentioning

confidence: 99%

Selective Activation of Fyn/PI3K and p38 MAPK Regulates IL-4 Production in BMMC under Nontoxic Stress Condition

Frossi

Rivera

Hirsch

et al. 2007

The Journal of Immunology

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Mast cells have the ability to react to multiple stimuli, implicating these cells in many immune responses. Specific signals from the microenvironment in which mast cells reside can activate different molecular events that govern distinct mast cells responses. We previously demonstrated that hydrogen peroxide (H2O2) promotes IL-4 and IL-6 mRNA production and potentates FcεRI-induced cytokine release in rat basophilic leukemia RBL-2H3 cells. To further evaluate the effect of an oxidative microenvironment (which is physiologically present in an inflammatory site) on mast cell function and the molecular events responsible for mast cell cytokine production in this environment, we analyzed the effect of H2O2 treatment on IL-4 production in bone marrow-derived, cultured mast cells. Our findings show that nanomolar concentrations of H2O2 induce cytokine secretion and enhance IL-4 production upon FcεRI triggering. Oxidative stimulation activates a distinct signal transduction pathway that induces Fyn/PI3K/Akt activation and the selective phosphorylation of p38 MAP kinase. Moreover, H2O2 induces AP-1 and NFAT complexes that recognize the IL-4 promoter. The absence of Fyn and PI3K or the inhibition of p38 MAPK activity demonstrated that they are essential for H2O2-driven IL-4 production. These findings show that mast cells can respond to an oxidative microenvironment by initiating specific signals capable of eliciting a selective response. The findings also demonstrate the dominance of the Fyn/p38 MAPK pathway in driving IL-4 production.

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“…As well as its role in B cells, Lyn also negatively regulates the differentiation of cultured DC in vitro [36,37]; and DC maturation and cytokine production is also stimulated by TLR signaling [38]. Therefore, we examined the DC populations of lyn -/-and DKO mice in vivo to determine if the lack of autoimmunity in DKO mice was reflected in DC differentiation and maturation.…”

Section: Autoimmune Disease In Lyn-deficient Mice Is Myd88 Dependentmentioning

confidence: 99%

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

et al. 2007

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Recent evidence suggests that systemic autoimmune disease depends on signals from TLR ligands, but little is known about how TLR-dependent pathways lead to the loss of self tolerance in vivo. To address this, we have examined the role of TLR signaling in Lyndeficient mice, which develop an autoimmune disease similar to SLE. We found that absence of the TLR signaling adaptor molecule MyD88 suppresses plasma cell differentiation of switched and unswitched B cells, and prevents the generation of antinuclear IgG antibodies and glomerulonephritis. In mixed chimeras the increased IgM and IgG antibody secretion in Lyn-deficient mice is at least partially due to B cellindependent effects of Lyn. We now show that MyD88 deficiency blocks the expansion and activation of DC in which Lyn is also normally expressed, and prevents the hypersecretion of proinflammatory cytokines IL-6 and IL-12 by Lyn-deficient DC. These findings further highlight the important role of TLR-dependent signals in both lymphocyte activation and autoimmune pathogenesis. IntroductionOur understanding of the pathways leading to autoantibody (autoAb) production in systemic lupus erythematosus (SLE) has been greatly enhanced by studies of murine SLE models, including mice with single targeted mutations to negative regulators of BCR signaling, e.g., the src-family protein tyrosine kinase Lyn [1][2][3], phosphatase SHP-1 [4] and coreceptor CD22 [5, 6]. Lyn deficiency manifests as the hypersecretion of IgM, IgA and IgG autoAb, which, by 17-20 weeks of age, develop specificity to nuclear components such as dsDNA, are deposited as immune complexes (IC) in the kidneys and lead to lethal proliferative glomerulonephritis [1][2][3]. Following BCR stimulation, Lyn-deficient B cells have greater and more prolonged intracellular calcium flux, more MAPK activation and hyperproliferate in comparison to WT B cells [1, 7, 8]. These findings, together with the fact that the expression of Lyn is limited to B, NK and myeloid cells [9], have led to the suggestion that B cell intrinsic effects are the main cause of SLE-like autoimmune disease. Growing support for the central role B cells play in the development of autoimmune disease (reviewed in [10]) and the discovery of lower levels of Lyn in B cells of human SLE patients have helped strengthen this idea [11].However, the development of high-affinity pathogenic autoAb, which are targeted at nuclear antigens and potentially damaging to organs including kidneys, depends on somatic hypermutation in the germinal center and collaboration between cells of the adaptive and innate immune systems. T cells play an important role in this process and autoantigen-specific T cells are required for secretion of IgG autoAb specific for nuclear components and end-organ damage in the spontaneous murine models, MRL-lpr/lpr and (NZBÂNZW)F 1 [18]. Disease in the gp96 transgenic mice is dependent on MyD88, an adaptor molecule required for signaling by all TLR except TLR3, which binds dsRNA, and TLR4, which also signals by a MyD88-independent pa...

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Lyn-Deficient Mice Develop Severe, Persistent Asthma: Lyn Is a Critical Negative Regulator of Th2 Immunity

Cited by 74 publications

References 64 publications

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung

Selective Activation of Fyn/PI3K and p38 MAPK Regulates IL-4 Production in BMMC under Nontoxic Stress Condition

MyD88‐dependent autoimmune disease in Lyn‐deficient mice

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