Opisthorchis viverrini infection was found to be highly prevalent in 3 riverside villages (Ang Svay Chek A, B, and C) of the Prey Kabas District, Takeo Province. This area is located in the southern part of Cambodia, where the recovery of adult O. viverrini worms was recently reported. From May 2006 until May 2010, fecal examinations were performed on a total of 1,799 villagers using the Kato-Katz thick smear technique. In the 3 villages, the overall positive rate for helminth eggs ranged from 51.7 to 59.0% (av. 57.4%), and the percentage positive for O. viverrini was 46.4-50.6% (47.5%). Other helminths detected included hookworms (13.2%), echinostomes (2.9%), Trichuris trichiura (1.3%), Ascaris lumbricoides (0.6%), and Taenia spp. (0.06%). The prevalence of O. viverrini eggs appeared to reflect a lower infection in younger individuals (<20 years) than in the adult population (>20 years). Men (50.4%) revealed a significantly higher (P=0.02) prevalence than women (44.3%). The Ang Svay Chek villages of the Prey Kabas District, Takeo Province, Cambodia have been confirmed to be a highly endemic area for human O. viverrini infection.

ABCG2 is a member of the ATP binding cassette (ABC) transmembrane proteins that plays an important role in stem cell biology and drug resistance of cancer cells. In this study, we investigated how expression of human ABCG2 gene is regulated in lung cancer A549 cells. Binding of Sp1 and Sp3 transcription factors to the ABCG2 promoter in vitro and in vivo was elucidated by electrophoretic mobility shift assay and chromatin immunoprecipitation assay. The ABCG2 promoter activity was impaired when Sp1 sites were mutated but was enhanced by overexpression of Sp1 or Sp3 proteins. Knockdown of Sp1 or Sp3 expression by short interfering RNA significantly decreased the expression of ABCG2 mRNA and protein, resulting in attenuated formation of the side population in A549 cells. In addition, Sp1 inhibition in vivo by mithramycin A suppressed the percentage of the side population fraction and sphere forming activities of A549 cells. Moreover, inhibiting Sp1- or Sp3-dependent ABCG2 expression caused chemosensitization to the anticancer drug cisplatin. Collectively, our results demonstrate that Sp1 and Sp3 transcription factors are the primary determinants for activating basal transcription of the ABCG2 gene and play an important role in maintaining the side population phenotype of lung cancer cells.

Chronic graft-versus-host disease (cGVHD) is an increasingly frequent complication of allogeneic stem cell transplantation. Current therapies for cGVHD reduce symptoms but are not cures. The B10.D23Balb/c (H-2 d ) minor histocompatibility antigen-mismatched model, which reflects clinical and pathological symptoms of human cGVHD, was used in this study. We demonstrated that a single injection of an agonistic monoclonal antibody (mAb) against CD137, a member of the tumor necrosis factor receptor superfamily, reverses skin fibrosis, ulceration, and alopecia, a dominant feature of cGVHD (cutaneous GVHD), ultimately improving general health conditions. The reversal is associated with markedly reduced CD4 ؉ T-cell cytokines and increased apoptosis of donor CD4 ؉ T cells. The Fas pathway is required for ameliorating cutaneous GVHD by anti-CD137 mAb. Taken together, these data indicate that the anti-CD137 mAb has a therapeutic effect on cutaneous GVHD by removing donor CD4 ؉ T cells that cause cutaneous GVHD. Thus, our study demonstrates an agonistic mAb, specific for a costimulatory molecule, as a possible target for therapeutic intervention in cutaneous GVHD. IntroductionChronic graft-versus-host disease (cGVHD) commonly occurs in patients who receive allogeneic stem cell transplants. Even though cGVHD differs among patients, the clinical complications of cGVHD often include fibrosis and scleroderma-like changes. 1 cGVHD is mediated by pathogenic donor T cells generated after alloreactivity to host minor histocompatibility (mH) antigens or autoantigens. 2 These T cells damage target tissue directly by cytolytic attack, through secretion of proinflammatory and fibrosing cytokines, or via promotion of autoantibody production. 2 Treatment of cGVHD, aside from systemic delivery of corticosteroids, has not been established.A limited number of model systems have been developed to examine cGVHD. Among these, the B10.D23Balb/c (H-2 d ) mH antigen-mismatched model of GVHD showed characteristics resembling human cGVHD such as relatively late time of onset, skin fibrosis, ulceration, and alopecia with increased collagen deposition. [3][4][5][6] This murine model has the following histologic features: lichenoid subepithelial infiltrates, follicular drop-out, loss of subdermal fat, and dermal mononuclear infiltrates (herein, this dominant feature of cGVHD will be referred to as cutaneous GVHD). 7 Other features include pulmonary fibrosis, 4 inflammation and destruction of salivary and lacrimal glands, 8 and hepatic disease characterized by intrahepatic and extrahepatic bile duct mononuclear infiltration followed by fibrous thickening and sclerosis of the bile duct wall. 9-11 The pathogenesis of cGVHD requires donor CD4 ϩ T cells. 9,12 Interestingly, both donor and host antigen-presenting cells (APCs) mediate CD4 ϩ T-cell-mediated cutaneous GVHD, indicating that endogenous and exogenous host mH antigens can be presented to donor CD4 ϩ T cells in the context of major histocompatibility complex (MHC) class II. 13 Since, in the B10.D...

IL-31, a newly identified member of the IL-6 cytokine family, is involved in many pathological conditions, including atopic dermatitis and pruritis. In this study, we investigated how expression of IL-31 is regulated in T cells and mast cells. We observed that expression of IL-31 required a calcium signal and was dependent on the calcineurin-NFAT signaling pathway. Moreover, we found that IL-31 promoter contains a positive regulatory region that mediates calcium- and IL-4-dependent induction of the IL-31 gene and demonstrated that a change into an open chromatin conformation occurs in this region after stimulation with calcium and IL-4. Whereas IL-4 responsiveness required STAT6 binding sites, calcium responsiveness of IL-31 promoter required NFAT binding sites that bind NFATc1 and NFATc2 in vitro and in vivo. The induction of IL-31 promoter activity was impaired when these sites were mutated but was enhanced by CA-NFATc1 or STAT6 proteins and further increased synergistically by combinations of both proteins. Furthermore, the importance of STAT6 proteins was indicated by impaired, IL-4-mediated induction of IL-31 in STAT6-diminished Jurkat cells. Thus, our data demonstrate that calcium and IL-4 signals are required to mediate induction of IL-31 in Th2 cells and mast cells and that this induction appears to result from specific binding of NFAT and STAT6 proteins.

IL-21, a pleiotropic cytokine strongly linked with autoimmunity and inflammation, regulates diverse immune responses. IL-21 can be potently induced in CD4+ T cells by IL-6; however, very little is known about the mechanisms underlying the transcriptional regulation of the Il21 gene at the chromatin level. In this study, we demonstrated that a conserved noncoding sequence located 49 kb upstream of the Il21 gene contains an enhancer element that can upregulate Il21 gene expression in a STAT3- and NFAT-dependent manner. Additionally, we identified enhancer-blocking insulator elements in the Il21 locus, which constitutively bind CTCF and cohesin. In naive CD4+ T cells, these upstream and downstream CTCF binding sites interact with each other to make a DNA loop; however, the Il21 promoter does not interact with any cis-elements in the Il21 locus. In contrast, stimulation of CD4+ T cells with IL-6 leads to recruitment of STAT3 to the promoter and novel distal enhancer region. This induces dynamic changes in chromatin configuration, bringing the promoter and the regulatory elements in close spatial proximity. The long-range interaction between the promoter and distal enhancer region was dependent on IL-6/STAT3 signaling pathway but was disrupted in regulatory T cells, where IL-21 expression was repressed. Thus, our work uncovers a novel topological chromatin framework underlying proper transcriptional regulation of the Il21 gene.