SOCS-3 regulates onset and maintenance of TH2-mediated allergic responses

Seki, Yasutaka; Inoue, Hiromasa; Nagata, Naoko; Hayashi, Kozaburo; Fukuyama, Satoru; Matsumoto, Koichiro; Komine, Okiru; Hamano, Shinjiro; Himeno, Kunisuke; Inagaki–Ohara, Kyoko; Cacalano, Nicholas A.; O’Garra, Anne; Oshida, Tadahiro; Saito, Hirohisa; Johnston, James A.; Yoshimura, Akihiko; Kubo, Masato

doi:10.1038/nm896

Cited by 325 publications

(370 citation statements)

References 36 publications

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“…After 48 h, the effects of IL-12 were clear and altogether 41 genes became regulated by IL-12 (Table II). Among these were only a few genes, such as SOCS3, CEBPB, and IL-7R that have a previously described role in Th1 and Th2 cell responses (13,19,20). Most of the genes regulated by IL-12 were also regulated by IL-4 and/or activation alone (Fig.…”

Section: The Slow Response To Il-12mentioning

confidence: 85%

Genome-Wide Identification of Novel Genes Involved in Early Th1 and Th2 Cell Differentiation

Lund

Löytömäki

Naumanen

et al. 2007

The Journal of Immunology

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Th cell subtypes, Th1 and Th2, are involved in the pathogenesis or progression of many immune-mediated diseases, such as type 1 diabetes and asthma, respectively. Defining the molecular networks and factors that direct Th1 and Th2 cell differentiation will help to understand the pathogenic mechanisms causing these diseases. Some of the key factors regulating this differentiation have been identified, however, they alone do not explain the process in detail. To identify novel factors directing the early differentiation, we have studied the transcriptomes of human Th1 and Th2 cells after 2, 6, and 48 h of polarization at the genome scale. Based on our current and previous studies, 288 genes or expressed sequence tags, representing ∼1–1.5% of the human genome, are regulated in the process during the first 2 days. These transcriptional profiles revealed genes coding for components of certain pathways, such as RAS oncogene family and G protein-coupled receptor signaling, to be differentially regulated during the early Th1 and Th2 cell differentiation. Importantly, numerous novel genes with unknown functions were identified. By using short-hairpin RNA knockdown, we show that a subset of these genes is regulated by IL-4 through STAT6 signaling. Furthermore, we demonstrate that one of the IL-4 regulated genes, NDFIP2, promotes IFN-γ production by the polarized human Th1 lymphocytes. Among the novel genes identified, there may be many factors that play a crucial role in the regulation of the differentiation process together with the previously known factors and are potential targets for developing therapeutics to modulate Th1 and Th2 responses.

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Section: The Slow Response To Il-12mentioning

confidence: 85%

Genome-Wide Identification of Novel Genes Involved in Early Th1 and Th2 Cell Differentiation

Lund

Löytömäki

Naumanen

et al. 2007

The Journal of Immunology

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“…These proteins were recently demonstrated to be able to inhibit IL-4-induced expression of Eotaxin-3/CCL26 [48], another chemokine. Further, SOCS-1 and SOCS-3 were shown to be inducible by IL-4 [29,38,49], and SOCS-3 appears to be involved in the regulation of allergic responses [50]. The prominent role TARC/CCL17 plays in allergic diseases calls for additional studies to elucidate the negative regulatory mechanisms of its expression.…”

Section: Ccl17 In T Cells and To Characterize The Regulatory Promotermentioning

confidence: 99%

IL‐4 induces expression of TARC/CCL17 via two STAT6 binding sites

et al. 2006

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A cardinal feature of allergic disorders and immune responses is enhanced leukocyte trafficking. This is largely orchestrated by chemokines. The CC chemokine thymus-and activation-regulated chemokine (TARC/CCL17) selectively attracts Th2 cells via the G protein-coupled chemokine receptor CCR4. We show here that TARC/CCL17 is expressed by human T cells upon stimulation with IL-4. Mapping of the transcriptional start site revealed the presence of two putative STAT6 binding motifs in proximity to the start position. EMSA and chromatin immunoprecipitation experiments demonstrated that STAT6 was able to bind to both motifs. A fragment of the TARC/CCL17 promoter containing both sites was tested in reporter gene assays for IL-4 inducibility. The promoter was inducible in a STAT6-deficient cell line only after introduction of functional STAT6. When mutations were inserted into one of the STAT6 motifs, IL-4-induced promoter activation was reduced. With both sites mutated, inducibility was completely abrogated. These data demonstrate collectively that T cells serve as a source of TARC/CCL17 when stimulated with IL-4 and that STAT6 is essential for this. IntroductionChemokines are structurally related 8-12-kDa chemoattractant cytokines that regulate leukocyte trafficking and inflammatory diseases. Depending on the motif displayed by the first or first two of their conserved cysteines, they have been classified into C, CC, CXC or CX3C chemokine subfamilies. Chemokines have been shown to not only regulate hemopoietic cell migration but also to be involved in a number of other physiological and pathological processes [1]. The 8-kDa thymus-and activation-regulated chemokine (TARC/CCL17) was first isolated from phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMC) by Imai et al. in 1996 [2] by means of a signal sequence trap method [3]. The TARC/CCL17 gene is located on chromosome 16q13 in a cluster with MDC/ CCL22 and Fractalkine/CX3CL1 [4]. It encodes a highly basic 94 amino acid residues long preprotein with a cleavage site between Ala23 and Ala24. The mature TARC/CCL17 protein is 71 amino acid residues in length and was shown to be constitutively expressed in thymus [2] and, upon activation with different inducers, in several cell types including PBMC [5], monocytes [6], dendritic cells [7], endothelial cells, and bronchial epithelial cells [8].Leukocytes are activated by chemokines through seven-transmembrane G protein-coupled receptors. Based on the subfamily of chemokines they bind, chemokine receptors are named XCR1, CCR1-9, CXCR1-5 and CX3CR1 [9]. The specific functional high-affinity receptor for TARC/CCL17 is the CC chemokine receptor 4 (CCR4), which has also been shown to serve as receptor for CCL22/MDC (macrophage-derived chemokine). CCR4 is predominantly Interleukin-4 (IL-4), mainly produced by Th2 T cells, mast cells, basophils and eosinophils, appears to be a crucial factor in allergic responses. IL-4 induces differentiation of allergen-specific Th2 cells and class switching towards IgE produc...

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“…Since 1997 [5], numerous studies have identified that SOCS-3 acts as a negative-feedback inhibitor to suppress the cytokine receptor signalling, for example, in myeloid cells, SOCS-3 is a key negative regulator of G-CSF signalling [6]. It negatively regulates IL-2 signalling [7] and IL-2 production via CD28 signalling [8], inhibits IL-6 signalling in macrophages [9e11], and promotes Th2 development by inhibiting IL-12 mediated STAT4 activation in T cells [12]. The knocking down SOCS-3 gene in T helper cells reduced the immune responses, and resulted in the overexpression of IL-10 and transforming growth factor [13].…”

Section: Introductionmentioning

confidence: 99%