While these differences

in tissue microRNA expression are

While these differences

in tissue microRNA expression are interesting, defining whether changes are disease-specific or fundamental to disease selleck chemicals llc pathogenesis remains a major challenge. Transition of epithelial to mesenchymal cells is recognized as a substantial contributor to the development of kidney fibrosis.63 Epithelial mesenchymal transition (EMT) describes a reversible series of events during which epithelial cells undergo morphological changes and acquire mesenchymal characteristics. These events involve epithelial cells losing cell–cell contacts, apical-basal polarity and epithelial-specific junctional proteins such as E-cadherin while acquiring mesenchymal markers including vimentin and N-cadherin.64 The end result is that immobile epithelial cells revert to an immature undifferentiated phenotype with enhanced migratory ability reminiscent of an earlier development stage and can embed in interstitium.

EMT is known to be involved in implantation, embryogenesis and organ development. It also has been shown to associate with cancer progression and metastasis.65 EMT has been suggested to contribute to kidney fibrosis, which is defined as an excessive deposition of extracellular matrix, mediated predominantly by fibroblasts and mesenchymal cells, FDA-approved Drug Library leading to structural destruction and renal failure. The possible sources of fibroblasts and mesenchymal cells in kidney fibrosis include de novo proliferation of resident tissue fibroblasts, circulating fibrocytes from bone marrow or perivascular smooth muscle cell expansion (myofibroblasts). It has been demonstrated recently that a

large proportion of interstitial fibroblasts actually originate from tubular epithelial cells via EMT in diseased kidney.66–68 Several studies have now found that EMT is regulated by miRNAs, notably the miR-200 family and miR-205.69–72 These miRNAs have been implicated in the EMT process occurring in cancer development.72 The miR-200 family and miR-205 are downregulated in Madin Darby canine kidney cells undergoing TGFβ-induced EMT.69 Their decrease with TGF-β exposure is linked to the EMT response. Evidence has recently emerged that the miR-200 MG-132 datasheet family and miR-205 are elevated in patients with hypertensive nephrosclerosis.58 Recently, Yamaguchi et al. have proposed an important mechanism for podocyte dehiscence and loss through EMT.73 In other disease processes, particular miRNAs were found to be substantially altered during EMT.65 Future work is required to determine the significance of miRNA involvement in EMT during the development of diabetic nephropathy. Renal transplantation is the treatment of choice for patients with end-stage kidney disease because of superior survival and quality of life when compared with patients on maintenance dialysis. Despite improvements in immunosuppression, acute rejection (AR) and chronic allograft nephropathy remain major challenges.

Posted in Uncategorized | Leave a comment

Future studies are needed to examine the role of S100A8, S100A9 a

Future studies are needed to examine the role of S100A8, S100A9 and S100A12 in other human MDSC subtypes with the aim of further characterization of these cells. This will help further our understanding of their mechanism of action and help to target them for BMS-777607 ic50 immunotherapeutic approaches. This research was supported (in part) by the Intramural Research Program of the National institutes of Health, National Cancer Institute, Center for Cancer Research.

This work was supported by a grant to MPM from the Initiative and Networking Fund of the Helmholtz Association within the Helmholtz Alliance on Immunotherapy of Cancer. We would like to thank the Experimental Transplantation and Immunology Branch cell sorting facility for technical assistance with cell sorting. None of the authors have any financial conflict of interest. Figure S1. PBMC were isolated by Ficoll density gradient and stained click here for CD14 and HLA-DR expression. “
“DNA is immunogenic and many cells express cytosolic DNA sensors that activate the stimulator of interferon genes

(STING) adaptor to trigger interferon type I (IFN-β) release, a potent immune activator. DNA sensing to induce IFN-β triggers host immunity to pathogens but constitutive DNA sensing can induce sustained IFN-β release that incites autoimmunity. Here, we focus on cytosolic DNA sensing via the STING/IFN-β pathway that regulates immune responses. Recent studies reveal that cytosolic DNA sensing via the STING/IFN-β pathway induces indoleamine 2,3 dioxygenase (IDO), which catabolizes tryptophan to suppress effector and helper T-cell responses and activate Foxp3-lineage CD4+ regulatory T (Treg) cells. During homeostasis, and in some inflammatory settings, specialized innate immune cells in the spleen and lymph nodes may ingest and sense cytosolic DNA to reinforce tolerance that prevents autoimmunity. However, malignancies and pathogens may exploit DNA-induced regulatory responses to suppress natural and vaccine-induced immunity to malignant and infected cells. In

this review, we discuss the biologic significance of regulatory responses to DNA and novel approaches to exploit DNA-induced immune responses for therapeutic benefit. The ability of DNA to drive tolerogenic Reverse transcriptase or immunogenic responses highlights the need to evaluate immune responses to DNA in physiologic settings relevant to disease progression or therapy. The immune adjuvant properties of DNA are well known and are exploited to enhance vaccine responses. Recent reports describe a surprisingly large array of cytosolic DNA sensors, many of which activate the stimulator of interferon genes (STING, aka MITA, ERIS, MPYS, TMEM173) to induce IFN-β in a broad range of cell types (reviewed in [1-6]. IFN-β is a potent immune cell activator, inciting host defense against many pathogens. As most mammalian cells express cytosolic DNA sensors, DNA sensing may have wider biological significance than signaling pathogen presence.

Posted in Uncategorized | Leave a comment

cDNA was synthesized using a high-capacity RNA-to-cDNA kit accord

cDNA was synthesized using a high-capacity RNA-to-cDNA kit according to the manufacturer’s instructions (Applied Biosystems). Real-time PCR for RORγt, T-bet, Gata3, and AHR expression was performed using power SYBR Green PCR Master Mix (Applied Biosystems, Foster City, CA). Primers utilized were: RORγt – 5′-GGCTGTCAAAGTGATCTGGA-3′ forward; 5′-CCTAGGGATACCACCCTTCA-3′ reverse; T-bet – IWR-1 solubility dmso 5′-CTGCCTGCAGTGCTTCTAAC-3′ forward; 5′-GCTGAGTGATCTCTGCGTTC-3′ reverse; Gata3 – 5′-ACTCAGGTGATCGGAAGAGC-3′ forward; 5′-AGAGGAATCCGAGTGTGACC-3′

reverse; AHR – 5′-CACTGACGGATGAAGAAGGA-3′ forward; 5′-TCGTACAACACAGCCTCTCC-3′ reverse. Expression was normalized to glyceraldehydes 3-phosphate dehydrogenase (GAPDH). BALB/c mice were divided into three

groups of 5. Mice were shaved selleck chemicals llc on the dorsum with electric clippers, and injected intradermally with 100 μL of PBS containing 530 pmol VIP, 530 pmol PACAP, or PBS alone. Fifteen minutes after injection, the mice were painted with 10 μL of DNFB (1% in acetone and olive oil (4:1)) epicutanousely at the injection site. Three days after immunization, mice were sacrificed and draining lymph nodes (axillary and inguinal) removed. Lymph nodes were mechanically disrupted and passed through a 70 μm nylon mesh to yield a single cell suspension. CD4+ T cells were isolated as described above. Ninety-six well flat-bottom plates were treated with 10 μg/mL of anti-mouse CD3 mAb in PBS overnight and washed. T cells were cultured (3 × 105 cells/well) in 250 μL of CM containing 2 μg/mL of anti-mouse CD28 mAb. Supernatants were collected 72 h after stimulation and cytokine content determined. Differences in average cytokine levels under different treatments at varying cOVA concentrations were analyzed using ANOVA. Average cytokine levels under each cOVA concentration were then compared between PACAP or VIP treatment and control groups. p-values were adjusted by controlling for the false discovery rate (FDR). For assessment of mRNA levels, effects of intradermal administration

of neuropeptides and effects of anti-IL-6 mAb on Ag presenting cultures, a linear mixed effects model was used to estimate the average level of the biomarkers under different treatments. This model takes into account Montelukast Sodium variations for each treatment both within and between plate and samples. Differences in the average level of the biomarker under pairs of experimental conditions of interest were evaluated using simultaneous tests for general linear hypotheses [[84]]. p-values were again adjusted for multiple comparisons by controlling the FDR. This work was supported by NIH Grant 5R01 AR042429 (R.D.G. and J.A.W.), the Jacob L. and Lillian Holtzmann Foundation (R.D.G.), the Edith C. Blum Foundation (R.D.G.), the Carl and Fay Simons Family Trust (R.D.G.), the Seth Sprague Educational and Charitable Foundation (R.D.G.), the Lewis B. and Dorothy Cullman Foundation (R.D.G.

Posted in Uncategorized | Leave a comment

Here we report the case of two brothers with collagenofibrotic gl

Here we report the case of two brothers with collagenofibrotic glomerulopathy confirmed by histology. Patient 1 presented with proteinuria and hypertension and patient 2 presented with nephrotic-range proteinuria. Immunohistochemistry revealed strong staining PF-02341066 purchase for antibodies to type III collagen in the widened subendothelial spaces in both patients. Electron microscopy revealed numerous collagenous fibers in the mesangium and subendothelial space. P III P levels were elevated in both patients. Most reported cases of collagenofibrotic glomerulopathy, including the adult-onset type, have been

sporadic. Within the limits of our literature search, this is only the third report of adult siblings with collagenofibrotic glomerulopathy confirmed by histology, suggesting that adult-onset collagenofibrotic glomerulopathy may also be an inheritable disease. This report indicates that it may be beneficial to measure serum P III JAK inhibitor P levels in the siblings of patients diagnosed

with adult-onset collagenofibrotic glomerulopathy. PRASAD NARAYAN1,2,3,4,5, JAISWAL AKHILESH2, AGARWAL VIKAS3, YADAV BRIJESH4, RAI MOHIT5 1Department of Nephrology, Sgpgims, Lucknow, India; 2Department of Nephrology, Sgpgims, Lucknow, India; 3Department of Clinical Immunology, Sgpgims, Lucknow, India; 4Department of Nephrology, Sgpgims, Lucknow, India; 5Department of Clinical Immunology, Sgpgims, Lucknow, India Introduction: Approximately 60–80% of steroid responsive Nephrotic Syndrome (NS) patients experience relapses of proteinuria and it is one of the most challenging clinicial issues. NS is a disorder of T cells function. The ratio of different Endonuclease T cells subpopulation may affect steroid response in NS. P-glycoprotein (P-gp) on lymphocyte acts as efflux pump and may affect drug response. However,

there are a few such studies in NS. Methods: We recruited 26 NS patients at baseline, with steroid therapy 24 undergone complete remission, and after discontinuation of steroid 15 relapsed. Frequency of Treg, Th1 and Th2 lymphocytes and P-gp expression were analyzed using flowcytometry at baseline and followup at remission and relapse. The PBMC culture for cytokine Elisa were also done. Results: The percentage of Treg was significantly increased after achieving remission (6.82 ± 4.12) compared to that of baseline (1.83 ± 0.84, P = 0.001) and again decreased after relapse (3.03 ± 1.18, P = 0.016) Fig. A. The percentage of TH1 cells was significantly decreased in remission (9.9 ± 4.65) compared to that of baseline value (16.18 ± 7.19, P = 0.018) and again increased in relapse (19.83 ± 3.47, P = 0.001) Fig. B. The percentage of Th2 was significantly decreased in remission (4.81 ± 1.42) compared to that of baseline values (10.5 ± 4.66, P = 0.001) and again increased after relapse (9.89 ± 5.18, P = 0.008) Fig C. The absolute P-gp expression (P-gp positive cell × RFI) was significantly low during remission (35.11 ± 18.

Posted in Uncategorized | Leave a comment

5A and B) Similarly, when BAFF activity was prevented by the add

5A and B). Similarly, when BAFF activity was prevented by the addition of a specific BAFF neutralizing Ab to PBMC cultures, a reduction in the TLR7-stimulated IgM and IgG production was obtained (Supporting Information Fig. 3). A different picture was found when Ig release was measured upon TLR9 triggering in either monocyte-depleted PBMCs or whole PBMCs treated with anti-BAFF Ab. Indeed, an enhanced release

of both IgM and IgG was observed in response to TLR9 stimulation in the absence of monocytes while the neutralization of BAFF poorly affected Ig BGJ398 mouse production (Fig. 5A and B and Supporting Information Fig. 3, respectively). This result was not obvious and, at this stage, it is difficult to explain but it suggests that monocytes could be associated to a negative feedback loop on TLR9-driven B-cell differentiation while they positively act on the TLR7 responsiveness of Ig-producing NVP-BEZ235 supplier B cells. Thus, we can envisage that changes in the basal and/or TLR-induced cytokine milieu of in vivo IFN-β-conditioned PBMCs could profoundly impact on Ig production from B cells in response to TLR7 or TLR9 stimulation. Collectively, these findings demonstrate that the cross-talk between monocytes and B cells is essential for the release of an effective humoral immune response in the context of

TLR7 stimulation affecting the maturation and differentiation status of B lymphocytes into Ig-secreting cells. Over the past decade, there has been growing understanding and acceptance of the pathological involvement

of B cells and humoral response in MS [1, 2]. The demonstration that peripheral B-cell depletion leads to a rapid decline in disease activity in MS is the strongest evidence of the central role of these cells in MS autoimmunity [9, 11]. However, the key question that still remains unsolved is when and how in the pheromone life of an individual B cell does provide immunopathogenic support or arise as a disease-relevant cell type in MS. In this study, we investigated whether IFN-β targets B lymphocytes and modulates their functions contributing to the protective effects of this treatment. Only a few studies have thus far addressed this point and most have investigated the ability of highly purified B cells from MS patients to present antigens and subsequently regulate T-cell responses [28, 29]. In contrast, we studied whether IFN-β therapy would regulate the maturation and differentiation of B cells into Ig-secreting cells in response to TLR7 or TLR9 stimulation. Indeed, it has been shown that TLR triggering is necessary for extensive human naïve B-cell proliferation, isotypic switching, and production of Abs providing the third signal upon BCR cross-linking by antigen and interaction with T helper cells [30].

Posted in Uncategorized | Leave a comment

The endothelial cell layer of these microvessels is a key modulat

The endothelial cell layer of these microvessels is a key modulator of vasodilation through the synthesis and release of vasoactive substances. Beyond their vasomotor properties, these compounds importantly modulate vascular cell proliferation, inflammation, and thrombosis. Thus, the balance between local regulation of vascular tone and vascular pathophysiology can vary depending

upon which factors are released from the endothelium. This review will focus on the dynamic nature of the endothelial released Ixazomib concentration dilator factors depending on species, anatomic site, and presence of disease, with a focus on the human coronary microcirculation. Knowledge how endothelial signaling changes with disease may provide insights into the early stages of developing vascular inflammation

and atherosclerosis, or related vascular pathologies. “
“Please cite this paper as: Farnebo, Zettersten, Samuelsson, Tesselaar and Sjöberg (2011). Assessment of Flood Flow Changes in Human Skin by Microdialysis Urea Clearance. Microcirculation 18(3), 198–204. Objective:  The aim of this study was to evaluate the urea clearance technique for the measurement of drug-induced blood flow changes in human skin and compare it to two non-invasive techniques: polarization light spectroscopy and laser Doppler perfusion imaging. Methods:  GSI-IX ic50 Fifteen microdialysis catheters were placed intracutaneously on the volar aspect of the forearms of healthy human subjects and were perfused with nitroglycerine, noradrenaline, and again nitroglycerine to induce local tissue hyperemia, hypoperfusion, and hyperemia, respectively. Results:  Urea clearance, but not the other techniques, detected the changes in blood flow during changes in flow. The last hyperemic response was detected by all three methods. Conclusion:  Urea clearance can be used as a relatively simple method to

estimate blood flow changes during microdialysis of vasoactive substances, in particular when the tissue is preconditioned eltoprazine in order to enhance the contrast between baseline and the responses to the provocations. Our results support that, in the model described, urea clearance was superior to the optical methods as it detected both the increases and decrease in blood flow, and the returns to baseline between these periods. “
“This study was undertaken to investigate how aging affects dermal microvascular reactivity in skin areas differentially exposed to sunlight, and therefore to different degrees of photoaging. We assessed, in young (18–30 years, n = 13) and aged males (≥60 years, n = 13), the thigh, forearm, and forehead’s skin vasodilatory response to local heating (LTH) with a LDI. In each subject and at each location, local Tskin was brought from 34°C (baseline) to 39 or 41°C for 30 minutes, to effect submaximal vasodilation, with maximal vasodilation then elicited by further heating to 44°C.

Posted in Uncategorized | Leave a comment

Whether or

not this is due to an intrinsic defect in the

Whether or

not this is due to an intrinsic defect in the immune system of DS individuals or mainly secondary to the various DS-associated characteristics needs to be investigated further. Chromosome 21 genes that may influence the immune response include SOD1 and RCAN1. Roxadustat solubility dmso Several components of the immune system are variably affected in DS subjects, from which the most consistently reported are defective neutrophil chemotaxis and low humoral immune responses, associated with infections being predominantly of the respiratory tract. Factors that may induce immunodeficiency have been postulated, such as zinc deficiency and accelerated immunosenescence, although their clinical significances have not been established. Common anatomical defects of DS disturb natural barriers and facilitate the infectious disease process and need be considered in the management of infections in these patients. We recommend investigation of DS children who present with increased frequency of infections for immunological and non-immunological factors that increase the risk of infection. In this evaluation, low specific antibody titres to routine childhood vaccines would suggest the need for additional booster immunization doses. The authors thank Dr Carla Davis and Dr Kathlyn

Ostermaier for critical review of this manuscript. The authors have nothing to disclose. “
“Macrophages altered by various Th2-associated and anti-inflammatory mediators – including find more IL-4 and IL-13 [inducing alternatively activated macrophages (AAMs)], IL-10 and TGF-β– were generically termed M2. However, markers that discriminate between AAMs and other M2 remain scarce. We previously described E-cadherin as a marker for AAMs, permitting

these macrophages to fuse upon IL-4 stimulation. To identify novel potential contributors to macrophage fusion, we assessed the effect of IL-4 on other adherens and tight junction–associated components. We observed an induction of claudin-1 (Cldn1), Cldn2 and Cldn11 genes by IL-4 in different mouse macrophage populations. Extending our findings to other stimuli revealed Cldn1 as a mainly TGF-β-induced gene and showed that Cldn11 is predominantly associated with IL-4-induced AAMs. Cldn2 is upregulated by diverse stimuli and is not associated with a specific macrophage Benzatropine activation state in vitro. Interestingly, different claudin genes preferentially associate with M2 from distinct diseases. While Cldn11 is predominantly expressed in AAMs from helminth-infected mice, Cldn1 is the major macrophage claudin during chronic trypanosomiasis and Cldn2 dominates in tumour-associated macrophages. Overall, we identified Cldn1, Cldn2 and Cldn11 as genes that discriminate between diverse types of M2. Macrophages are very versatile innate immune cells that adopt various activation states depending on the environment.

Posted in Uncategorized | Leave a comment

Calpains do not generally function as destructive proteases, but

Calpains do not generally function as destructive proteases, but act as calcium-dependent modulators that remove limited portions of protein substrates. Their proteolysis is usually a late-stage common buy Ruxolitinib pathway toward cell death induced by excitotoxic compounds. Calpains can also cleave other potentially important apoptosis-related proteins, including caspase-12, Bax, Bcl-XL, GRP94, c-Fos, and p53 [18-21]. They are also thought to play a critical role in a form

of neuronal cell death involved in the pathogenesis of several diseases [22-24]. However, calpain activity and expression are increased in activated glial and inflammatory cells [25-28]. The application of calpain inhibitor effectively reduces the frequency of spontaneous release of neurotransmitter in Alzheimer’s disease. C/EBP-β is one of the members of the C/EBP subfamily of bZIP transcription factors, which is thought to regulate proinflammatory gene expression

click here primarily expressed by microglia with lower upregulation in astrocytes [8, 29, 30]. Raised C/EBP-β levels have also been demonstrated in vivo in situations wherein neuroinflammation occurs, such as systemic LPS injection, cerebral ischemia, excitotoxic insult, or aging. Straccia et al. [8] have reported that the lack of C/EBP-β results in greater attenuation of proinflammatory gene expression activated by LPS+IFN-γ compared with that with LPS alone in the activating stimulus. The neurotoxicity elicited by LPS+IFN-γ treated microglia is abrogated by the lack of C/EBP-β. Valente et al. [31] have also shown that C/EBP-β may control

the expression of potentially neurotoxic genes in microglial cells in amyotrophic lateral sclerosis. Dasgupta et al. [32] showed that overexpression of ΔC/EBP-β, a truncated alternate C/EBP-β translation product, Glycogen branching enzyme LIP, which acts as a dominant-negative inhibitor of C/EBP-β activity, inhibited the myelin basic protein primed T-cell-induced expressions of IL-1β, IL-1α, TNF-α, and IL-6 in microglial cells. Thus, C/EBP-β plays a role in the regulation of neurotoxic effects in activated glial cells. Abrogation of C/EBP-β expression or its downregulation by gene regulation may serve as a therapeutic target to attenuate deleterious effects in neural tissue and ultimately prevent the development of neurodegenerative disorders. In the present study, IL-13 directly enhanced calpain and C/EBP-β interaction, resulting in decreased C/EBP-β. These findings imply that the anti-inflammatory cytokine IL-13 protects neurons by mechanisms probably involving the regulation of ER stress by calpain activation. These results provide evidence that IL-13-induced calpain activation in activated microglia under ER stress condition can aggravate microglia cell death and, consequently, promote neuronal cell survival.

Posted in Uncategorized | Leave a comment

, but with the two structures repeatedly alternating every 2 min

, but with the two structures repeatedly alternating every 2 min. Under these circumstances, there was no evidence of learning either of the two syllable statistics, presumably because the 2-min exposure was insufficient to “tag” the fact that there were two structures. However, when each structure was spoken by a different talker or voice, this tagging was obvious and now subjects learned both syllable statistics. Thus, as in Gebhart et al., when there is a strong cue that indicates the presence

of two different contexts, beta-catenin inhibitor learners are quite adept at keeping track of two separate sets of statistics that describe the two underlying structures. This notion of context is crucial not only for the efficacy and efficiency of learning, but also for the propensity to generalize. Consider a situation in which a naïve learner is attempting to understand a corpus of environmental input. Even if the learner has a stationarity bias, there are a variety of contextual cues that are very obvious (e.g., time of the day as indicated by sunlight versus darkness or when a given parent is present versus a preschool teacher). How does the learner decide which of Hydroxychloroquine manufacturer these contextual cues is relevant—leading

to the inference that there is a new structure to be learned—and which contextual cues should be ignored because they are uncorrelated with a change in structure? As noted by Qian, Jaeger, and Aslin (2012), this distinction between cue-sensitivity and cue-relevance is what was earlier referred to as Problem 3—the presence of contextual ambiguity. That is, learners must be open to the possibility that a cue serves as a contextual signal for a change of structure, but Histamine H2 receptor not overly willing to assume that every cue that is discriminable signals such a contextual cue. Problem 3 has a further implication for

what a learner should do after they have partitioned (or not) the environmental input into separate structural representations. If a learner has a stationarity bias and treats multiple structures as being generated by a single representation, then they will incorrectly generalize across those multiple structures. This overgeneralization is a common property of early language productions for certain grammatical morphemes (e.g., the –ed ending on verbs). In contrast, if a learner has a nonstationarity bias and falsely infers multiple structures when they are not present in the input, then they will incorrectly restrict generalization. This undergeneralization is seen in 5-month-old infants who, after exposure to multiple views of a single person’s face, fail to generalize to a novel view of that same person’s face (Fagan, 1976).

Posted in Uncategorized | Leave a comment

Tumor necrosis factor (TNF) is a pleiotropic cytokine expressed <

Tumor necrosis factor (TNF) is a pleiotropic cytokine expressed BAY 73-4506 cost by various types of lymphoid and myeloid cells, including T cells, B cells, NK cells, monocytes, macrophages, DCs, and mast cells (reviewed in [1, 2]). TNF is involved in development, homeostasis, and activation of the immune system [3-8]. Physiological functions mediated by TNF depend on the cellular sources and the molecular form of this cytokine [9-11]. In particular, TNF produced by macrophages and T cells plays different roles in immune and inflammatory reactions [9, 10]. TNF is the primary response

gene in macrophages where it has a permissive chromatin conformation [12, 13]. Even without stimulation, the proximal TNF promoter and transcription start site (TSS) have an open chromatin configuration in primary monocytes and macrophages and in the majority of tested myelomonocytic cell lines[14-22]. Various T-cell subsets produce different amounts of TNF in correlation with their pathophysiological

potential [23]. Earlier studies [24] as well as recent advances in high-throughput analysis of DNaseI chromatin accessibility indicate that the proximal part of the TNF promoter in T cells is open (Supporting Information Fig. 1); however, in contrast to macrophages, the TSS of TNF in T cells acquires Ibrutinib open chromatin conformation only after activation or polarization under Th1 or Th17 (where Th is T helper) conditions. TNF gene expression in T cells is regulated by the NFAT and AP-1 families of transcription

factors; in particular, activation of the proximal TNF promoter region involves functional interactions with the transcription factors NFATc2 and c-Jun [25-31]. Numerous reports also supported the involvement of the NF-κB family members in transcriptional regulation of the TNF gene in macrophages, in spite of the lack of canonical high-affinity NF-κB binding sites within the proximal TNF promoter [32-39]. However, specific role of NF-κB family members in regulation of the TNF gene is still being debated ([1, 2] and Discussion section). In murine T cells, members of the NF-κB family were shown to bind to the distal Bcl-w part of the TNF promoter [40] and to the enhancer element immediately downstream of the TNF gene (3′-TNF enhancer) [24], but the functional significance of these interactions is not clear. Here, we demonstrate the difference in chromatin structure around TNF TSS between T cells and macrophages. We further show that active forms of c-Jun and NFATc2 transcription factors are involved in chromatin remodeling occurring at the TNF TSS in activated Th cells and in T cells polarized under Th1 and Th17 conditions. c-Jun alone appears to be sufficient for the maintenance of such open chromatin conformation at the TNF TSS. Thus, our data uncover additional level of TNF expression control occurring through chromatin remodeling.

Posted in Uncategorized | Leave a comment