PTEN protein was present heterogeneously in 42 cases and homogeneously in 18

cases. In homogeneous glioblastomas, no correlation was found between PTEN protein expression and the GPCR Compound Library solubility dmso LOH of the gene. Surprisingly, in the heterogeneous glioblastomas, LOH was found significantly more frequently (P < 0.001) in PTEN-positive areas (81%) than in PTEN-negative ones (35.7%). In general, molecular results of frozen tissue were representative of the tumour. Only two cases of methylation of the PTEN promoter were identified. A significant difference was found for overall survival for LOH10q23 status (P = 0.005) and for homogeneous vs. heterogeneous tumours (P = 0.014). The expression of PTEN protein does not correlate with the abnormalities of the LOH of the gene. Interestingly, patients with glioblastomas presenting either LOH of 10q23 or heterogeneous PTEN expression have a poorer prognosis. "
“In the CNS, primary tumors with rhabdoid components are classified as atypical teratoid/rhabdoid tumor, rhabdoid meningioma or rhabdoid glioblastoma. The authors present a young adult patient with supratentorial rhabdoid tumor incidentally found after head trauma as a small pre-existing lesion

in the parahippocampal gyrus. this website MRI demonstrated an area of hypointensity on T1-weighted images and hyperintensity on T2-weighted and fluid attenuated inversion recovery images. A serial MR scan revealed no change 3 months after the initial examination but drastic changes at 6 months. As the tumor and accompanying intratumoral hemorrhage enlarged rapidly, resection of the tumor was performed. Histopathology Methane monooxygenase revealed that the main component of the tumor was typical rhabdoid cells with some necrotic areas. There were also pathological features consistent with oligoastrocytoma. The specimen had neither vascular

proliferation usually seen in high-grade glioma nor the meningothelial pattern that suggests meningioma. Immunohistochemical findings revealed that cells were strongly positive for vimentin, epithelial membrane antigen and INI-1 antibody throughout the specimen. Further, monosomy 22 was detected by fluorescence in situ hybridization. The tumor was finally thought to be an unclassifiable primitive rhabdoid tumor with oligoastrocytoma that arose in the CNS. The patient died within 5 months of detection of the tumor, regardless of surgical resection, radiotherapy and chemotherapy. “
“Institut de Neurociències, Department of Cell Biology, Physiology and Immunology and Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Barcelona, Spain Auditory Neurophysiology Unit, Institute of Neuroscience of Castilla y León, University of Salamanca, Salamanca, Spain Dithiocarb (diethyldithiocarbamate, DEDTC) belongs to the group of dithiocarbamates and is the main metabolite of disulphiram, a drug of choice for the treatment of alcohol dependence.

Conversely, an increase in Bim could have interesting consequences. Activation of Bim-mediated lymphocyte killing upon pro-apoptotic BH3-mimetics could adjust the balance between activated and regulatory lymphocyte populations and ameliorate colitis. Inducing apoptosis of autoreactive lymphocytes could be a new promising therapeutic

strategy for CD patients. This work was supported by the Swiss National Foundation (M.H., 31003A_127247) and the Broad Medical Research Program (M.H., IBD-0324R). We thank the microscopy centre at the University of Zurich (ZMB) for technical assistance. K.L., M.K., M.F. and M.H. have no conflicts this website of interest to disclose. G.R. discloses grant support from Abbot, Ardeypharm, Essex, FALK, Flamentera, Novartis, Roche, Tillots, UCB and Zeller.

“
“The adenosine A2A receptor (A2AR) is the major cellular adenosine receptor commonly associated with immunosuppression. Here, we investigated whether A2AR activation holds the potential for impacting the severity of experimental autoimmune myasthenia gravis (EAMG) induced following immunization of Lewis rats with the acetylcholine receptor (AChR) R97–116 peptide. This buy PD0332991 report demonstrates reduced A2AR expression by both T cells and B cells residing in spleen and lymph nodes following EAMG induction. A2AR stimulation inhibited anti-AChR antibody production and proliferation of AChR-specific lymphocytes in vitro. Inhibition was blocked with the A2AR antagonists or protein kinase A inhibitor. We also determined that the development of EAMG was accompanied by a T-helper cell imbalance that could be restored following A2AR stimulation that resulted in increased Treg cell levels and a reduction in Th1-, Th2-, and Th17-cell subtypes. An EAMG-preventive treatment regimen was established that consisted of (2-(p-(2-carbonylethyl)phenylethylamino)-5-N-ethylcarboxamidoadenosine) (CGS21680; A2AR agonist) administration 1 day prior to EAMG induction. Administration

of CGS21680 OSBPL9 29 days post EAMG induction (therapeutic treatment) also ameliorated disease severity. We conclude that A2AR agonists may represent a new class of compounds that can be developed for use in the treatment of myasthenia gravis or other T-cell- and B-cell-mediated autoimmune diseases. Myasthenia gravis (MG) is a B-cell-mediated, T-cell-dependent autoimmune disease characterized by excessive muscle weakness and fatigue [[1]]. The development of an autoimmune response to the neural acetylcholine receptor (nAChR) present at neuromuscular junctions leads to the production of function-blocking anti-nAChR antibodies and this results in symptoms characteristic to MG [[2, 3]].

Overall, these findings sustain a prominent role for TNF-α in the pathogenesis of PBC, suggesting that anti-TNF-α treatment, currently used for most inflammatory rheumatic conditions, such as RA, ankylosing

spondylitis (AS), and CD, may also represent a promising agent in PBC. Pathway analysis find more of both the Italian and Canadian GWAS PBC cohorts have highlighted the phosphatidylinositol signaling system pathway, which is an integral component of the adaptive immune response and is essential for the maintenance of self-tolerance [41]. Possible involvement of the phosphatidylinositol pathway in PBC appears to fit well with the TNF hypothesis as this signaling system has been shown to mediate the effects of TNF-α on NF-κB activation [72, 73]. The same pathway analysis also identified the hedgehog (Hh) signaling system, suggesting

its involvement in PBC genetic susceptibility. Hh proteins comprise a group of secreted proteins that are involved in organogenesis and have been shown to promote adult stem cell proliferation [74-76]. Hh signaling has been widely described in PBC. It is involved in the ductular response to cholestatic damage in PBC, characterized by periportal accumulation of proliferating bile ductular cells and associated stromal elements, including myofibroblastic cells and fibrous matrix [77]. Hh signaling was found to be increased in a murine model of bile see more duct ligation in periportal epithelial cells expressing pan-cytokeratin, representing potential liver progenitor cell populations [63]. Hh signaling has also been shown to be able to promote the survival of biliary epithelial cells, possibly mediated through the inhibition of caspase activity [16]. Lastly, Hh signaling pathway activation has

been associated with upregulation of ductular cell expression of genes that promote inflammatory response, such as the gene producing Cxcl16; Hh dependent induction of Cxcl16, demonstrated Edoxaban in both bile duct ligated rats and humans with PBC, resulted in Natural Killer T (NKT) cell chemotaxis toward cholangiocytes in vitro [17]. Hh signaling may represent an important protective factor within the damaged liver, promoting the survival of small periportal epithelial cells representing potential hepatic progenitor cells. Despite the preliminary nature of these studies, the Hh signaling pathway may represent a new therapeutic target to protect or promote cell proliferation and tissue repair within the chronically damaged liver in PBC and other chronic liver diseases. Some scientists believe that, as humans did not evolve in an environment of drug therapies, there is no evolutionary pressure on responses to recently developed pharmacologic agents.

72 Allopurinol has a protective effect in diseases involving oxidative stress in their pathogenesis. Allopurinol treatment

of diabetic mice attenuated hyperuricaemia, albuminuria, and tubulo-interstitial injury.73 Several studies in human CKD patients have shown the benefit of treatment with allopurinol. For example, Kao et al. reported that allopurinol ameliorated endothelial dysfunction and prevented increased left ventricular mass in patients with CKD,74 and Siu et al. reported that allopurinol slowed progression of CKD through its ability to lower serum uric acid levels.75 The kidneys contain the highest endogenous levels of CoQ9 and CoQ10 compared with all other organs.76 This is likely due to the reliance of the kidney on aerobic metabolism and high density of mitochondria. It is NVP-BKM120 ic50 imperative that endogenous CoQ10 levels are maintained to ensure mitochondrial health, and this forms the rationale for CoQ10 therapy. CoQ10 has three well-characterized functions: (i) the transfer of electrons from complexes I and II to complex III along the ETC of the inner mitochondrial membrane and subsequent membrane polarization and ATP generation;77 (ii) the pro-oxidant generation www.selleckchem.com/products/sotrastaurin-aeb071.html of

O2- and H2O2;78 and (iii) the anti-oxidant quenching of free radicals.79 The major direct anti-oxidant role of CoQ10 is prevention of lipid peroxidation, and it also acts indirectly through its interactions with α-tocopherol.80 Although results regarding its benefit are disparate, Ishikawa and colleagues81 demonstrated a decrease in kidney O2- levels and improved renal function in hemi-nephrectomized rats on a CoQ10 supplemented diet. There is a general lack not of human studies investigating CoQ10 therapy for the treatment and/or prevention of CKD, but CoQ10 levels decrease with age82 and identification of patients with low CoQ10 levels may allow for targeted therapy with beneficial outcome. Mitochondrial-targeted compounds have created much interest for their application in reducing oxidative stress. One of the most tested is the mitochondrial-targeted derivative of endogenous CoQ10, termed MitoQ (mitoquinone

mesylate). This compound and those alike, such as mitochondrial-targeted vitamin E (MitoVitE), are prepared by covalently attaching a lipophilic cation to an alkyltriphenylphosphonium, allowing rapid accumulation into the mitochondria driven by the large negative value of the mitochondrial membrane potential. Administration of MitoQ in a rat model of diabetic nephropathy decreased mesangial expansion and tubulointerstitial fibrosis, thereby improving renal function.83 Human trials have shown that MitoQ can decrease biomarkers of liver inflammation in hepatitis C patients.84 However, a larger scale, double-blinded, placebo-controlled study found that MitoQ did not slow the progression of untreated Parkinson’s disease, a disease associated with mitochondrial oxidative stress.

To determine the mechanisms by which dimedone decreases prosurvival and cell cycle progression signals, we examined signaling processes that require reversible cysteine sulfenic acid formation.

Global tyrosine, Lyn, Syk (spleen tyrosine kinase), PLCγ2, and ERK 1/2 phosphorylation were determined in the presence of vehicle or dimedone. Immunoblot analysis of global tyrosine phosphorylation revealed an approximately 2.0-fold increase in phosphorylation within 1 min of BCR stimulation (Fig. 6A and F). Dimedone treatment did not decrease the global tyrosine phosphorylation at 1 min. However, after 5 and 15 min of BCR stimulation, dimedone treatment decreased tyrosine phosphorylation compared with that of vehicle-treated samples. Thus, reversible cysteine sulfenic acid formation plays a role in the maintenance of global tyrosine phosphorylation. Because we observed Selleckchem BGB324 Selleck PD0325901 a decrease in global tyrosine phosphorylation, we wanted to determine if specific tyrosine

phosphorylation events following BCR ligation were altered in the presence of dimedone. Immunoblot analysis of Lyn phosphorylation identified similar phosphorylation levels in the vehicle and dimedone-treated samples at all timepoints (Fig. 6B and G). Phospho-Syk analysis by western blot demonstrated an approximately 12-fold increase in phosphorylation after 1 min of BCR stimulation in the absence of dimedone (Fig. 6C and H). By 5 min, the phosphorylation of Syk had increased approximately 39-fold over ex vivo. However, treatment of cells with dimedone significantly decreased

Syk phosphorylation at 5 and 15 min. Similar results were detected with PLCγ2 (Fig. 6D and I) and ERK 1/2 (Fig. 6E and J) RVX-208 phosphorylation in the presence of dimedone. Therefore, reversible cysteine sulfenic acid formation is necessary for the maintenance of global tyrosine, Syk, PLCγ2, and ERK 1/2, but not Lyn, phosphorylation during BCR activation. Since the early tyrosine phosphorylation events were inhibited by dimedone pretreatment, we wanted to determine whether sulfenic acid modification of proteins was altered. To address this, purified B cells were pretreated with vehicle or dimedone prior to measuring sulfenic acid formation in the total proteome and individual candidates. Although somewhat elevated cysteine sulfenic acid levels following dimedone pretreatment were observed, no increase in sulfenic acid levels following B-cell activation were observed in the presence of dimedone (Supporting Information Fig. 2A). Furthermore, when individual proteins were analyzed, dimedone pretreatment decreased (SHP-1 and PTEN) or blocked (SHP-2) sulfenic acid formation following B-cell activation when compared with vehicle (Supporting Information Fig. 2B–D).

Since total numbers of migrated CD4+ T cells did not differ between HD and RR-MS samples, lower Treg percentages under non-inflammatory Pexidartinib concentration conditions can be excluded to be due to increased migration of non-Treg. In line with our data on murine Treg transmigration, human HD Treg displayed consistent basolateral accumulation in the absence of endothelial cells. Higher Treg motility compared to non-Treg has previously been suggested as a mechanism of suppression of T effector cell function

as Treg were shown to be superior to TH cells in establishing close contact to dendritic cells, subsequently inhibiting their full maturation 27. Our finding of an augmented Treg motility in HD therefore is very well in line with this previous data. Furthermore, our observation of a migratory dysfunction of MS patient derived Treg introduces the idea that the presumed “regulatory deficiency” of CD4+ Treg in MS could at least be partially due to impairment in Treg motility. Our study provides first evidence of augmented overall cell motility as a constitutive feature of both Pembrolizumab order murine and human naturally occurring regulatory T cells. Adhesion ligand and chemokine receptor patterns expressed by Treg and their non-regulatory counterparts presumably determine

site-specific homing and have recently been a matter of substantial interest. Their innate cell motility, however, forms the basis of transendothelial diapedesis to and locomotion within any tissue and has been completely neglected in the past. Our data demonstrate Depsipeptide mouse an innate migratory superiority of murine and human Treg over naïve non-Treg. This migratory advantage should contribute to the role of Treg in maintaining tissue immune homeostasis and CNS immune surveillance.

However, this can be disturbed under conditions of autoimmunity, as demonstrated for MS patient-derived Treg. Albeit speculative, our findings could have relevance for the understanding of early lesion development and remitting phases during MS course. Twelve patients (9 female, 3 male) suffering from clinically definite RR-MS according to the revised McDonald diagnostic criteria 28 were enrolled in this study. All patients were in a stable phase of the disease, with relatively low scores on Kurzke’s expanded disability status scale (EDSS<3.5) and neither currently nor previously receiving any immunomodulatory treatment (age: 41.7±12.6 years, disease duration: 4.9±6.6 years, EDSS: 1.4±0.8). Ten HD (7 female, 3 male) with no previous history of neurologic disease served as controls (age: 34.1±12.2 years). There was no significant difference in age and gender distribution between patients with MS and healthy individuals. The study was approved by the local ethics committee and informed written consent was obtained from all participants. Six-wk-old female C57BL/6 mice were obtained from Harlan Laboratories.

5 × 108 CFU mL−1 was prepared in a 0.1 M isotonic saline solution using gentle maceration

to disperse the bacterial microcolonies. Eighty-four male mice of the wild-type Taconic strain were used, each weighing about 30 g (Hernández-Hernández et al., 1995). They Selleckchem Decitabine were divided into 21 groups of four mice each. A noninoculated mouse group (NI-MG) was sacrificed at the beginning of the experiment (T0) and was used to locate and measure the basal TLR2 and TLR4 expression levels. Five groups were inoculated with 0.1 mL of isotonic saline solution (isotonic saline solution-inoculated mice group: ISSI-MG) and used as a control; these were sacrificed Nutlin-3 datasheet at 2, 4, 8, and 48 h postinoculation (PI) and at 10 days PI. Seven groups were inoculated with 0.1 mL of a 2% carrageenan solution (carrageenan-inoculated mice group: CI-MG), and eight groups were inoculated with 0.1 mL of the N. brasiliensis suspension (N. brasiliensis-inoculated mice group: NbI-MG). All inoculations were in the right footpad. Animals in the CI-MG

and NbI-MG were sacrificed at 2, 4, 8, and 48 h PI; at 10, 20, and 50 days PI; and at 6 months PI. All animal experiments were approved by the Ethics Committee of the Faculty of Medicine of the Universidad Nacional Autónoma de México and were performed in accordance with institutional Sorafenib in vivo and national guidelines. The tissue samples from every group were longitudinally cut (5 μm) and treated with different cell staining methods, including haematoxylin and eosin (H&E), toluidine blue, Giemsa, and Gram, to identify cell populations during infection by N. brasiliensis and relate them to the TLR2 and TLR4 localization detected by immunohistochemistry. To detect and quantify TLR2 and TLR4 expression, RT-PCR was used to amplify fragments of mRNA; β-actin was used as a housekeeping gene. Cell localization of TLR2 and TLR4 was determined by specific immunohistochemistry. Total footpad tissue from three mice from each of NI-MG,

ISSI-MG, CI-MG, and NbI-MG was washed with a sterile saline solution, pulverized in liquid nitrogen, and homogenized in 1 mL of QIAzol lysis reagent (Qiagen Sciences, MD). The subsequent steps of the total RNA extraction procedure were performed according to the manufacturer’s protocols. For the RT reaction, 1.3 μg of RNA was used. The reaction mixture also included final concentrations of 1 × RT buffer, 10 mM dithiothreitol, 5 mM dNTP, 10 ng oligo dT, and 400 U of M-MLV reverse transcriptase (Invitrogen, CA) in a 10 μL reaction volume. The reaction was incubated at 30 °C for 10 min and then at 38 °C for 60 min. The PCR technique used the primers first reported by Jin et al.

CD103+ DCs display an enhanced capacity to produce RA [26], high expression of IDO [27], thymic stromal lymphopoietin- [28] and β8-integrin-mediated activation of TGF-β [29]. Thus LP-derived DCs in the mLNs through various mechanisms support the efficient conversion of conventional T cells into iTreg cells. Besides their ability to foster iTreg-cell generation, intestinal CD103+ DCs are imprinted with an enhanced capacity to induce the gut-homing molecules β7-integrin and CCR9 in activated T cells

[25, 26]. Yet, in vivo induction of gut-homing potential in such cells required additional factors that were provided by nonhematopoietic stroma cells [30]. We observed that BM-derived DCs fail to support gut-homing molecule induction in vitro, but can do so in vivo when injected into mLN afferent lymphatics. Conversely, Selleck HKI 272 endogenous LP-derived Selleckchem ITF2357 DCs failed to induce gut-homing molecules in lymph node grafts of peripheral origin [30]. This indicates that in vivo non-DC-dependent factors contribute to the quality of the T-cell response (reviewed in [31]). We may conclude that the microenvironment of mLNs and the unique properties of intestinal DCs synergize to enable the efficient generation of iTreg cells and a gut-homing signature on these cells. Despite the previous findings regarding the generation of iTreg cells in the mLNs, such iTreg-cell

generation still seems insufficient to generate intestinal tolerance. Instead, Aspartate we found that tolerance to the model antigen OVA requires gut homing of iTreg cells and a subsequent local modulation of the Treg cells in the LP [23] (Fig. 1; for a recent review on oral tolerance refer to

[32]). As described in “iTreg-cell generation in the mesenteric lymph nodes”, gut homing requires the β7-integrin, which binds to its ligand MadCAM-1 that is expressed by gut venules. Consistently, β7-integrin-deficient mice fail to generate tolerance to OVA and this defect can be rescued by the adoptive transfer of β7-competent OVA-specific T cells in WT but not MadCAM-1-deficient mice [23]. Within the gut LP, iTreg cells proliferate vigorously and macrophage-dependent signals enable a shift in the overall ratio of Foxp3+ to Foxp3− cells in favor of Treg cells. Thus the gut LP takes an active role in shaping the Treg-cell pool by expanding iTreg-cell populations, which also explains why the TCR repertoire of gut Treg cells differs from that of Treg cells of other origins. Notably, we observe Treg cells in the afferent lymph connecting the intestine to the mLNs, thus documenting that these cells can travel back to their place of birth (O. Pabst, unpublished observation). Interestingly, there is evidence that Treg-cell populations might be modulated in other tissues as well. In skin-draining LNs the frequency of skin-derived Treg cells increases after inflammation [33] and, in an allograft model, Treg-cell-mediated suppression requires the migration of Treg cells from the graft to the draining LNs [34].

Cells challenged with higher doses of antigen (>10 pg DNP-HSA) delivered as single doses achieved significant β-hexosaminidase release. The black Selleck Fer-1 bar in Fig. 1A (1 ng DNP) represents the optimal triggering dose of 1 ng DNP-HSA used as target dose for rapid desensitization

to 1 ng of DNP-HSA (DNP Des). The release obtained with single-dose additions in Fig. 1A was compared to that obtained with doses added sequentially, following every step of the desensitization protocol (see Fig. 1B, white bars). White bars represent β-hexosaminidase release at each particular point in the cumulative sequence of antigen additions. A maximum of 10% β-hexosaminidase release was achieved at all points in the sequence, showing that the desensitization process did not induce a slow release of mediators. To determine whether there was a threshold dose that initiated hypo-responsiveness, replicate samples were used, and at each particular point in the sequence of antigen additions, cells were also challenged with a triggering dose of 1 ng DNP-HSA (see Fig. 1B, gray bars). Response to the triggering dose declined with increasing number

of sequential selleck inhibitor doses. The greatest hypo-responsiveness was achieved with the highest number of sequential additions (11, in Fig. 1B), indicating that hypo-responsiveness was not stabilized until the end of the desensitization protocol. To test whether cells’ hypo-responsiveness achieved with rapid desensitization to

1 ng DNP-HSA could be overcome with higher challenging doses, we analyzed the response of desensitized cells to activating doses of 1, 2, 3, 4 and 5 ng of DNP-HSA. Up to five-fold increase in challenging dose did not reverse desensitization (see Fig. 1C). The protocol was effective when increasing the target dose to 5 and 10 ng, with the same number of steps, time between steps and starting dose (1/1000 the target dose), but less inhibition of β-hexosaminidase release was observed (see Fig. 1D). Cells desensitized to 1 ng DNP-HSA showed a 75% inhibition whereas cells desensitized to 5 and 10 ng DNP-HSA had a 65 and 41% inhibition of β-hexosaminidase release, respectively. BMMCs sensitized with anti-DNP IgE or anti-OVA IgE were rapid-desensitized STK38 as per the protocol presented in Table 1. In both DNP and OVA systems, we measured the release of β-hexosaminidase when antigen was delivered as a single dose (1 ng DNP-HSA/10 ng OVA, black bars in Fig. 2A) or when antigen was delivered following the rapid desensitization protocol (white bars in Fig. 2A). Cells desensitized to 1 ng DNP-HSA and 10 ng OVA showed a 78 and 71% inhibition of β-hexosaminidase, respectively. Exocytosis of pre-formed mediators from granules cannot occur without external calcium entry.

STAT1 can

exert its effect on target DNA either by direct binding or indirectly through the formation of complexes with other transcription factors. We hypothesized that the DNA-binding region of STAT1 may contain a site click here that is important for the constitutive interaction of STAT1 and the GILT promoter. Therefore, we tested whether known DNA-binding mutants – V426D/T427D,29 E428A/E429S30 and K544A/E545A,31– can alter the activity of the GILT promoter. Our luciferase reporter gene experiment indicated that only V426D/T427D was unable to decrease the activity of the GILT promoter, suggesting that STAT1 binding to DNA is necessary and that residues V426/T427 are the most important for the STAT1 suppressive effect on the ligand-independent activity of the GILT promoter. The mutant V426D/T427D is defective in the IFN-γ-induced STAT1 DNA binding selleck chemicals llc to specific GAS sites and shows weakened, non-specific protein–DNA interactions,29 and therefore the implication is that GAS sites remain an important target for STAT1, even in the absence of IFN-γ stimulation. The DAPA confirmed

that indeed the V426D/T427D (Mut 1) mutant cannot bind to GAS-like sites in the GILT promoter in vitro, whereas the K544A/E545A (Mut 3) mutant binds to GAS-like sites, albeit weakly. However, we were unable to show that the mutant E428A/E429S (Mut 2), which suppresses GILT promoter activity as in the WT, binds in vitro to a GAS-like site in the GILT promoter. This apparent discrepancy

may be caused by very weak binding to the GAS site in the GILT promoter that is below the limits of detection by DAPA, and/or perhaps is caused by the binding of this mutant to another, as yet unidentified, transcription factor. The fact that the absence of STAT1 increases the activity of the GILT promoter and GILT protein expression may be caused by competition/interaction of STAT1 with other transcription factors. For example, STAT3 can replace STAT1 in STAT1−/− cells to drive the transcription of certain genes in response mTOR inhibitor to IFN-γ or interleukin-6.41 STAT1 and STAT3 dimers bind selectively to very similar, but not identical, elements27,42 and thus activate different, but overlapping, sets of genes. In addition, Egr-1 (also designated zif268, TIS 8, NFGI-A, Krox 24) has been identified as one of the transcription factors that targets GILT.43 Egr-1 is a member of the immediate-early gene family that includes FOS, JUN and early growth-response genes.44,45 Egr-1 binds to 5′-GCGGGGGCG-3′ consensus sequences within the promoter region of target genes.46 The GILT promoter contains several GC-rich domains in the vicinity of GAS-like sites and it is therefore possible that the binding of Egr-1 and STAT1 to some regions of the GILT promoter are mutually exclusive. The competition for binding to the GILT promoter, if any, remains to be shown.