5a). In addition, the percentage and total number of switched GC B cells were also enhanced after late stage Treg-cell disruption. These data indicate that Treg cells participate in the control of GCs throughout the entire response, and not just at the induction phase. Given the observation that Treg cells participate in the control of GC reactions, it was of interest to explore the frequency and phenotype of the splenic Treg-cell population after immunization with SRBC. To monitor Treg cells, Foxp3-GFP reporter mice were used.47 As shown in Fig. 6(a), CD4+ Foxp3+ T cells are readily detected in the spleens of these mice, allowing for enumeration and phenotypic

characterization. Of interest, the proportion of Foxp3+ Treg cells within the splenic CD4+ compartment was unaltered throughout the GC response this website (Fig. 6b), although total cellularity of the spleen increased modestly at days 8 and 12 (data not shown). As iTreg cells are probably activated to control the humoral Selleckchem KU-60019 response to novel antigens,

a range of surface markers were examined in an attempt to identify an activated iTreg-cell sub-set. When comparing naive with SRBC-challenged mice, no differences were found in the proportion of Treg cells expressing CD103, CD45RB, CD62L, CD178, GITR or PD-1 at any time-point (data not shown). Several reports have demonstrated the presence of Treg cells within the GCs of human and mouse secondary lymphoid tissue,44,45,60,61 indicating their ability to migrate into activated follicles.62 Accordingly, CXCR5 and CCR7 expression was examined on CD4+ Foxp3+ T cells from naive and immunized mice. As shown in Fig. 6(a), the splenic Treg-cell population consists of four sub-sets defined as CXCR5− CCR7+, CXCR5lo CCR7lo, CXCR5 CCR7− and CXCR5+ CCR7−. CXCR5− CCR7+ Treg cells would be expected to reside in T-cell zones with CXCR5lo CCR7lo Treg cells positioned at the borders of T-cell : B-cell

areas. CXCR5− CCR7− Treg cells would probably be found in red pulp tissue. Importantly, CXCR5+ CCR7− Treg cells should have the ability to migrate into B-cell follicles with the potential to control B-cell activity locally. In naive mice (day 0), the CXCR5− CCR7+, CXCR5lo CCR7lo, CXCR5− CCR7− and CXCR5+ CCR7− sub-sets composed 29%, 14%, 30% Oxymatrine and 27% of the Treg-cell compartment, respectively. It is of interest that all four sub-sets exist in unimmunized mice, suggesting that Treg cells patrol all areas of the spleen under steady-state conditions. The four Treg-cell sub-sets were similarly enumerated in SRBC-immunized mice at days 8, 12 and 18 post-challenge. Figure 6(c) shows no change in the frequency of CXCR5− CCR7+ and CXCR5+ CCR7− Treg cells during the course of the response, indicating no major shift of Treg cells from the T-cell zone into activated follicles. Percentages of CXCR5lo CCR7lo and CXCR5− CCR7− Treg cells were also unchanged (data not shown).

11 Interleukin-32 is selectively expressed in activated natural killer cells, T cells, epithelial cells, endothelial cells and blood monocytes.11,12 The IL-32 induced by IL-18 has a number of splice variants, namely, IL-32α, -β, -γ, -δ, -ε and -ζ. Their receptors have yet to be identified, although proteinase 3 has been recently identified as a specific IL-32-binding protein. Interleukin-32 has emerged as

an important player in innate and adaptive immune responses13 and IL-32 associated with TNF-α appears to exacerbate TNF-α-related inflammatory arthritis and colitis.14 Expression of IL-32 may be a cancer biomarker, and high levels of IL-32 expression have been detected in several cancer cell types.15,16 Interleukin-32 knock-down was also shown to suppress anti-apoptotic proteins such as bcl-2, and induced apoptosis.15,17 see more Recent studies have

demonstrated that viral infection stimulates IL-32 expression; IL-32 suppressed replication of HIV18 during HIV infection, thereby reducing the levels of T helper type RG7422 1 and pro-inflammatory cytokines,19,20 and was induced by infection with the influenza A virus.21 However, the role of HPV in IL-32 expression remains unclear. We detected IL-32 expression in tissues and cells obtained from patients with cervical cancer. Furthermore, as HPV plays a critical role in cervical cancer, we attempted to assess the possible role of IL-32 as an inducer of cancer and inflammation in response to HPV infection. Cyclo-oxygenase-2 (COX-2) is over-expressed in HPV-induced diseases, including cervical cancer,22,23 and is stimulated by HPV-16 E6 and

E7 Methocarbamol oncoproteins via the epidermal growth factor receptor/Ras/mitogen-activated protein kinase pathway.24 As COX-2 and IL-32 are associated with inflammatory processes, we attempted to characterize the relationship between COX-2 and IL-32 in the context of HPV infection. In this study, we evaluated the role of HPV in cervical cancer associated-IL-32 regulation as well as the feedback mechanisms between COX-2 and IL-32 occurring in response to the E7 oncogene. Human cervical cancer cells (C33A, SiHa and CaSki) were obtained from the American Type Culture Collection (Rockville, MD). An HPV-negative cervical cancer cell line (C33A) was prepared to establish stable cell lines expressing the E7 oncogene, and two stable cell lines (C33A/pOPI3, vector control C33A and C33A/E7, E7 expressing C33A) were established as previously described.25,26 All cells were grown in Dulbecco’s modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum (Hyclone, Logan, UT) and were cultured at 37° in a humidified atmosphere of 5% CO2. N-(2-cyclohexylosyl-4-nitrophenyl)-methane sulphonamide (NS-398) was purchased from Alexis Biochemicals (San Diego, CA), dissolved in DMSO, and used at final concentrations of 50 μm and 100 μm.

Screening based on title and abstract identified 56 citations for full-text review (Fig. 1). Additional five studies[25-27, 39, 53] were identified from reference lists of the identified articles and from other databases. Of the 56 potentially relevant articles,

32 were excluded for reasons given in Figure 1, leaving a total of 24 studies[24-47] that met the inclusion criteria. Twenty one studies[24-30, 32, 34-38, 40-47] reported associations see more between use of statins and AKI, and 14 studies[28, 31-35, 37, 39-41, 43-46] reported associations between use of statins and AKI requiring RRT. Five studies[24-28] used RCT design, and the rest applied a cohort design.[29-47] Only one RCT[28] defined AKI as the primary endpoint. The other four RCTs defined postoperative thrombocytosis,[24] postoperative inflammatory responses,[25]

postoperative myocardial injury,[26] and the number of postoperative endothelial progenitor cells[27] as primary endpoints. Among the cohort studies, only three used prospective design; the remaining studies were retrospective in design. As for the study population, two studies involved nation-wide populations, while most of the other studies were conducted at one single centre. Among the two population-based studies, one was conducted in Canada,[43] and the other in the USA.[47] We assessed the quality buy 3-deazaneplanocin A of included studies with the Jadad scale.[54] The study conducted by Prowle JR and colleagues[28]

had the highest score on the Jadad scale. The results were summarized in the Appendix 1 (Table App1). The studies varied in their types of surgery, mean age, and case definition (Table 1). The types of surgery were restricted to cardiac or vascular surgery in most studies. Specific type, dosage, and duration of preoperative statin therapy Pyruvate dehydrogenase were not available in most studies. In contrast to AKI defined by database codes, AKI defined by a pre-specified increase of serum creatinine level was regarded as ‘AKI defined by laboratory criteria’. Among these, there were seven studies[28, 37, 38, 41, 44-46] using AKIN or RIFLE criteria[48, 49] as the definition for AKI. In all studies, the definition of AKI requiring RRT was based on clinical judgment without additional objective laboratory criteria. Specific statin type available i Dosage and duration not available Increase of sCr level > 30% (AKIN stage 1) Atorvastatin 20 mg/day or simvastatin 20 mg/day for at least 6 months Started before surgery Type, dosage and duration not available At least one dose of statin between admission and surgery In the 21 studies reporting the association of statin use and AKI, the incidence of AKI ranged from 1.88%[43] to 52.17%[44] (Table 1). The pooled incidence of AKI for all 21 studies was 4.89%. The pooled incidence of AKI among statin user and nonstatin user were 6.13% and 4.28%, respectively (Table 2).

5A), microvillar

extensions (Fig. 5C) and, for SEMA6A only, motility in T cells (Fig. 6A). Interestingly, SEMA-mediated cytoskeletal interference did not affect the overall β1-integrin-stimulated front-rear polarization or receptor-segregation (Fig. 5B and C) thereby essentially differing from actin cytoskeletal https://www.selleckchem.com/products/abc294640.html paralysis induced on MV exposure of these cells 18, 47. In line with hypothesis, induction of ceramides as found relevant for MV actin interference 18 was not detectable on SEMA3A/6A exposure of T cells (not shown) indicating the SEMA-induced signalling may not involve SMase activation. In addition to adding to the current view on the role and regulation of human SEMA receptors in the IS in general (such as plexA1 IS recruitment and its importance for IS function in T cells, plexA4 expression in human T cells, plexA1/NP-1 turnover in maturing DC, SEMA3A and SEMA6A in regulation of T-cell protrusions and chemokinetic migration), our study to the best of our knowledge is the first to address regulation of those by a pathogen and their importance in the established MV interference with IS function. Recruitment to and concentration of SEMA receptors

to the IS might, however, also be of relevance for viral transmission there as indicated by the function of NP-1 as physical and functional partners of HTLV env proteins during transmission in the virological synapse 32, 52. Primary human cells were obtained from the Department of Transfusion Medicine, University of Würzburg, Tamoxifen and analyzed anonymized. All experiments involving human material were conducted according to the principles expressed in the Declaration of Helsinki and ethically approved by the Ethical Committee of the Medical Faculty of the University of Würzburg. Primary human T cells were enriched from peripheral blood

obtained from healthy Aldehyde dehydrogenase donors by Ficoll gradient centrifugation followed on nylon wool columns and maintained in RPMI1640/10% FBS. Immature DC (iDC) were generated from monocytes in RPMI 1640/5% FBS by culture with GM-CSF (500 U/mL; Strathmann) and 250 U/mL IL-4 (250 U/mL; Promocell) and, when indicated, exposed to LPS (100 ng/mL) (LPS-DC) or a mock preparation obtained by freeze/thawing and subsequent low-speed centrifugation of human lymphoblastoid BJAB cells (kept in RPMI1640/10% FBS)(mock-DC) for 24 h. The MV WT strain WTF and the MVrecombinant MGV (expressing VSV-G protein instead of the MV gps 53) were grown on human lymphoblastoid BJAB cells and titrated on marmoset lymphoblastoid B95a cells (kept in RPMI1640/10% FBS). For exposure experiments, MV was purified by sucrose gradient ultracentrifugation as was the mock control from uninfected BJAB cells. T cells were co-cultured with MV (at a multiplicity of infection (m.o.i.) of 0.

044 (−.034 for the original stimuli) for /buk/ and .023 (.034 for the original stimuli) for /puk/. Importantly, the variance in both was much lower in the present experiment (/buk/: SDoriginal = .0046, SDmodified = .0023; /puk/: SDoriginal = .026, SDmodified = .0026). Thus, by both relative measures, the variance in the information

available for voicing was minimized dramatically. Given the relatively slight contribution of this cue to perception in adults, it is clear that we have significantly reduced (if not altogether eliminated) variation in contrastive information in Experiment 3. A final concern was that the coda (/uk/) portion of the two words was not physically identical between /buk/ and /puk/ tokens within a speaker, as it was in Experiments 1 and 2. Coda information could have provided an additional source of constrastive information about voicing. It seems unlikely that such information would be sufficient to distinguish the GSK-3 activity words for two reasons: first, if coda information was necessary to distinguish the word-initial voicing, prior experiments using natural recordings that preserved coda information (Pater, Stager, & Werker, 2004; Rost & McMurray, 2009) would have provided sufficient information selleckchem for categorization in this task. Second, the effect of voicing on the vowel is small: most of the established cues to word-initial

voicing are found at the release or the aspiration/voicing juncture (Allen & Miller, 1999). Nonetheless, if there was information correlated with voicing, then variability in these cues could have helped the infants. Experiments 1 and 2 rule out contrastive variability alone (particularly as the contrastive cues varied there were much more robust cues to voicing than anything in the coda), but it is possible that these cues, combined with the noncontrastive variability we manipulated, were driving Etofibrate the effect. To

determine if the coda portions of the words contained any information that could contribute to a voicing decision, we measured a number of cues to voicing: the length of the syllable (measured from the release to the onset of closure), the pitch (F0), and the first and second formant frequencies. Measurements of F0, F1, and F2 were conducted twice, once during the first pitch pulse after the onset of voicing and once at the midpoint of the vowel (see Table 1). All of the measurements showed substantial variability. For example, at voicing onset, F0 had an SD of 84 Hz for /buk/ at onset and 97 Hz for /puk/. Similarly, F2 varied by well over 150 Hz at both points. This is perhaps to be expected given the variability in speakers (especially the variability in gender) and register across the Experiment 3 stimulus set and it validates our assumption that these stimuli had substantial variation. However, none of these measures showed significant differences as a function of the word.

Results: TGF-β1 induced EMT in HPMC

was ameliorated by metformin. TGF-β1 significantly increased the ROS generation and NOX activity from 30 minutes, and mitochondrial ROS production from 6 hours. TGF-β1 increased the phosphorylation of smad2/3 and MAPK at 30 minutes and 3 hours, respectively, which was followed by nuclear selleck screening library translocalization of β-catenin and snail up-regulation. Metformin ameliorated ROS production, the activation of smad2/3 and MAPK, and snail expression. Oral administration of metformin also decreased peritoneal thickening and EMT with an increase in ratio of reduced to oxidized glutathione and the expression and activity of superoxide dismutase in peritoneal dialysate whereas it decreased the expression of nitrotyrosine in peritoneum and 8-hydroxy-2′-deoxyguanosine in dialysate in 8 weeks of peritoneal dialysis. Conclusions: AMP-activated protein kinase activator prevented the peritoneum from phenotype transition and fibrosis via an amelioration of oxidative stress. MORI YOSHITAKA1, KAKUTA TAKATOSHI1, see more MIYATA TOSHIO2, FUKAGAWA MASAFUMI1 1Department of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Japan; 2United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Japan Introduction: Peritoneal

dialysis (PD) is an excellent modality of renal replacement therapy. However, PD has occasionally to be discontinued in few years primarily due to peritoneal membrane dysfunction, eventually leading to the ultrafiltration failure. Pyridoxamine inhibits the formation of AGEs by entrapping GDPs. We are studying whether pyridoxamine could prevent

the progressive deterioration of peritoneal function in uremic patients on peritoneal dialysis. We demonstrated that intraperitoneally and orally administrated pyridoxamine can prevent the deterioration of peritoneal function in uremic rats. For translating this animal research into clinical benefit, we performed a single-dose administration VAV2 of oral pyridoxamine in PD patients. Method: Pyridoxamine 600 mg was administered orally to 6 continuous ambulatory peritoneal dialysis (CAPD) patients. 2.5% peritoneal dialysis solution (PDS) was replaced 4times, 6hours each. Blood and PDS were collected for blood concentration of pyridoxamine and total carbonyl level in PDS. Same patients underwent the same procedure without oral pyridoxamine on another day. Single-dose administration to 6 non-uremic healthy volunteers was performed to compare the pharmacokinetics of pyridoxamine with PD patients. Result: Compared with non-uremic subjects, pyridoxamine level in blood elevated (Cmax 6.28 ± 2.45 μg/ml vs. 3.70 ± 1.04 μg/ml, AUC 30.10 ± 11.4 μg*hr/ml vs. 10.90 ± 1.30 μg*hr/ml). However, pyridoxamine concentration decreased almost to the original level within 24hours.

While these data suggest a potential utility of testing for the HPV DNA and antibody status before vaccinating older women who have already initiated sexual contacts [61],

current guidelines do not recommend screening with HPV testing because very few women have click here been exposed to all types in the vaccine, and protection against other vaccine types is not affected by the presence of infection with one vaccine type. Moreover, there is no evidence of clinical utility for HPV genotyping at young ages (<25 years), as nearly all HPV infections will clear spontaneously and unnecessary HPV testing could generate over-diagnosis and treatment [62,63]. Immunization of males.  Immunization of boys with VLPs elicits a serum immune response similar to that in girls. Because genital HPV infection is sexually transmitted, immunization of men may help to prevent infection of women. Modelling studies on herd immunity, i.e. indirect protection of those who remain susceptible, owing to a reduced prevalence of infections in the risk group for disease, have been published check details [64–66]. The utility of immunization of males depends upon the assumed population coverage of vaccination, with successively smaller additional benefits seen in scenarios with high population coverage [67]. Modelling of programmes with high population coverage (90%) have found that addition of male vaccination gives a more rapid infection control

and have suggested that both sex vaccination programmes may be required to achieve an ultimate eradication of the infection [60]. Vaccination programme strategies as a randomized health-care policy.  Design of HPV vaccination programmes has been based upon estimations of the impact of HPV vaccination on the burden of cervical cancer incidence and mortality using mathematical modelling of projected effects from the observed surrogate endpoint effects [59,67,68]. Whereas

clinical end-points are essential for estimates of effects on health economy, the control of HPV infections is a more immediately relevant cAMP end-point in models that compare different programme designs [60]. For programme design issues that are ambiguous, notably which age groups should be targeted and whether vaccination of males is required, randomization of vaccination programmes is an interesting option. That the incidence of cervical and other HPV-associated cancers does eventually decrease in vaccinated populations should then be verified by monitoring HPV incidences in sexually active youth groups and incidences of HPV-associated diseases by registry-based follow-up [69–72]. HPV types.  Antibody responses elicited by VLP immunization are, in general, specific for the individual HPV type. However, lower titre cross-reactivity is noted for closely related HPV types [31,33,45,52] as well as partial protection against disease end-points associated with these non-vaccine types [35,73].

Following stimulation, Smad6/7 could be detected in Foxp3− cells in the presence or absence of TGF-β, whereas Smad6/7 could not be detected in Foxp3+ cells cultured under any conditions. As the expression pattern of Smad6/7 in stimulated nTregs is similar to that seen in TGF-β/simvastatin-generated iTregs, it appears likely that one of the primary mechanisms responsible for the synergistic effects of simvastatin on TGF-β-mediated induction of Foxp3 is the inhibition or down-regulation of Smad6/7 expression. Statins are widely used drugs in the treatment of hypercholesterolaemia and have

proven to be extremely useful in the prevention of cardiovascular diseases. Studies since 2000 have also demonstrated that statins have pleiotropic effects on immune responses. They were initially shown to prevent and reverse relapsing and remitting experimental autoimmune encephalomyelitis in the mouse model by inducing a shift TSA HDAC in vitro from a Th1 to a Th2 cytokine profile.7 Similarly, in acute graft-versus-host disease in the mouse, the effects of statins were mediated through induction ABT-263 clinical trial of Th2 cells with increased IL-4 production and reduced tumour necrosis factor-α and interferon-γ production.8 Subsequent studies have claimed that statins can act on many distinct cell types in

the immune system as well as vascular endothelial cells.17 Most recently, statins have been shown to modulate the production of IL-17 by inducing the expression of suppressors of cytokine signalling (SOCS) 3 and SOCS7 in monocytes resulting in inhibition of the transcription of IL-6 Phloretin and IL-23 and by inhibiting the transcription factor RORγT in CD4+ T cells.18 Very few studies have addressed the effects of statins on nTregs or on the developments of iTregs in peripheral sites. One study claimed that culture of human peripheral blood mononuclear cells in the presence of atorvastatin, but not mevastatin or pravastatin, increased the number of Foxp3+ T cells and claimed that the effects of atorvastatin were mediated by conversion of Foxp3− to Foxp3+ T cells.14 The results of this study are difficult to interpret

because conversion of Foxp3− to Foxp3+ T cells requires that the responsive T cell be stimulated through their TCR and TCR stimulation was not used in this paper.2,19 The goal of our studies was to examine the potential effects of statins on the conversion of mouse Foxp3− T cells to Foxp3+ Tregs. We used an in vitro model system in which highly purified Foxp3− T cells, obtained from TCR transgenic mice on a RAG−/− background, were cultured in the absence of antigen-presenting cells in the presence of a TCR stimulus, CD28-mediated co-stimulation and IL-2. Under these conditions the addition of simvastatin alone had a modest effect on the induction of Foxp3+ T cells that was partially independent of the presence of TGF-β. Importantly, simvastatin exerted a potent synergistic effect on Foxp3 induction when combined with low concentrations of TGF-β.

The protocol of the animal experiment was reviewed and approved by the Ethics Committee on Animal Experiments at the Faculty of Medical Sciences, Kyushu University. This was carried out by counting this website the numbers of colony formers. In the case of HBO treatment, appropriate numbers (ca. 10 to 107 per plate) of bacterial cells were spread on yeast extract agar plates, which were exposed to HBO (see above) and incubated overnight in ambient air. For UV killing, approximately 106 bacteria suspended in 5 mL of PBS were irradiated in a shallow dish under a 10 W germicidal lamp (Toshiba, Tokyo, Japan) at a distance

of 35 cm for various lengths of time. For killing by chemicals, similar bacterial suspensions were incubated with various concentrations of each test substance at 37°C for 30 mins. The bacterial suspensions thus treated were diluted appropriately

with PBS and plated on yeast extract agar plates, which were incubated overnight. Cells in 50 mL of a log-phase culture in yeast extract broth (turbidity 600 nm ≈ 0.2) were placed under HBO at 3 atm or in ambient air for 2 hrs in shallow vessels. The cells were collected by centrifugation, washed twice with PBS, and resuspended in 1 mL PBS. The cell suspension was sonicated on ice for 2 mins using a sonicator (Sonifier 250, Branson, Danbury, CT, USA) set at 50% duty cycle and 10% output control. After removal of cell debris by centrifugation, the protein concentration of LY2606368 mouse the supernatant was determined using a Pierce BCA protein assay kit (Thermo Scientific, Waltham, MA, USA) with BSA as standard, and adjusted to 1 mg/mL with PBS. Catalase activity was determined by measuring the amount of remaining H2O2 with titanium sulfate as previously described (12), one unit of activity being defined as the amount capable of decomposing 1.0 μmol of H2O2 per min. The activity of NADH peroxidase was assayed as previously described (13), one unit of activity being defined as the amount required for oxidizing 1.0 nmol of NADH per min. SOD

activity was assayed by the NBT reduction method as previously described (14,15), one unit of activity being defined as the amount Cyclin-dependent kinase 3 required to cut the rate of reduction of NBT by 50%. O2 and N2 gases were purchased from Fukuoka Sanso (Fukuoka, Japan). Hydrogen peroxide (H2O2), mitomycin C, methyl methane sulfonate, xanthine oxidase and NADH were obtained from Sigma-Aldrich (St. Louis, MO, USA). Titanium (IV) sulfate solution (5%) was from Nakarai Tesque (Kyoto, Japan). Xanthine was from Katayama Chemical (Osaka, Japan) and NBT from Boehringer Mannheim (Mannheim, Germany). All other chemicals used were of reagent grade. A Genesys 10UV spectrophotometer (Thermo Electron, Kyoto, Japan) was used for determination of turbidity and absorbance. The light path was 1 cm in length. All experiments were repeated at least three times and the results expressed as mean ± standard deviation.

I.n. application of the nanogel-associated antigen was also efficacious, with the chitosan/alginate nanogels displaying the most noticeable effect in terms of reducing cerebral parasite load. Protection was mostly associated with a mixed Th1/Th2 response, but there was no clear indication that either a Th1- or Th2-biased response would

favour protection or reduced cerebral parasite load. Further studies are necessary to elucidate the potential mechanisms that lead to protection, particularly the role that the nanogels may be having on innate immune defence mechanisms. Overall, chitosan-based nanogels represent an innovative platform for both i.n. and i.p vaccination approaches to limit the disease caused by N. caninum infection. The authors wish to thank Joachim Müller for his invaluable help in statistical analysis and Norbert Müller for great support and helpful suggestions during the course of the project. J.P. Dubey (USDA, Beltsville, Alectinib molecular weight USA) is gratefully acknowledged for the kind gift of the N. caninum Nc-1 isolate. This work was made possible through the National Science Foundation (grant No. 31-127374). “
“Gamma interferon-inducible lysosomal thiol reductase (GILT) is an enzyme that catalyzes thiol bond reduction

and plays an important role in the early steps of antigen processing. The key factor involved in the regulation of GILT expression upon cell stimulation with interferon-γ (IFN-γ) is signal transducer and activator of transcription 1 (STAT1). In this click here study, we examined the role of STAT1 in regulating the constitutive expression of GILT. We showed that STAT1 interacts with the GILT promoter, even in the absence of IFN-γ, and that STAT1 represses GILT expression. These results reveal an atypical negative regulatory

role for STAT1 in the constitutive regulation of genes involved in antigen processing. Thiol reductases are enzymes that carry out the oxido-reduction of disulphide bonds in proteins.1 They are located in various cellular compartments such as the mitochondria,2 Bay 11-7085 endoplasmic reticulum3 and lysosomes.4–6 Gamma interferon-inducible lysosomal thiol reductase (GILT) is a unique thiol reductase that reduces disulphide bonds under the low-pH conditions found within lysosomes. Through the reduction of thiol bonds of endocytosed proteins, GILT unfolds native protein antigens in preparation for subsequent processing by lysosomal proteases. The mature form of GILT is a 30 000 molecular weight (MW) enzyme, which has the conserved active-site motif (-CGAC-)1,3 typical of thiol reductases. However, it functions at an acidic pH of 4·5–5·5, and thus differs from other thiol reductases that function at neutral or alkaline pH.7 GILT is constitutively expressed in professional antigen-presenting cells (APCs),8 but also in T cells9 and fibroblasts.10 GILT is also secreted in tissue culture supernatants of GILT-expressing B-cell lines.11 GILT protein expression is moderately increased upon treatment with interferon-γ (IFN-γ).