IL-4 Signaling, Gene Transcription Regulation, and the Control of Effector T Cells

Department of Pathology, Microbiology and Immunology, Vanderbilt University, Нашвилл, Michigan, United States
Immunologic Research (Impact Factor: 3.1). 02/2001; 23(2-3):179-91. DOI: 10.1385/IR:23:2-3:179
Source: PubMed


The central goal of our laboratory is to understand the regulation of lymphoid cells through molecular mechanisms of signal transduction and transcriptional control. A long-standing focus has been on changes that influence the effector function of mature lymphocytes. Work in the laboratory is oriented toward the identification of new regulatory mechanisms using cell lines and primary cells, and the validation of these in vitro findings in mouse models of immune responses and diseases. In this review, we summarize key insights into the regulation of T helper cell function during the phase of immunity where effector responses arise de novo. Particular interest has been centered on cytokine gene regulation as part of T cell differentiation into the Th1 and Th2 subsets. Information on IL-4 receptor signaling and the role of NF-kappaB transcription factors is reviewed. Our more recent work is designed to understand how regulation at the Th1/2 effector stages is related to the control of memory T cell survival, immune recall responses, and the role of these responses in immune-mediated disease.

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    • "The homozygous genotype IL-1RN*2/2 of the IL-RN gene was strongly associated with early-stage gastric cancer [28]. IL-4R develop allergic reactions, modulate the function of monocytes and macrophages and has been shown over-expressed in a variety of human cancer cells in vitro and in vivo like melanoma, breast, ovarian, renal, and head and neck [29]. NMI interacts with the oncogenes C-myc and N-myc and other transcription factors containing a ZIP, HLH, or HLH-Zip motif first isolated and characterized by Bao and Zervos [30]. "
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    ABSTRACT: Carcinogenesis is a multi-step process indicated by several genes up- or down-regulated during tumor progression. This study examined and identified differentially expressed genes in cutaneous squamous cell carcinoma (SCC). Three different biopsies of 5 immunosuppressed organ-transplanted recipients each normal skin (all were pooled), actinic keratosis (AK) (two were pooled), and invasive SCC and additionally 5 normal skin tissues from immunocompetent patients were analyzed. Thus, total RNA of 15 specimens were used for hybridization with Affymetrix HG-U133A microarray technology containing 22,283 genes. Data analyses were performed by prediction analysis of microarrays using nearest shrunken centroids with the threshold 3.5 and ANOVA analysis was independently performed in order to identify differentially expressed genes (p < 0.05). Verification of 13 up- or down-regulated genes was performed by quantitative real-time reverse transcription (RT)-PCR and genes were additionally confirmed by sequencing. Broad coherent patterns in normal skin vs. AK and SCC were observed for 118 genes. The majority of identified differentially expressed genes in cutaneous SCC were previously not described.
    Full-text · Article · Feb 2006 · Molecular Cancer
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    • "Thus, IKK-a is involved in dermal and skeletal development and cannot be compensated for by IKK-b. Furthermore, it was recently shown that IKK-a plays a role in B-cell maturation and secondary lymphoid organ formation through processing of the NF-kB2 precursor p100 (Senftleben et al., 2001; Muller & Siebenlist, 2003). On the other hand, IKK-b-deficient mice (ikk-b À/À ) die as embryos and show massive liver degeneration due to hepatocyte apoptosis (Li QT et al., 1999; Li ZW et al., 1999; Tanaka et al., 1999). "
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    ABSTRACT: 1 Pulmonary inflammatory diseases such as asthma are characterized by chronic, cell-mediated inflammation of the bronchial mucosa. 2 Recruitment and activation of inflammatory cells is orchestrated by a variety of mediators such as cytokines, chemokines, or adhesion molecules, the expression of which is regulated via the transcription factor nuclear factor kappa B (NF-kappaB). 3 NF-kappaB signaling is controlled by the inhibitor of kappa B kinase complex (IKK), a critical catalytic subunit of which is IKK-beta. 4 We identified COMPOUND A as a small-molecule, ATP-competitive inhibitor selectively targeting IKK-beta kinase activity with a K(i) value of 2 nM. 5 COMPOUND A inhibited stress-induced NF-kappaB transactivation, chemokine-, cytokine-, and adhesion molecule expression, and T- and B-cell proliferation. 6 COMPOUND A is orally bioavailable and inhibited the release of LPS-induced TNF-alpha in rodents. 7 In mice COMPOUND A inhibited cockroach allergen-induced airway inflammation and hyperreactivity and efficiently abrogated leukocyte trafficking induced by carrageenan in mice or by ovalbumin in a rat model of airway inflammation. 8 COMPOUND A was well tolerated by rodents over 3 weeks without affecting weight gain. 9 Furthermore, in mice COMPOUND A suppressed edema formation in response to arachidonic acid, phorbol ester, or edema induced by delayed-type hypersensitivity. 10 These data suggest that IKK-beta inhibitors offer an effective therapeutic approach for inhibiting chronic pulmonary inflammation.
    Full-text · Article · Jun 2005 · British Journal of Pharmacology
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    • "IL-4Ra heterodimerizes with a common g-chain following ligand binding and generates the appropriate intracellular signals for the development of immune responses that are characterized by the production of speci®c antibody isotypes (IgA) and inhibition of Type 1 T cell cytokine synthesis (i.e. IL-2 and IFNg) (Boothby et al., 2001). IL-4 has also been reported to function as a potent anti-in¯ammatory cytokine and may serve to limit the production/activities of in¯ammatory cytokines implicated in follicle rupture. "
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    ABSTRACT: Prior to the development of high-throughput methods for the analysis of differential gene expression, genes required for proper ovarian function were identified on a case-by-case basis. Recently, however, several techniques have been developed that enable investigators to study large-scale changes in gene expression under a variety of experimental conditions. The utilization of these methodologies has led to the identification of a number of novel or previously unappreciated genes that are expressed within distinct cell types in the ovary or at specific stages of the ovarian cycle. This review details the recent use of differential analysis strategies in identifying (i) genes that are expressed exclusively or preferentially in the ovary, (ii) genes that are differentially expressed in isolated ovarian cells in response to hormonal stimulation, and (iii) those genes that are expressed at specific stages of the ovarian cycle. The genes identified through the use of these approaches represent potential targets for designing agents capable of regulating ovarian physiology and thus fertility.
    Full-text · Article · May 2004 · Human Reproduction Update
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