Itm2a, a Target Gene of GATA-3, Plays a Minimal Role in Regulating the Development and Function of T Cells

The integral membrane protein 2a (Itm2a) is one of the BRICHOS domain-containing proteins and is structurally related to Itm2b and Itm2c. It is expressed preferentially in the T lineage among hematopoietic cells and is induced by MHC-mediated positive selection. However, its transcriptional regulation and function are poorly understood. Here we showed Itm2a to be a target gene of GATA-3, a T cell-specific transcription factor. Deficiency of Itm2a had little impact on the development and function of polyclonal T cells but resulted in a partial defect in the development of thymocytes bearing a MHC class I-restricted TCR, OT-I. In addition, Itm2a-deficient mice displayed an attenuated T helper cell-dependent immune response in vivo. We further demonstrated that Itm2b but not Itm2c was also expressed in T cells, and was induced upon activation, albeit following a kinetic different from that of Itm2a. Thus, functional redundancy between Itm2a and Itm2b may explain the minimal phenotype of Itm2a deficiency

Ets-1, a functional cofactor of T-bet, is essential for Th1 inflammatory responses

To mount an effective type 1 immune response, type 1 T helper (Th1) cells must produce inflammatory cytokines and simultaneously suppress the expression of antiinflammatory cytokines. How these two processes are coordinately regulated at the molecular level is still unclear. In this paper, we show that the proto-oncogene E26 transformation–specific-1 (Ets-1) is necessary for T-bet to promote interferon-γ production and that Ets-1 is essential for mounting effective Th1 inflammatory responses in vivo. In addition, Ets-1–deficient Th1 cells also produce a very high level of interleukin 10. Thus, Ets-1 plays a crucial and unique role in the reciprocal regulation of inflammatory and antiinflammatory Th responses

Altered expression of protein tyrosine phosphatase, non-receptor type 22 isoforms in systemic lupus erythematosus

Introduction: A C-to-T single nucleotide polymorphism (SNP) located at position 1858 of human protein tyrosine phosphatase, non-receptor type 22 (PTPN22) complementary DNA (cDNA) is associated with an increased risk of systemic lupus erythematosus (SLE). How the overall activity of PTPN22 is regulated and how the expression of PTPN22 differs between healthy individuals and patients with lupus are poorly understood. Our objectives were to identify novel alternatively spliced forms of PTPN22 and to examine the expression of PTPN22 isoforms in healthy donors and patients with lupus. Methods: Various human PTPN22 isoforms were identified from the GenBank database or amplified directly from human T cells. The expression of these isoforms in primary T cells and macrophages was examined with real-time polymerase chain reaction. The function of the isoforms was determined with luciferase assays. Blood samples were collected from 49 subjects with SLE and 15 healthy controls. Correlation between the level of PTPN22 isoforms in peripheral blood and clinical features of SLE was examined with statistical analyses. Results: Human PTPN22 was expressed in several isoforms, which differed in their level of expression and subcellular localization. All isoforms except one were functionally interchangeable in regulating NFAT activity. SLE patients expressed higher levels of PTPN22 than healthy individuals and the levels of PTPN22 were negatively correlated with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC-DI). Conclusions: The overall activity of PTPN22 is determined by the functional balance among all isoforms. The levels of PTPN22 isoforms in peripheral blood could represent a useful biomarker of SLE

ROG, Repressor of GATA, Regulates the Expression of Cytokine Genes

AbstractGATA-3 is a T cell–specific transcription factor and is essential for the development of the T cell lineage. Recently, it was shown that the expression of GATA-3 is further induced in CD4+ helper T cells upon differentiation into type 2 but not type 1 effector cells. Here, we report the molecular cloning of a GATA-3 interacting protein, repressor of GATA (ROG). ROG is a lymphoid-specific gene and is rapidly induced in Th cells upon stimulation with anti-CD3. In in vitro assays, ROG represses the GATA-3-induced transactivation. Furthermore, overexpression of ROG in Th clones inhibits the production of Th cytokines. Taken together, our results suggest that ROG might play a critical role in regulating the differentiation and activation of Th cells

Ets-1 is a negative regulator of Th17 differentiation

IL-17 is a proinflammatory cytokine that plays a role in the clearance of extracellular bacteria and contributes to the pathology of many autoimmune and allergic conditions. IL-17 is produced mainly by a newly characterized subset of T helper (Th) cells termed Th17. Although the role of Th17 cells in the pathology of autoimmune diseases is well established, the transcription factors regulating the differentiation of Th17 cells remain poorly characterized. We report that Ets-1–deficient Th cells differentiated more efficiently to Th17 cells than wild-type cells. This was attributed to both low IL-2 production and increased resistance to the inhibitory effect of IL-2 on Th17 differentiation. The resistance to IL-2 suppression was caused by a defect downstream of STAT5 phosphorylation, but was not caused by a difference in the level of RORγt. Furthermore, Ets-1–deficient mice contained an abnormally high level of IL-17 transcripts in their lungs and exhibited increased mucus production by airway epithelial cells in an IL-17–dependent manner. Based on these observations, we report that Ets-1 is a negative regulator of Th17 differentiation

Slow conduction and gap junction remodeling in murine ventricle after chronic alcohol ingestion

<p>Abstract</p> <p>Background</p> <p>Long-term heavy alcohol drinkers are prone to the development of cardiac arrhythmia. To understand the mechanisms, we evaluated the cardiac structural and electrophysiological changes in mice chronically drinking excessive alcohol.</p> <p>Results</p> <p>Male C57BL/6J mice were given 36% alcohol in the drinking water. Those given blank water were used as control. Twelve weeks later, the phenotypic characteristics of the heart, including gap junctions and electrical properties were examined. In the alcohol group the ventricles contained a smaller size of cardiomyocytes and a higher density of capillary networks, compared to the control. Western blots showed that, after drinking alcohol, the content of connexin43 (Cx43) protein in the left ventricle was increased by 18% (p < 0.05). Consistently, immunoconfocal microscopy demonstrated that Cx43 gap junctions were up-regulated in the alcohol group with a disorganized distribution, compared to the control. Optical mapping showed that the alcohol group had a reduced conduction velocity (40 ± 18 vs 60 ± 7 cm/sec, p < 0.05) and a higher incidence of ventricular tachyarrhythmia (62% vs 30%, p < 0.05).</p> <p>Conclusion</p> <p>Long-term excessive alcohol intake resulted in extensive cardiac remodeling, including changes in expression and distribution of gap junctions, growth of capillary network, reduction of cardiomyocyte size, and decrease of myocardial conduction.</p