0404, Wilcoxon p=0 0280; progression-free survival: Log-Rank p=0

0404, Wilcoxon p=0.0280; progression-free survival: Log-Rank p=0.0225; Wilcoxon p=0.0136). In vitro assays revealed increased proliferation and migration of medulloblastoma cell lines after PAX8 siRNA knockdown. In summary, high PAX8 expression is linked to better prognosis in

medulloblastomas potentially by suppressing both proliferative and migratory properties of MB cells. The distinct spatio-temporal expression pattern of PAX8 during brain development might contribute to the understanding of distinct MB subtype histogenesis. “
“Cerebral amyloid angiopathy (CAA) represents the deposition of amyloid β protein (Aβ) in the meningeal and intracerebral Selleckchem Caspase inhibitor vessels. It is often observed as an accompanying lesion of Alzheimer’s disease (AD) or in the brain of elderly individuals even in the absence of dementia. CAA is largely age-dependent. In subjects with severe CAA a higher frequency of CT99021 datasheet vascular lesions has been reported. The goal of our study was to define the frequency and distribution of CAA in a 1-year autopsy population (91 cases) from the Department of Internal Medicine, Rehabilitation, and Geriatrics, Geneva. Five brain

regions were examined, including the hippocampus, and the inferior temporal, frontal, parietal and occipital cortex, using an antibody against Aβ, and simultaneously assessing the severity of AD-type pathology with Braak stages for neurofibrillary tangles identified with an anti-tau antibody. In parallel, the relationships of CAA with vascular brain Thymidylate synthase lesions were established. CAA was present in 53.8% of the studied population, even in cases without AD (50.6%). The strongest correlation was seen between CAA and age,

followed by the severity of amyloid plaques deposition. Microinfarcts were more frequent in cases with CAA; however, our results did not confirm a correlation between these parameters. The present data show that CAA plays a role in the development of microvascular lesions in the ageing brain, but cannot be considered as the most important factor in this vascular pathology, suggesting that other mechanisms also contribute importantly to the pathogenesis of microvascular changes. “
“Glioblastomas display marked phenotypic and molecular heterogeneity. The expression of the PTEN protein in glioblastomas also shows great intratumour heterogeneity, but the significance of this heterogeneity has so far received little attention. We conducted a comparative study on paraffin and frozen samples from 60 glioblastomas. Based on PTEN immunostaining, paraffin glioblastomas were divided into positive (homogeneous staining) and both positive and negative (heterogeneous staining) tumours. DNA was extracted from manually microdissected samples from representative areas, and from frozen samples taken randomly from the same tumours.

29 This model is used to evaluate the pathophysiology of diabetic

29 This model is used to evaluate the pathophysiology of diabetic nephropathy. In this experimental model of diabetic nephropathy,24 the expression of renal hL-FABP and urinary excretion of hL-FABP increase significantly in STZ-induced diabetic hL-FABP Tg mice as compared to control Tg mice at 8 and 14 weeks after STZ injection. The dynamics of hL-FABP in this model may reflect its dynamics under similar pathological conditions in humans. With regard to the role of hL-FABP in diabetic nephropathy, the production

of oxidative stress is strongly suppressed in the diabetic Tg mice and thus, the production of inflammatory cytokines such as monocyte chemoattractant protein (MCP)-1 and MCP-3, the production of fibrosis-accelerating factors such as transforming growth factor-β (TGF-β) and procollagen, and the degree of tubulointerstitial inflammation and fibrosis are significantly inhibited in the diabetic learn more Tg mice as compared to the diabetic wild type (WT) mice.24 Therefore, hL-FABP has an effective antioxidant function and attenuates tubulointerstitial damage in diabetic mice. The factors that upregulate the expression of renal hL-FABP in the proximal tubules could serve as

important therapeutic targets for the prevention of tubulointerstitial damage in diabetic nephropathy. Unilateral ureteral obstruction CH5424802 (UUO) is a well established model to evaluate the pathophysiology of hydronephrosis or progressive tubulointerstitial damage observed in CKD, in which the left ureter is ligated with sutures at two locations and cut between the ligatures to prevent retrograde urinary tract infection, thereby inducing the production of inflammatory cytokines, invasion of inflammatory cells, tubular dilatation and tubulointerstitial fibrosis. The interstitium in the setting of UUO is under Evodiamine continuous

oxidative stress produced by tension or hypoxia induced by marked decline in renal plasma flow. In this model, the expression of renal hL-FABP is upregulated, and the development of tubulointerstitial damage in the hL-FABP Tg mice with UUO is suppressed.22 In the UUO as well as diabetic nephropathy models, the factors that upregulate the expression of renal hL-FABP have been proposed as new strategies for inhibiting the progression of kidney disease. This model is used frequently to evaluate the pathophysiology of the transplanted kidney. The experimental model involves induction of renal ischemia by clamping the renal arteries with microclips, and after 30–60 min, the clamps are removed and the renal arteries are subsequently allowed to reperfuse followed by collection of kidney specimens 0–72 hours after clamp release. The initial pathogenic factor for progression of the tubulointerstitial damage in this model is considered to be oxidative stress induced by reperfusion after ischemia. The pathological analysis of this model shows tubular cell death, in the form of necrosis or apoptosis.

43,44 Studies are currently underway to identify such cells in sh

43,44 Studies are currently underway to identify such cells in sheep through a combination Palbociclib mw of phenotypic (CD4, CD25, Foxp3, IL-10 and TGF-β expression) and function (suppression assays). TH17 cells have not been defined in sheep, although they may not be a primary target for reproductive studies, as it appears that peripheral blood TH17 levels in women are not influenced by pregnancy.45 Collectively, these technologies for ruminant immunology will allow us to assess more fully the paradigms relating to immune regulation and cell function

during reproduction in normal and infected sheep. GE, SW and MR are funded by the Scottish Government Rural and Environment Research and Analysis Directorate (RERAD). NW is funded by the Biotechnology and Biological Sciences Research

Council (BBSRC; grant number BBE0189391). We thank Dr David Longbottom (Moredun Research Institute) for kindly providing the image of the aborted placenta. None of the authors have any conflicts relating to this publication. “
“Lipopolysaccharides (LPS) have been associated with a protective role in the development of asthma while higher levels of endotoxin have been linked with more severe asthma. LPS recruit neutrophils and eosinophils and activate macrophages via the CD14 receptor. The soluble CD 14 receptor (sCD14) has been found in bronchoalveolar lavage fluid in different diseases including allergic asthma. To elucidate the kinetics and the regulation of sCD14 concentrations in BAL in asthma, 18 patients with allergic asthma underwent segmental allergen challenge at different time points (10 min, 18, 42 and 162 h). In addition, CD14+ peripheral blood Selleck MAPK Inhibitor Library mononuclear cell (PBMC-CD14+) GPX6 cultures from seven allergic and seven non-allergic subjects were stimulated with LPS, leukotrien D4 (LTD4), a combination of LPS and LTD4, IL-17 and LTD4 in presence of the leukotriene-receptor antagonist (LTRA) Montelukast for 6, 12 and 24 h. sCD14 concentrations in BAL and the supernatants were measured by ELISA. sCD14 concentrations in BAL were significantly increased 18 h after allergen challenge and peaked at 42 h. At 162 h, concentrations had returned to baseline levels.

In PBMC-CD14+ cultures, sCD14 levels increased significantly 24 h after stimulation with LTD4 and Montelukast was able to block LTD4-induced stimulation. Allergen challenge leads to a significant increase in sCD14 concentrations in BAL and might modulate the allergen-induced inflammation. In addition, LTD4 might play a role in the release of sCD14, and it could be speculated that sCD14 reduction by LTRA might contribute to the mechanisms of LTRA in the treatment of allergic asthma. Endotoxins have been implicated in the pathogenesis of asthma. Following the ‘hygiene hypothesis’, endotoxins might even have a protective role in the development of allergic asthma [1] and endotoxin exposure at home has been associated with a reduced prevalence of atopy [2].

TNF-α production induced by a human-type PO-CpG ODN2006 was also

TNF-α production induced by a human-type PO-CpG ODN2006 was also increased by co-incubation

with DNase I-treated GpC ODN2006 or DNase I-treated ODN1720 in the cells (Supporting Information Fig. 2). To evaluate the involvement of TLR9 in the DNase I-treated DNA-mediated increase in cytokine production, similar experiments were carried out using splenic macrophages and the production of TNF-α (Fig. 1C) and IL-6 (Fig. 1D) was examined. The addition of LPS, a positive control, induced significant TNF-α production in splenic macrophages from both WT and TLR9 knockout (KO) mice, indicating the ability of these cells to produce cytokines. In the cells from WT mice, DNase I-treated DNA significantly increased the ODN1668-induced production of TNF-α and IL-6. click here However, no such increase was observed in splenic macrophages from TLR9 KO mice. Next, we evaluated the effect of DNase I-treated DNA on the TNF-α production induced by ligands other than ODN1668. The following ligands were selected and used: pCMV-Luc, a double-stranded circular DNA containing many CpG motifs; ODN2216, a CpG ODN with phosphorothioate (PS) bonds at the both ends; PS-1668, a PS-type CpG ODN having the same sequence as ODN1668; non-CpG lipoplex, a complex consisting of pCpG-ΔLuc and cationic liposomes, which was reported to be a ligand for cytosolic DNA

receptors 18, 19; polyI:C, a double-stranded RNA and a ligand for TLR3; LPS, a ligand for TLR4; and imiquimod, a ligand for TLR7 20, 21. Based on preliminary experiments, the concentration of each ligand was set at low levels to avoid saturation of TNF-α production in cells. Each ligand induced AZD9291 significant TNF-α production in RAW264.7 cells at varying levels (Fig. 2, hatched bars). DNase I-treated ODN1720 significantly increased pCMV-Luc-induced TNF-α production, but it hardly affected TNF-α production induced by other ligands (Fig. 2, black bars). GNA12 Again, ODN1720 showed no significant effects on the TNF-α production induced by any of these ligands (Fig. 2, gray bars). These results indicate that the DNase-I-treated DNA-mediated increase in cytokine production is specific to two TLR9 ligands, ODN1668

and pCMV-Luc. Additionally, we examined the effects of DNase I-treated DNA on TNF-α production induced by another 26-mer ODN containing three potent CpG motifs, 5′-TCGACGTTTTGACGTTTTGACGTTTT-3′. The addition of DNase I-treated ODN1720 also increased the TNF-α production induced by this CpG ODN (data not shown). Taken together, these results suggest that the effect of DNase I-treated ODN1720 on cytokine production is independent of the sequence and length of CpG DNA, and not restricted to single-stranded DNA. To examine which components of DNase I-treated DNA were responsible for the increase in the CpG motif-dependent TNF-α production, RAW264.7 cells were incubated with ODN1668 in the presence of nucleotides or nucleosides (Fig. 3A).

The expulsion of another intestinal nematode, Nippostrongylus bra

The expulsion of another intestinal nematode, Nippostrongylus brasiliensis, also occurs independently of mMCP-1 (15,36). Our results hence confirm that, despite a number of common features in the host response to various gut parasites, differences in intestinal niches between parasites will bring along different excretion mechanisms (37,38). For instance, expelling the adult (sub)epithelial T. spiralis or N. brasiliensis may be expected to depend on different mechanisms

than the facilitation of egg passage through the intestinal wall in case of S. mansoni. Moreover, the maturing schistosome eggs actively release proteases (39) and several other proteins. Although the function of these proteins remains largely unknown, it is likely that they modulate the host’s immune response to promote egg excretion (40–43). This may reduce the significance of mast cell-derived Hydroxychloroquine research buy products, such as mMcp-1, in the process of egg excretion.

NVP-BKM120 order Alternatively, mucosal mast cell mediators other than mMCP-1 may play a role in the S. mansoni egg excretion. For example, tumour necrosis factor (TNF)-α, which is involved the pathology of schistostomiasis (44), is also released by MMC (9,45). In vitro, TNF-α increases intestinal TJs permeability by modifying the distribution and the expression levels of ZO-1 (46) and by altering the lipid composition in membrane microdomains of TJs (47,48). IL-1β, another cytokine released by MMC, (49,50) increases TJs permeability of Caco-2 monolayers which is accompanied by changes in the expression levels and distribution of occludin and claudin-1 (51). Other

mast cell mediators such as IL-4, IL-10 and IL-13 (52) also modulate TJs permeability, in vitro, via several specific mechanisms (53) and thus potentially participate in the impairment of the intestinal barrier observed in S. mansoni-infected mice. The peak time of S. mansoni egg excretion was accompanied by a decrease in electrical resistance and secretory capacity of the ileal tissue, which are, as far as we are aware, quantified here for the first time. The ileal resistance was reduced to 25% of control values, which is much lower than reported for infection with Heligmosomoides polygyrus, N. brasiliensis or T. spiralis (to 55%) (54) or, for instance, in response to chronic psychological stress (to 54%) (55) and acute pancreatitis (to 75%) MTMR9 (24). The relatively large reduction in the mucosal resistance is in accordance with the increase of the flux of NaFl (to about 150% of control) and might indicate a disturbed function also of the epithelial cells proper. This suggestion is strongly supported by our finding that spontaneous secretion of the tissues and also their maximal secretion capacity are 8 w p.i. reduced to 39% and 11% of control respectively. This contrasts with the increase in secretion reported in other models of inflammation, such as experimental acute pancreatitis (24) or chronic stress (55).

Hydrogen bonding between conserved heavy-chain cleft residues and

Hydrogen bonding between conserved heavy-chain cleft residues and the N- and C-termini of associated peptides typically limit their length to 8–13 residues (though exceptions abound [2]), and strictly dictate peptide directionality. Additionally, six defined

pockets (termed A–F) in the cleft confer specificity for peptide side chains oriented toward the groove [3]. Extensive polymorphism between the binding grooves of different MHC allomorphs (>7000 known alleles (and climbing) in human populations with up to six allomorphs expressed per person from the HLA-A, -B, and -C loci (http://hla.alleles.org/nomenclature/stats.html)), ensures that a wide spectrum of peptides is presented to the immune system, essentially preventing pathogen escape at the population level. Despite allelic preferences, common themes guide peptide/MHC (pMHC) binding. Pooled aa sequencing of peptides eluted from many different individual class I allomorphs revealed residues overrepresented Kinase Inhibitor Library mouse at each position [4, 5], though notably, these allele-specific peptide-binding motifs are also influenced by peptide liberation, transport, and trimming (reviewed in [6]). Most peptide pools exhibit highly dominant specific aas (or chemically similar aas) at or near their N- and C-termini [4, 5]. These “anchor” residues

greatly influence peptide-binding Sorafenib chemical structure affinity. The more N-terminal anchor is typically located at peptide position 2 or 3 (denoted as p2 and p3) and is accommodated by the B-pocket of the peptide-binding cleft, though it can be located up to p5 (C-pocket, as is the case for the mouse H-2Db allomorph [4]). The deep F-pocket cradles the C-terminal anchor, typically an aliphatic or aromatic residue for mouse class

I allomorphs (some human allomorphs also favor basic C-terminal anchors). Predictably, detailed peptide mapping [7] and high-throughput mass spectrometry [8] identify numerous high-affinity peptides that break these simple rules, increasing both the size of the immunopeptidome and the difficulty of in silico peptide-binding prediction. Class I molecules present tens of thousands of different self-peptides among approximately 105 pMHC complexes on the surface Tryptophan synthase of each cell [9], consistent with their role in tumor immunosurveillance. How does the cell supply this diverse array of pMHCs? Most MHC class I peptides arise from rapidly degraded polypeptides, ensuring representation among the translatome independently of protein stability and minimizing the time to detect viral translation [10]. To enhance immunosurveillance of tumor-associated Ags (TAAs), ribosome subpopulation sampling [11, 12] likely enables surveillance of low abundance bona fide and defective mRNAs [13, 14]. TAA–peptide abundance is critical, since many TAAs derive from nonmutated genes and are thus recognized by low-affinity T cells that escape self-tolerance [15]. The affinity of peptides for MHC governs the stability of complexes and hence levels of cell surface expression [16].

An overall defect of 10 mm was made in the sciatic nerve of the a

An overall defect of 10 mm was made in the sciatic nerve of the animals in the experimental groups. Each group consisted of two time intervals of 6 and 12 weeks (n = 6). After each experimental interval, sciatic functional index (SFI) along with area and diameter of the axons and fibers of each group were calculated. Muscle mass measurements were also evaluated to see any functional recovery in the groups. Expression of

neurotrophins in the graft and distal stump Temsirolimus supplier were analyzed with the help of RT-PCR. SFI obtained from walking track analysis showed poor motor recovery in the experimental groups during both time intervals. No significant differences in the histological, morphometric (P > 0.05), and muscle mass measurements (P > 0.05) between the two experimental groups were observed. Analysis of RT-PCR data exhibited an increase in the expression of NT-3 with time in both the grafts (6 weeks 0.428 ± 0.392, 12 weeks 1.089 ± 0.455, P < 0.05) and distal stump (6 weeks 0.411 ± 0.306, 12 weeks 0.807 ± 0.303,

P < 0.05) of the SVG group. The study concludes that there is no substantial difference in the nerve regeneration ability between both the techniques. Also, the difference in the level of NT-3 between SVG and IOVG suggests a distinct regulation of NT-3 in peripheral nerve regeneration. © 2014 Wiley Periodicals, Inc. Microsurgery, 2014. "
“In Gamma-secretase inhibitor this report, we present the results of investigation of the effects of prostaglandin E1 (PGE1) on entrapment neuropathy using a diabetic rat. A total of 60 male Sprague-Dawley rats were used many in the study. The model of tibial nerve entrapment neuropathy associated with diabetes mellitus was created by streptozotocin-induced diabetic rats reared in cages with wire grid flooring. Rats were assigned to four groups: nondiabetic (n = 15), untreated diabetic (n = 15),

diabetic treated with 30 μg/kg PGE1 (n = 15), and diabetic treated with 100 μg/kg PGE1 (n = 15). Pain tests and electrophysiological tests were performed at 0, 2, and 4 weeks, and assessments of gait, histology, and mRNA expression levels were performed at 4 weeks after initiating the PGE1 administration. In the 30 and 100 μg groups, the mechanical withdrawal thresholds measured by pain tests at 4 weeks (36.2 ± 16.4 g and 31.7 ± 15.3 g, respectively) and the motor conduction velocity (24.0 ± 0.2 m/s and 24.4 ± 0.3 m/s, respectively) were significantly higher than the untreated diabetic group (all P < 0.05) and lower than the nondiabetic group (all P < 0.001). In the gait analysis, the mean intensities in the 30 and 100 μg group (128.0 ± 20.1 a.u. and 109.0 ± 27.8 a.u., respectively) were significantly higher than the untreated diabetic (P < 0.01) and were not significantly different from the nondiabetic group (P = 0.81). Fiber density (P = 0.46) and fiber diameter (P = 0.15) did not show any significant differences.

8% in 2008) [16] In the Australian dialysis population, infection

8% in 2008).[16] In the Australian dialysis population, infection accounted for 11% of mortality, the third most common cause of death following dialysis withdrawal (35%) and cardiac disease (43%)[17] Of the 11% (n = 148), approximately 25% was secondary to bacterial septicaemia. Similarly, 17% of mortality was attributed to infection in the New Zealand dialysis population. CRI has an enormous adverse impact, not only at individual level of increased morbidity and mortality, but also financial implications with the costs of hospital admissions, antibiotics use and catheter change. Cost-per-infective-episode has been estimated to be between US$3703 and US$29 000 in the USA from non-tunnelled catheters in intensive care

units.[18] With the high incidence of catheter use in incident haemodialysis patients, it is imperative to develop strategies to prevent https://www.selleckchem.com/products/acalabrutinib.html and treat CRI. There have been studies examining the application of topical agents to the exit site to prevent both local and systemic infections. Intense interests have been concentrating on the use of antimicrobial lock solutions (ALS) to reduce CRI in recent years. Once bacteraemia has occurred, catheter removal, with or without delay in insertion of a new vascular catheter, is often indicated. Alternative therapy such as combining systemic antibiotics and ALS, without changing the catheter, has been evaluated in the literature. The objective of this guideline is to identify appropriate recommendations for central mTOR inhibitor venous catheter insertion and catheter care, as well as prevention and treatment of CRI in dialysis patients with tunnelled catheters in-situ. Dressing type, frequency of dressing changes and cleansing solutions will be addressed. The use of topical agents or intraluminal lock solutions will be investigated as will be the various treatment strategies for CRI. The use of real-time ultrasound guidance is strongly recommended for the placement of haemodialysis catheters and results in improved rates of successful catheter

placement, and reduced rates of both haematoma formation and inadvertent arterial puncture. (Level 1 evidence) (Suggestions are based on Level III and IV evidence) The adherence to strict aseptic technique is proven to reduce the catheter related bacteraemia rate and all units should therefore audit this practise. Tunnelled haemodialysis CHIR99021 catheters should be used as they are associated with lower rates of catheter related bacteraemia, catheter dysfunction and vascular damage (venous trauma, and stenosis) compared with temporary non-tunnelled catheters. The right internal jugular vein is the preferred insertion site with respect to ease of access and lower rates of short and long-term complications. In ICU settings, subclavian catheter placement has excellent short-term outcomes compared with jugular and femoral approaches but has significant long-term sequelae recommending against their use.

(Table 1) In the CKD group, mean serum creatinine was 2 4 mg/dl

(Table 1). In the CKD group, mean serum creatinine was 2.4 mg/dl. 73% patients were in CKD stage 111. Conclusion: CKD was the most common renal syndrome observed in 44% patients. Mesangial proliferation followed by focal endocapillary proliferation were the predominant histological pattern observed in our study. SIVATHASAN SUDHAHARAN Department of Nephrology, Hospital Kuala Lumpur Djengkol bean (Pithecellobium jeringa) is frequently used in the Malay Archipelago as a staple in local cuisine and for its purported medicinal value (Figure). It contains djenkolic acid, a sulphur-containing

amino acid. Its precipitation in urine forms sludge, causing obstructive uropathy. Djenkolism has been reported almost exclusively involving the South East Asian population principally Malaysians and Indonesians. A healthy 44 year old Indonesian gentleman had consumed a kilogram of djengkol beans with CH5424802 price boiled rice (nasi ulam). He presented 48 hours later with colicky abdominal pain, inability to pass urine or have bowel openings. Examination revealed a distended abdomen with sluggish bowel sounds. There was no pedal edema. He had an initial urea of 14.8 mmol/L,

potassium 4.3 mmol/L and creatinine 443 μmol/L. It had deteriorated to a peak urea of 27.1 mmol/L and creatinine 1088 μmol/L. He had compensated metabolic acidosis, with a pH of 7.332, bicarbonate 12.1 mmol/L and this website base excess −11.6. A urine examination revealed microscopic hematuria. An ultrasound on admission revealed good sized kidneys with mild right hydronephrosis but no calculi, confirmed by a CT urogram. He was anuric the first three days of admission despite aggressive hydration. Haemodialysis via a femoral catheter was performed twice. On day three of admission he developed frank haematuria and was put on bladder irrigation by the Urology team. He was initially planned for stent

insertion for obstructive uropathy; however the hematuria resolved and he was polyuric after bladder irrigation. As for the constipation, an abdominal Xray revealed prominent large bowel dilatation. He MycoClean Mycoplasma Removal Kit was treated conservatively by the Surgical team. When he produced urine, he was also able to open his bowels. He was discharged well on day seven of admission with resolution of the acute kidney injury. Djenkolism occurs predominantly in males, with a seasonal increase between September and February in keeping with the rainy season and blossoming of the djengkol tree. The development of renal failure is not dependent on the method of preparation or amount consumed. The prognosis is good, with all case reports published reporting resolution of renal failure with conservative measures, one requiring bilateral stenting. This is believed to be the first report of djenkolism requiring acute dialysis, and one that caused acute intestinal obstruction.

For example, type I and type II IFNs both inhibit the IL-4-induce

For example, type I and type II IFNs both inhibit the IL-4-induced STAT6

activation in human monocytes to CHIR-99021 purchase suppress IL-4-inducible gene expression 22. In polarized Th1 cells, IFN-γ may suppress phosphorylation of STAT6 by inhibiting its recruitment to the IL-4R 23. As compared to IFN-γ, the effects of IFN-α on the IL-4 signaling pathway have been studied in limited cell systems, which indicated rather a complex regulation involving both inhibition and promotion of the STAT6-mediated IL-4 response by IFN-α 22, 24. IRF7 is shown as a counter-regulation target of IFN-α signaling by IL-4. It plays important roles in type I IFN responses such as antiviral effects and Th1 immune functions 25, 26. It was previously reported that IL-4 reduced the increment of IFN-α-induced IRF7 and IFNARs through

the inhibition of the initial phosphorylation of see more STAT1 and STAT2, which suppressed antiviral effects by IFN-α in myeloid DC 17. IRF7 was first identified within the biological context of EBV latency and was found to be expressed at high levels by latent membrane protein-1 to increase virally induced IFN production in EBV-transformed B cells 27, 28. However, the mechanism of IRF7 gene expression through counter-regulation by IFN-α and IL-4 in B cells has not been studied in detail and thus remains unclear. To elucidate the molecular mechanism of reciprocal regulation of IFN-α and IL-4 signal transduction, we have employed a human B-cell line Ramos, sensitive to both IL-4 and IFN-α which counter-regulate CD23 and IRF7 expression.

Our data demonstrate that (i) IFN-α inhibits IL-4-signaling else mainly through the suppression of STAT6 nuclear localization without a decrease in total STAT6 phosphorylation, (ii) IL-4 and IFN-α treatment leads to the concomitant cytosolic accumulation of IL-4-induced pY-STAT6 and IFN-α-induced pY-STAT2:p48, which interact at the molecular level, and finally (iii) the over-expression of STAT2 or STAT6 induces cytosolic capture of pY-STAT6 or pY-STAT2 and adversely affects CD23 or IRF7 expression induced by IL-4 or IFN-α, respectively. Together, the results of the present study provide a novel molecular mechanism of counter-regulation by IL-4 and IFN-α through the formation of a molecular complex containing pY-STAT6, pY-STAT2, and p48 retained in the cytosol. In order to investigate the regulation of IL-4 signal transduction by IFN-α, the CD23-expressing Ramos B-cell system was chosen. CD23 is known as the low-affinity IgE receptor and recognized as a B-cell activation molecule involved in B-cell growth and differentiation through cell-to-cell interaction. It is found to be constitutively and atypically expressed on malignant B cells in patients with chronic lymphocytic leukemia 18, 29 and Burkitt’s lymphoma 30.