Tomoko Yoshioka

Kyushu University, Fukuoka-shi, Fukuoka-ken, Japan

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Publications (4)23.13 Total impact

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    ABSTRACT: TNF receptor superfamily members, such as CD40 and the Toll-like receptors (TLRs), regulate many aspects of B cell differentiation and activation. TRAF6 is an intracellular signaling adaptor molecule for these receptors, but its role in B cells has not been clarified by previous genetic approaches, as the systemic deletion of the TRAF6 gene results in perinatal lethality. Here we show that B cell-specific TRAF6 deficiency results in a reduced number of mature B cells in the bone marrow and spleen. Optimal T cell-dependent (TD) antigen responses, as characterized by isotype switching and long-lived plasma cell generation, are also impaired in B cell-specific TRAF6-deficient mice. B cell-specific TRAF6-deficient mice also exhibit lower levels of serum IgM and IgG2b and defective antigen-specific IgM production in response to T cell-independent (TI) antigens. Unexpectedly, TRAF6-deficient B cell progenitors are unable to generate CD5+ B-1 cells. These results reveal critical roles for TRAF6 in TD and TI humoral immune responses and in inductive fate decisions necessary to generate the B-1 B cell compartment.
    PLoS ONE 03/2009; 4(3). DOI:10.1371/journal.pone.0004736 · 3.23 Impact Factor
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    ABSTRACT: Type I interferons (IFN-alpha/beta) are essential for immune defense against viruses and induced through the actions of the cytoplasmic helicases, RIG-I and MDA5, and their downstream adaptor molecule IPS-1. TRAF6 and the downstream kinase TAK1 have been shown to be essential for the production of proinflammatory cytokines through the TLR/MyD88/TRIF pathway. Although binding of TRAF6 with IPS-1 has been demonstrated, the role of the TRAF6 pathway in IFN-alpha/beta production has not been fully understood. Here, we demonstrate that TRAF6 is critical for IFN-alpha/beta induction in response to viral infection and intracellular double-stranded RNA, poly(I:C). Activation of NF-kappaB, JNK, and p38, but not IRF3, was impaired in TRAF6-deficient mouse embryo fibroblasts in response to vesicular stomatitis virus and poly(I:C). However, TAK1 was not required for IFN-beta induction in this process, since normal IFN-alpha/beta production was observed in TAK1-deficient mouse embryo fibroblasts. Instead, another MAP3K, MEKK1, was important for the activation of the IFN-beta promoter in response to poly(I:C). Forced expression of MEKK1 in combination with IRF3 was sufficient for the induction of IFN-beta, whereas suppression of MEKK1 expression by small interfering RNA inhibited the induction of IFN-beta by poly(I:C). These data suggest that IPS-1 requires TRAF6 and MEKK1 to activate NF-kappaB and mitogen-activated protein kinases that are critical for the optimal induction of type I interferons.
    Journal of Biological Chemistry 12/2008; 283(52):36211-20. DOI:10.1074/jbc.M806576200 · 4.57 Impact Factor
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    ABSTRACT: Inflammation associates with insulin resistance, which dysregulates nutrient homeostasis and leads to diabetes. The suppressor of cytokine signaling 3 (SOCS3), which is induced by pro-inflammatory cytokines, such as TNFalpha and IL-6, has been implicated in inflammation-mediated insulin resistance in the liver and adipocytes. However, no genetic evidence has been provided for the involvement of SOCS3 on insulin resistance. Here, we generated hepatocyte-specific SOCS3-deficient (L-SOCS3 cKO) mice and examined insulin sensitivity. Being consistent with a previous idea, the loss of SOCS3 in the liver apparently improved insulin sensitivity. However, unexpectedly, L-SOCS3 cKO mice exhibited obesity and systemic insulin resistance with age. Insulin signaling was rather suppressed in muscles, suggesting that deletion of the SOCS3 gene in the liver modulates insulin sensitivity in other organs. Anti-inflammatory reagent, sodium salicylate, partial improved insulin resistance of aged L-SOCS3 cKO mice, suggesting that enhanced inflammatory status is associated with the phenotype of these mice. STAT3 was hyperactivated and acute-phase proteins were elevated in L-SOCS3 cKO mice liver, which were reduced by sodium salicylate treatment. We conclude that hepatic SOCS3 is a mediator of insulin resistance in the liver; however, lack of SOCS3 in the liver promotes systemic insulin resistance by mimicking chronic inflammation.
    Genes to Cells 03/2007; 12(2):143-54. DOI:10.1111/j.1365-2443.2007.01044.x · 2.81 Impact Factor
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    ABSTRACT: Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-kappaB pathway was shown to play an essential role in promoting inflammation-associated cancer, but the role of the JAK/STAT pathway, another important signaling pathway of proinflammatory cytokines, remains to be investigated. Suppressor of cytokine signaling-1 (SOCS1) acts as an important physiological regulator of cytokine responses, and silencing of the SOCS1 gene by DNA methylation has been found in several human cancers. Here, we demonstrated that SOCS1-deficient mice (SOCS1-/- Tg mice), in which SOCS1 expression was restored in T and B cells on a SOCS1-/- background, spontaneously developed colorectal carcinomas carrying nuclear beta-catenin accumulation and p53 mutations at 6 months of age. However, interferon (IFN)gamma-/- SOCS1-/- mice and SOCS1-/- Tg mice treated with anti-IFNgamma antibody did not develop such tumors. STAT3 and NF-kappaB activation was evident in SOCS1-/- Tg mice, but these were not sufficient for tumor development because these are also activated in IFNgamma-/- SOCS1-/- mice. However, colons of SOCS1-/- Tg mice, but not IFNgamma-/- SOCS1-/- mice, showed hyperactivation of STAT1, which resulted in the induction of carcinogenesis-related enzymes, cyclooxygenase-2 and inducible nitric oxide synthase. These data strongly suggest that SOCS1 is a unique antioncogene which prevents chronic inflammation-mediated carcinogenesis by regulation of the IFNgamma/STAT1 pathways.
    Journal of Experimental Medicine 07/2006; 203(6):1391-7. DOI:10.1084/jem.20060436 · 12.52 Impact Factor