Long-term survival in the case of this GBM patient likely resulted from a combination

of factors, including hypermethylation of the MGMT (O6-methyl guanine methyl transferase) CpG island, young age at diagnosis, good performance status, and complete surgical resection of the tumor. To the best of our knowledge, this case report describes one of the longest-surviving GBM patients and is the first on radiation-induced cavernous angioma in a GBM patient. “
“Chemotherapy has been considered as an effective treatment for malignant glioma; however, it becomes increasingly ineffective with tumor progression. Epithelial-to-mesenchymal transition (EMT) is a process Selleck AZD6738 whereby cells acquire morphologic and molecular alterations that facilitate tumor metastasis and progression. Emerging evidence associates chemoresistance with the acquisition of EMT in cancer. However,

it is not clear whether this phenomenon is involved in glioma. We used the previously established human glioma cell lines SWOZ1, SWOZ2 and SWOZ2-BCNU to assess cellular morphology, molecular changes, migration and invasion. We found that BCNU-resistant cells showed multiple drug resistance and phenotypic changes consistent with EMT, including spindle-shaped morphology and enhanced pseudopodia formation. Decreased expression of the epithelial adhesion molecule E-cadherin and increased expression of the mesenchymal marker vimentin were see more observed in BCNU-resistant SWOZ1 and SWOZ2-BCNU cells compared to SWOZ2 cells. Migratory and metastatic potentials were markedly enhanced in SWOZ1 and SWOZ2-BCNU cells compared to SWOZ2 cells. These data suggest that there is a possible link between drug resistance and EMT induction in glioma cells. Gaining further insight into the mechanisms underlying chemoresistance and EMT may enable the restoration

of chemosensitivity or suppression of metastasis. “
“P. S. Pahlavan, W. Sutton, R. J. Buist and M. R. Del Bigio (2012) Neuropathology and Applied Neurobiology38, 723–733 Multifocal haemorrhagic brain damage following hypoxia and blood pressure lability: case 4-Aminobutyrate aminotransferase report and rat model Aims: Haemorrhagic brain damage is frequently encountered as a complication of premature birth. Much less frequently, multifocal petechial haemorrhage is identified in asphyxiated term newborns. Our goal was to develop an experimental rat model to reproduce this pattern of brain damage. Methods: Neonatal rat pups were exposed to a 24-h period of 10% or 8% hypoxia followed by a single dose of phenylephrine. Acute and subacute changes, as well as long-term outcomes, were investigated by histology, brain magnetic resonance imaging and behavioural assessment. Immunostaining for vascular endothelial growth factor and caveolin-1 was performed in the rat brains as well as in a 17-day human case.

Precipitating CD177 from the neutrophil see more membrane and performing mass spectrometry, we found that several molecules co-precipitated with CD177. Among those proteins were the FcγIIIR as well as Mac-1 [55]. CD177 and Mac-1 co-localized, co-precipitated and showed direct protein interactions by plasmon-resonance analysis and when Mac-1 transfected cells interacted with immobilized NB1. We subsequently established that Mac-1 was a functionally important transmembrane component of the PR3 membrane complex, allowing subsequent PR3–ANCA-induced activation predominantly of mPR3high/NB1positive neutrophils (Fig. 2). However, we observed that degranulation and

extracellular superoxide generation, but not intracellular hydrogen peroxide formation depended on the mPR3 phenotype. Interestingly, PR3–ANCA were equally potent in inducing DHR oxidation MK-1775 concentration in mPR3high/NB1positive and mPR3low/NB1negative cells an observation also made by Hu et al. [27]. The underlying mechanism for this finding still needs to be elucidated. As mentioned, MPO membrane expression by neutrophils is somewhat scarce and much less is known as to how signalling is initiated after MPO–ANCA bind their target. Hess et al. found that large amounts of MPO can

be acquired by resting neutrophils from supernatants of activated neutrophils. This acquired surface MPO allowed MPO–ANCA binding and neutrophil activation [56]. Others showed that MPO is presented by CD11b promoting neutrophil activation even in the absence and presence of anti-MPO antibodies [57,58]. Initial studies on ANCA-induced signalling events showed that distinct intracellular signalling events Ribose-5-phosphate isomerase mediated ANCA-induced neutrophil

activation. Tyrosine kinase and protein kinase C activation by ANCA, but not by control IgG, was observed by Radford et al. [59]. Blocking both kinases using pharmacological inhibitors abrogated ANCA-induced superoxide generation. These experiments encouraged further characterization of the signal transduction cascade involved in ANCA-induced neutrophil activation. The implication was to block important key elements specifically and thereby identify novel and more specific treatment targets. P38 mitogen-activated protein kinase (MAPK) and extracellular regulated kinase (ERK) are important during both priming and the ANCA-induced neutrophil activation. Priming increases the amount of membrane-expressed antigens, but also sparks signalling pathways that are needed for a subsequent ANCA-induced full-blown activation. Both p38 MAPK and ERK are initiated during TNF-α priming and their blockade abrogates subsequent ANCA-induced activation. However, both pathways show differential effects in that p38 MAPK, but not ERK, controls the ANCA-antigen translocation [60].

Intuitively these patients Torin 1 supplier might have better quality of life (QOL) than the general dialysis population, but their QOL scores are not well characterized. The aim of this study was to compare QOL of patients about to undergo kidney or SPK transplants with Australian dialysis outcomes and practice patterns (DOPPS) data and multiple comorbidity and age-adjusted general population data. Patients attending Westmead Hospital for transplants from August 2009 to December 2011 were invited to complete the Kidney Disease QOL-SF™ 1.3 (KDQOL-SF™ 1.3) questionnaire regarding their immediate

pretransplant QOL. This QOL instrument is predictive of hospitalizations and mortality. The questionnaire was completed within 4 weeks of transplantation.

Of 180 patients seen within 4 weeks of transplantation 95 (53%) responded, with no differences from non-responders in age, sex, comorbidities or perioperative complications. Compared with DOPPS, Z-VAD-FMK mouse these patients had better physical function and less pain, but significantly lower scores for role physical (CI: −19 to −4, P = 0.004) and role emotional (CI: −17 to −2, P = 0.018). Patients undergoing SPK transplants reported even poorer general health, energy, social support and function. Patients had lower emotional and social function than people with multiple comorbidities, with whom they shared poor general and mental health and vitality. Scores were markedly lower than the general population except for bodily pain (female). Younger, fitter patients Tyrosine-protein kinase BLK are more vulnerable to effects of their illness on social, emotional and physical interactions and may benefit from targeted support. “
“The proportion of patients using home dialysis in Australia varies from 6% to 62% between renal units. The aim of this study was to determine if the variance is attributed to any underlying renal

unit factors including pre-end stage education practices. An online survey was distributed to all Australian units that offered home dialysis. Logistic regression was performed to estimate the effects of renal unit characteristics on the binary outcome of <30% versus ≥30% of patients using home dialysis, and for ≥10% of patients using home haemodialysis (HHD) dialysis specifically. Prevalent home dialysis rates were sourced from the Australia and New Zealand Dialysis and Transplant Association registry. 33 of 43 units (77%) completed the survey. Factors shown to predict ≥30% of patients using home dialysis were; a metropolitan based renal unit compared with a rural or remote unit (OR 1.08, 95% CI 1.01–1.15), a New South Wales unit compared with other states (OR 1.13, 95% CI 1.04–1.22), and a unit that offered multiple group education sessions per year (OR 1.01, 95% CI 1.01–1.02). A unit that offered >1 h of pre-end stage education per patient, compared with ≤1 h predicted more than 10% of patients on HHD (OR 2.84, 95% CI 1.17–6.90).

3), consistent with their maturation into macrophages.[12, 13] After 7 days, culture supernatant from monocyte-derived macrophages was replaced with fresh media or fresh media plus hBD-3 and cells were then incubated overnight. Chemokines were detected in supernatants from these cells by infrared array. In three of four experiments, hBD-3 induced Gro-α, MIP1α, MCP-1, whereas in four

of four experiments we found evidence of MIP-1β and RANTES induction (Fig. 3). Unlike monocytes, there was no evidence of induction of MDC (Fig. 3) MK-8669 ic50 or VEGF (not shown) in these cells. It is possible in the case of MDC that increased spontaneous production of this chemokine may have limited the capacity for further induction. These data suggest that the induction of chemokines by hBD-3 is also likely to occur in more mature, monocyte-derived macrophages. We have recently demonstrated that monocytes from HIV+ donors respond less well to hBD-3 stimulation as determined

by the induction of CD80 surface expression. SB203580 This defect was observed in cells from viraemic as well as treated, aviraemic donors suggesting that viraemia was not a critical determinant. To investigate the possibility that chemokine induction might also be altered in HIV infection, we compared hBD-3 induction of chemokines in cells from nine HIV+ donors with that in monocytes from six control donors. The HIV+ donors included three viraemic donors (plasma HIV RNA levels of 28 124, 157 792 and 166 206 copies/ml) and six aviraemic donors (< 48 copies/ml). The median CD4 cell count of our HIV+ donors was 370 cells/µl, ranging from

140 to 871 cells/μl. Interestingly, several chemokines including MCP-1, MIP-1α and MIP-1β were produced Clomifene at heightened levels spontaneously in purified monocytes from HIV+ donors that were incubated overnight in medium alone (Fig. 4). After hBD-3 stimulation, induction of VEGF, Gro-α and MDC were all diminished in cells from HIV+ donors and a similar trend was noticed for MIP-1β (Fig. 4). We have recently shown that hBD-3 can cause membrane damage in monocytes from healthy donors at the concentration used in these studies and that this could result in cell death in a minority of monocytes.[14] Comparison of propidium iodide staining in monocytes cultured in medium alone or in medium supplemented with hBD-3 did not demonstrate appreciable differences in PI bright cells when comparing cells from HIV+ and control donors, suggesting that cell death as a result of hBD-3 exposure was not responsible for the differences in chemokine induction by cells from HIV+ and HIV− donors (%PI bright monocytes in cell cultures from HIV+ donors versus % bright from control donors after hBD-3 treatment).

While four other surface lipoproteins encoded on various cp32 plasmids (i.e. ErpG, ErpL, ErpX, and ErpY) have been shown to bind FH/FHL-1 from other animal sources, such as cattle, cat,

or dog (Stevenson et al., 2002), it is not clear what, if any, role this may play in the enzootic cycle of B. burgdorferi. In addition to the lipoproteins discussed in the preceding sections, there have also been several lipoproteins identified on the surface of B. burgdorferi that currently have no known function. Many of these were identified by Carroll and co-workers (i.e. lipoproteins CHIR-99021 mw BBA65, BBA66, BBA71, and BBA73; Hughes et al., 2008) and through an examination of genes regulated by environmental cues through global expression profile analyses by Brooks et al. (Brooks et al., 2006; BBA689, BBA36, BBA66, BBA69, and BBI42). Given their cellular location on the surface, these lipoproteins likely perform an important role in either the tick or mammalian host environment, but future studies are needed to fully elucidate their functional role(s)

in B. burgdorferi virulence and/or Lyme disease pathogenesis. In addition to the numerous outer surface lipoproteins described previously, B. burgdorferi also contains integral OMPs that have transmembrane-spanning domains. OMPs are structurally different find more than lipoproteins in that they do not contain N-terminal lipid anchors. Bacterial OMPs, in general, provide an array of important functions, such as nutrient acquisition

(e.g. porins), antibiotic resistance (e.g. drug efflux pumps), protein transport and assembly, and cellular adhesion (Koebnik et al., 2000; Schulz, 2002; Bos et al., 2007). Likewise, B. burgdorferi OMPs also provide critical physiological functions for the spirochete cell, which is in accordance with the observation that nearly all known ID-8 B. burgdorferi OMPs are encoded from stable chromosomal loci (Fraser et al., 1997). Interestingly, freeze-fracture electron microscopy has demonstrated that B. burgdorferi possesses a characteristically low abundance of integral OMPs, approximately 10-fold fewer than that detected in the Escherichia coli OM (Lugtenberg & van Alphen, 1983; Radolf et al., 1994). This paucity of integral membrane-spanning surface proteins, combined with the apparent limited antigenicity of OMPs, has seriously hindered identification of B. burgdorferi OMPs. As a result, relatively few nonlipoprotein surface proteins have been identified in B. burgdorferi, and even fewer have been fully characterized at the functional level. P66, encoded by ORF bb0603, was first identified as a 66-kDa chromosomally encoded B. burgdorferi antigen (Barbour et al., 1984; Coleman & Benach, 1987) with an immunogenic surface-exposed loop region (Bunikis et al., 1995, 1996; Probert et al., 1995).

Infected red blood cells from the blood of infected mice (parasitemia, 30–50%) were purified (> 95%) by centrifugation in 74% Percoll density gradient as described previously [21]. MHC II+CD11chiCD3−CD19−, MHC

II+CD11c−CD3−CD19−IgM+, and MHC II+CD11c−CD3−CD19−IgM− cells were purified by GPCR & G Protein inhibitor cell sorting as described. Cells (1 × 105) were cultured in the presence of iRBC or RBC (4 × 106) in a final volume of 200 µL for 16 hr and the concentrations of cytokines in the supernatant determined by a sandwich ELISA as described previously [22]. OT-II mice were immunized i.p. with OVA (200 µg) in complete Freund’s adjuvant. After 5 days, CD4+ T cells were prepared from the spleens of OT-II mice using a CD4+ T cell isolation kit (Milteny Biotech, CD4+ T cells; 87.5%) and labeled with 15 µM CFSE (Invitrogen, Carlsbad, CA, USA) for 10 min. MHC II+CD11chiCD3−CD19− DCs and MHC II+CD11c−CD3−CD19− cells were prepared by cell sorting and pulsed with OVA323–339 (10 µg/mL) or with OVA (1 mg/mL) for 3 hr. OT-II (1 × 105) and MHC II+CD3−CD19− cells (1 × 104) were cocultured for 3 days and cell divisions assessed on the basis of diminution of CFSE dye using a FACS Canto II. The supernatant was collected after 2 days of culture to measure the concentrations of IL-2. ELISA was performed as described previously [22]. The statistical significance

of differences was determined by two-sided Student’s t-test using SRT1720 datasheet GraphPad PRISM 5 software. P values less than 0.05 were considered significant. After excluding T and B cells with CD3 and CD19 markers, MHC class II+ cells were examined using spleen cells from B6 mice infected with P. yoelii. Splenic CD3−CD19− cells were medroxyprogesterone stained for CD11c and MHC II, and MHC II+ cells divided into three subpopulations based on the degree of CD11c expression, namely CD11chi, CD11cint and CD11c− cells (Fig. 1a). In MHC II+CD3−CD19− cells, the degree of MHC II expression was greater in CD11chi cells (MFI: uninfected, 6199; infection day 8, 3279) than in CD11cint (MFI: uninfected, 2884; day 8, 2219) or CD11c− (MFI: uninfected, 2638; day 8, 1295) cells.

MHC II+CD11chiCD3−CD19− cells included conventional DCs and constituted the major population of MHC II+ cells prior to infection. MHC II+CD11cintCD3−CD19− cells included plasmacytoid DCs and regulatory DCs [7]. After day 5 post-infection, the numbers of both MHC II+CD11chiCD3−CD19− and MHC II+CD11cintCD3−CD19− cells decreased steadily (Fig. 1b). In contrast, the number of MHC II+CD11c−CD3−CD19− cells increased until day 9 post-infection in parallel with the degree of parasitemia (Fig. 1c). However, the number of these cells decreased after day 11 post-infection despite continuing increase in parasitemia. These MHC II+CD11c−CD3−CD19− cells were next stained for CD138, a plasma cell marker, and Igs (Fig. 2a).

The exact composition of tolerosomes is not known, but it is thought that they may contain other co-stimulatory molecules, which may induce tolerance to the MHC-associated peptide (42). The discovery of tolerosomes is relatively recent, having occurred less than 10 years ago. It has been known since 1983 that, in order for oral tolerance to develop, an intact portal circulation

is needed, and that oral tolerance is transferrable through serum. These cell fragments, the so-called tolerosomes, first discovered by electron microscopy in 2001, were found in the insoluble fraction produced by ultracentrifugation from the serum of animals which had been subjected to induction of oral tolerance. The soluble fraction, serum without tolerosomes, was no longer able to mediate the transfer of oral tolerance (41). This proved that intercellular communication occurs through exosomes

during development MK-2206 manufacturer of oral tolerance. The fate of tolerosomes after their production has not yet AZD6738 chemical structure been fully elucidated. It is supposed that they bind to local or distant antigen presenting cells (43, 44), conveying the necessary information for mounting tolerance to food antigens. In any case, the fact that the portal circulation is involved in this process has lead to the speculation that tolerosomes can be directed to the liver, another recognized tolerogenic site (45, 46). Oral tolerance

has been exploited for therapeutic purposes to inhibit all forms of unwanted immune responses, from the secretion of different antibody classes, to type IV hypersensitivity reactions. It is to be noted that Th1-type responses are much easier to inhibit than Th2 responses. In order to suppress a Th2 immune response, it is necessary to administer greater antigen quantities, or to increase the frequency of administration (47). An exception to this rule is that of IgE-mediated Th2 immune responses associated with increased production of IL-4, such as allergies, Liothyronine Sodium which respond very well to oral tolerization schemes (48). The idea of using SEA in order to augment oral tolerance to different peptides arose from epidemiologic studies (49). Staphylococcus aureus is now a common commensal in the gut in the occidental population (50, 51). It has been demonstrated that Western infants with a greater degree of colonization with SEA-producing S. aureus strains are protected against food allergy (52, 53). Toxigenic S. aureus residing in the gut induce greater concentrations of IgA in children’s serum and protect from eczema (54). Animal models of allergic diseases suggest that neonatal oral administration of SEA followed by feeding the sensitizing protein OVA in adulthood prevents the development of airway allergy when the mice are re-exposed to intranasal OVA (35).

As shown here, stimulation with CXCL4 induces an increased SphK1 expression in monocytes and rescues these cells from apoptosis. It should be mentioned here that transfection of monocytes either RNA Synthesis inhibitor with empty vector or with SphK1-plasmid resulted in decreased apoptosis but at the same time led to increased necrotic cell death, while overexpression of SphK1 (by transfection) did not further support cell survival (Fig. 6E). This indicates that cell survival in monocytes (non-proliferating cells) requires

at least one additional signal provided by CXCL4 apart from those leading to increased expression of SphK1. Furthermore, this result also might explain why stimulation with exogenous S1P only partially protects monocytes from cell death (Fig. 6A and 7B). In addition to the effects of SphK1 overexpression, Olivera et al. 28, 29 demonstrated that administration of micromolar (but not nanomolar) concentrations of exogenous S1P suppresses apoptosis in a dose-dependent manner, and these effects were independent

of S1P receptors. Similar results were published by Van Brocklyn et al. 24, who could demonstrate that S1P at high concentrations acts not necessarily through binding to S1P receptors, but rather following cellular uptake of the phospho-lipid. Mononuclear phagocytes mainly express two S1P receptors, S1P1 and S1P2 12. While S1P1 exclusively interacts with Gi proteins, S1P2 couples with multiple G proteins 30. In a previous report, we have shown that CXCL4-mediated oxidative burst is only marginally reduced in the presence BMS-907351 concentration of PTX, indicating that Gi proteins do not play a relevant role selleck products in this context 2. Furthermore, CXCL4-mediated rescue from apoptosis is not affected in PTX-pretreated cells (Fig. 7B). Although we

cannot fully exclude a minor role of S1P receptors coupled to PTX-insensitive G proteins, the lack of S1P in culture supernatants of CXCL4-stimulated cells argue against the involvement of any S1P surface-expressed receptors. We, thus, conclude that CXCL4 effects are transduced predominantly by intracellularly generated S1P. Monocytes or macrophages undergo spontaneous apoptosis in the absence of serum and/or survival factors. In these cells apoptosis is accompanied by an increase of caspase-9 and caspase-3 activity 31–34. As shown here, stimulation with CXCL4 not only rescues monocytes from apoptosis but also resulted in a nearly complete block of caspase activation (Fig. 4 and 6C). In addition, also treatment with high dosages of S1P resulted in reduction of caspase activity, and cell death. The protective effect of CXCL4 on apoptosis and caspase activation is partially reversed in the presence of SphK or MEK/Erk inhibitors (Fig. 3B and 4, or published earlier by our group 3), indicating that caspase activity is regulated by these kinases in monocytes. Our results support previous findings by Edsall et al.

Lysis of the cells was performed on ice for 30 min in 50 mm Tris–HCl, pH 7·5, containing 150 mm NaCl, 0·5 mm EDTA, 0·5% Nonidet P-40, 1 mm PMSF, 1 μg/ml aprotinin, 0·5 μg/ml pepstatin, 1·25 μg/ml leupeptin Selleck Ruxolitinib and 1 mm dithiothreitol. After centrifugation (10 000 g, 10 min at 4°), 30 μg protein lysate supernatants were incubated in 100 μl lysis buffer with 40 μm substrate (final concentration) in microtitre plate wells at room temperature, and the increase of fluorescence due to the release of AMC was detected at 460 nm, using a 355-nm excitation wavelength in a Wallac 1420 Victor2 fluorimeter-luminometer (Wallac Oy, Turku,

Finland). The concentrations of secreted IL-1β in the cell culture supernatants after the indicated times of treatments were measured

by ELISA (BD Biosciences, San Diego, CA) according to the manufacturer’s instructions. Detection limit of the assay was 10 pg/ml. Significance of the differences between mean values was evaluated using a Student’s t-test. Data presented as mean ± SD values. To determine the effect of RWE on IL-1β production, THP-1 macrophages were treated with different combinations IDH assay of RWE, NADPH and LPS. Although in good agreement with previous findings,[19] LPS treatment resulted in a substantial increase of the secreted IL-1β, the treatment with RWE in the absence or presence of NADPH did not trigger the secretion of this cytokine, nor did NADPH alone (Fig. 1a). However, RWE in the presence of NADPH strongly enhanced the LPS-induced IL-1β production in a dose-dependent manner at the lowest saturating LPS concentration (100 ng/ml) (Fig. 1a). A similar induction was observed at an even 10-fold higher LPS Ketotifen concentration and the substantial dose-dependent elevation required 24 hr after treatment (data not shown). Treatment of human monocyte-derived macrophages and dendritic cells with LPS alone or in combination with RWE led to results similar to those found with the THP-1 cell line (Fig. 1b). Pollen extract has been reported to stimulate ROS production in epithelial cells, for this reason we aimed

to see if pollen extract could induce ROS production in THP-1 macrophages. H2O2, used as a positive control, induced a fast increase in intracellular ROS (Fig. 2a). Whereas RWE but not NADPH alone induced some ROS production, their combined effect yielded a continuously increasing ROS level (Fig. 2a). Lipopolysaccharide alone did not produce detectable ROS by this method, in good agreement with previous findings,[20] nor did it enhance the ROS produced by RWE treatment in the presence of NADPH (Fig. 2a). To determine whether the RWE-dependent enhancement of LPS-induced IL-1β production is mediated by ROS, THP-1 macrophages were pre-treated with the ROS-scavenger NAC. NAC completely inhibited IL-1β secretion, indicating that ROS play an indispensable role in LPS-induced as well as in RWE-enhanced IL-1β production (Fig. 2b).

Cells were treated with inhibitors of JNK or p38 and then GXM was added to the cells for 2 h. Cytofluorimetric analysis was performed; the results showed that inhibition of JNK or p38 activation resulted in inhibition of FasL up- regulation GSK2126458 (Fig. 7a,b). Given that FasL up-regulation is greatly responsible for apoptosis induction, we evaluated the effect of FcγRIIB blockade on GXM-induced apoptosis of cells. MonoMac6 cells were treated with antibody to FcγRIIB or with inhibitors of JNK or p38 MAPK, then GXM was added. After 2 h of incubation, peripheral blood

lymphocytes (PBL), both activated and not activated, were added, and apoptosis was evaluated after 1 day of culture. The results (Fig. 7c) showed that an inhibition of apoptosis was observed in the presence of Ab to FcγRIIB as well as with inhibitors of JNK or p38 MAPK. Conversely, cells not treated with PHA did not show significant variations in apoptosis. Microbial polysaccharides from bacteria or fungi are an inexhaustible source of biopharmaceutical compounds. Some of these have received attention, such as curdlan, which shows anti-tumour and anti-viral activity [36]. In addition, many of these

compounds are classified as biological response modifiers [1]. This study RG-7388 manufacturer is devoted to clarifying the immunoregulatory mechanism ascribed to GXM, a capsular polysaccharide of the opportunistic fungus C. neoformans. The ability of GXM to induce immunosuppression has been reported previously and mechanisms contributing to immunosuppression have, at least in part, been elucidated. GXM can interact with macrophages via cell surface receptors such as TLR-4, CD14, CD18, FcγRIIB [15], and the main immunosuppressive effects are mediated by GXM uptake via FcγRIIB. The capacity of GXM to dampen the immune Dynein response involves the induction of T cell apoptosis. This effect is dependent on GXM-induced

up-regulation of FasL on antigen-presenting cells [15]. In the present study we describe the mechanism exploited by GXM to induce up-regulation of FasL, which leads to apoptosis induction. In particular, we demonstrate that: (i) activation of FasL is dependent on GXM interaction with FcγRIIB; (ii) GXM is able to induce activation of JNK and p38 signal transduction pathways; (iii) this leads to downstream activation of c-Jun; (iv) JNK and p38 are simultaneously, but independently, activated; (v) activation of JNK, p38 MAPK and c-Jun is dependent on GXM interaction with FcγRIIB; (vi) FasL up- regulation occurs via JNK and p38 activation; and (vii) apoptosis occurs via FcγRIIB engagement with consequent JNK and p38 activation. FcγRIIB, via immunoreceptor tyrosine-based inhibition motif (ITIM) in its intracytoplasmatic domain, is responsible for negative immunoregulation [37].