Tacrolimus (FK-506) is a

calcineurin inhibitor that was developed especially for the treatment of AD [17]. The immunosuppressive action of tacrolimus was found to be T cell specific, because it did not inhibit B cells, natural killer cells or various bone marrow-derived cell lines [18]. It also inhibits the production of several proinflammatory EX 527 cytokines such as IL-3, IL-4, IL-5, IFN-γ, tumour necrosis factor-α and granulocyte/macrophage colony-stimulating factor [19]. In NC/Nga mice, tacrolimus inhibited the spontaneous dermatitis and was effective against established dermatitis by suppressing T cells, eosinophils, mast cells, IL-4, IL-5 and IgE [20, 21]. In a study on patients with AD, concomitant treatment with tacrolimus and another immunosuppressive agent was proven superior to monotherapy with either of the agents in improving overall dermatological scores [22]. Current treatments for severe AD are not always effective, and therefore, alternative therapies that are more effective need to be identified. The present study investigated the therapeutic potential of glucosamine and tacrolimus in combination on AD by an in vivo experiment performed using Df-induced dermatitis in NC/Nga mice, which is histologically and clinically similar to AD in humans [23], and determined its underlying therapeutic mechanisms. Animals.  Eight-week-old male NC/Nga

mice purchased Panobinostat in vivo from Shizuoka Laboratory Animal Center (Hamamatsu, Japan) were included in the study. The mice were maintained under uncontrolled conventional

air conditions in the Laboratory Animal Facilities at the Dongguk University School of Medicine. The animal care and use committee of the research institute at Dongguk University Hospital approved all ID-8 described studies. Drugs and reagents.  Glucosamine was purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). Tacrolimus (FK-506) was kindly provided by Chong Kun Dang pharma Inc. (Seoul, Korea). Df body ointment was prepared by Biostir Inc. (Kobe, Japan), and 1 g of Df body ointment contained 136.4 mg protein, 234 μg Der f 1 and 7 μg Der f 2. Induction of AD in NC/Nga mice.  Induction of AD using Df body ointment was performed as described previously [24]. The hair on the back of the NC/Nga mice was shaved using an electric shaver, followed by treatment with a skin-hair remover (Niclean, Ildong, Korea). Barrier disruption was achieved by 4% sodium dodecyl sulphate treatment on the shaved dorsal skin and both surfaces of each ear 3 h before the Df body ointment (100 mg/mouse) application. These procedures were repeated twice a week for 4 weeks. Scoring of skin lesion.  The extent of (1) erythema/haemorrhage, (2) scarring/dryness, (3) oedema and (4) excoriation/erosion was scored as 0 (none), 1 (mild), 2 (moderate) and 3 (severe). The total skin score was defined as the sum of individual scores [25]. The administration of drugs on Df-induced NC/Nga mice.

In the case of splenic macrophages, 10 units/mL IFN-γ was added to the culture medium to prime cells. In addition, 5 μg/mL polymyxin B was also added to avoid cell activation by LPS in the IFN-γ sample. Separately, RAW264.7 cells were incubated with pDNA/LA2000 complex for 2 h, then the cells were washed with RPMI-1640 Selleckchem Small molecule library and incubated with fresh growth medium for an additional 6 h, and the supernatants were collected for ELISA and kept at −80°C until use. PMDC05 cells were incubated with ODNs for 24 h, then the supernatants were collected for ELISA and kept at −80°C until

use. The level of murine TNF-α and murine IL-6 in the media was determined by ELISA using the OptEIA set (BD Biosciences Pharmingen, San Diego, CA, USA). The level of human TNF-α in the media was determined by human TNF-α ELISA set (eBioscience, San Diego, CA, USA). RAW264.7 cells were incubated with Alexa488-labeled ODN1668 with or without ODN1720 or DNase-treated ODN1720 for 4 h and INCB024360 purchase washed

three times with PBS. Then, the intensity of cell fluorescence was analyzed by flow cytometry (FACScan; BD Biosciences) using CellQuest software (version 3.1; BD Biosciences). Cellular uptake was estimated by subtracting the mean fluorescence intensity (MFI) at 4°C from that at 37°C (ΔMFI) and was plotted against the incubation time. ODN1668 was mixed with DNase I- or DNase II-treated ODN1720. The mixture containing 0.5 μg ODN1668 was incubated with DNase I (2 units/μg ODN1668) or DNase II (3 units/μg ODN1668) at 37°C. After 0, 5, 15, 30 min of incubation (DNase I treatment) or 0, 20, 40, 80 min of incubation (DNase II treatment), the mixture next was placed on ice and the reaction was terminated by the addition of 3 μL 0.2 M EDTA solution per 10 μL of samples. The ODN samples were run on a 21% PAGE and stained with ethidium bromide. The image of the gel was recorded using LAS 3000 (Fujifilm Life Science, Tokyo, Japan) and analyzed using Multi Gauge software (Fujifilm Life Science). Differences in the cytokine release were statistically evaluated by Student’s t-test. Differences in the thickness

of mouse footpad were statistically evaluated by one-way analysis of variance (ANOVA) followed by the Tukey–Kramer test for multiple comparisons. A p-value of less than 0.05 was considered to be statistically significant. We wish to thank Dr. Hiroyuki Yoshitomi (Graduate School of Medicine, Kyoto University) for providing technical assistance for subcutaneous injection of ODN into the footpad of mice. This work is partly supported by the 21st Century COE Program “Knowledge Information Infrastructure for Genome Science” and by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Sciences and Technology, Japan. Conflict of interest: The authors declare no financial or commercial conflict of interest. Detailed facts of importance to specialist readers are published as ”Supporting Information”.

Thus, the continuation of ROS generation in gC1qR-overexpressing cells was associated with intracellular Ca2+ accumulation, which may lead to mitochondrial dysfunction. Indeed, a synergistic interaction was observed between intracellular Ca2+ influx and ROS generation. It was expected that interference with electron transport by ROS and intracellular Ca2+ would influence mitochondrial membrane potential. Losses in Δψm also occurred in gC1qR-treated

HTR-8/SVneo and HPT-8 cells. These observations of gC1qR augment our present observations that mitochondrial Ca2+ overload occurs in gC1qR-overexpressing cells and apoptosis follows its accumulation in the mitochondria; meanwhile, apoptogenic factors (e.g. cytochrome c) release into the cytoplasm

(see Figure S5), suggesting its role IWR1 selleck chemicals in mitochondria-dependent apoptosis. This observation was also supported by the results following treatment with metformin because metformin can promote mitochondrial biosynthesis.[28, 29] These findings indicate that promoting mitochondrial biosynthesis may reverse gC1qR-induced EVCT-derived transformed cell apoptosis. Our findings demonstrated a mechanism whereby gC1qR could play an important role in EVCT-derived transformed cell apoptosis through a mitochondria-dependent pathway. Therefore, the veracity of the in vitro studies described in the present data need enough to be validated using suitable animal models in which the gC1qR gene is overexpressed. Future studies need to prove that gC1qR-associated trophoblast cell apoptosis is related

to the ability of gC1qR gene to induce mitochondrial dysfunction, which in turn mediates spontaneous miscarriage. LJG designed this study and drafted the manuscript. YW helped to draft the manuscript and performed the statistical analyses. XMW and SYG carried out the molecular biological studies and interpreted the data. NS collected the patient information. The authors thank Dr. Ya-juan Su for generously helping to revise the manuscript. This work was supported by grants from the National Natural Science Foundation of China (No. 81000251) and Nanjing Medical Science and Technique Development Foundation (No. QRX11112). The authors declare that they have no competing interests. The authors alone are responsible for the content and writing of this article. “
“Citation Sunderland N, Hennessy A, Makris A. Animal models of pre-eclampsia. Am J Reprod Immunol 2010; 65: 533–541 The cardinal features of human pre-eclampsia, hypertension and proteinuria, are mimicked in animal models. Increasingly, the accuracy of inducing ‘pure’ systemic endothelial dysfunction is regarded as critical in differentiating mechanisms of pre-eclampsia from other conditions which induce hypertension (e.g. glomerulonephritis, renal denervation or manipulation of the renin-angiotensin system).

U. B. received travel grants and consultancy honoraria from CSL Behring, Baxter, Octapharma and Biotest. S. M. and C. V. are employees of CSL Behring. “
“National

Research Centre for the Working Environment, Copenhagen, Denmark Maternal immune responses may interfere with offspring allergy development as maternal immunization may suppress IgE development, while maternal allergy may promote allergy. Therefore, we investigated the effect of two different maternal treatments on airway allergy in female and male offspring. Pregnant mice were immunized (IMM) with ovalbumin (OVA) or immunized and airway-challenged find more (IMM+AI). At different ages, airway allergy to OVA was induced in offspring by intranasal sensitization. Maternal IgG1 was found at higher levels in IMM+AI than in IMM offspring. After sensitization, the suppression of OVA-specific IgE and IgG1 was complete in juvenile offspring but waned with age concurrently with maternal IgG1 levels. Cytokine secretion, lung inflammation, and B cell

priming were not suppressed although IgE responses were. High compared with low levels of maternal IgG1 were associated with lower TH2 antibody production after adult offspring were re-exposed to OVA. Thus, offspring allergy-related responses

appeared to Smoothened Agonist ic50 be shaped by maternal antibody levels. “
“There is a strong correlation between intrauterine bacterial infection and preterm labor. While inflammation is a common mechanism, certain pathogens may trigger placental apoptosis. TLR2 activation by gram-positive bacterial peptidoglycan (PDG) induces first-trimester trophoblast (-)-p-Bromotetramisole Oxalate apoptosis and decreased IL-6 secretion. This is dependent upon the presence of TLR1 and the absence of TLR6 and both TLR2 coreceptors. As TLR10 is also a TLR2 coreceptor, the objective of this study was to determine its expression and function in the trophoblast. First-and third-trimester human placental tissue and isolated trophoblast were evaluated for TLR10 expression. A first-trimester human trophoblast cell line stably transfected with a TLR10 dominant negative (TLR10-DN) or vector control was treated with or without PDG and analyzed for apoptosis and IL-6. TLR10 was expressed by trophoblasts during the first and third trimesters of pregnancy. PDG-induced trophoblast caspase-3 activity was inhibited by the presence of the TLR10-DN. The presence of the TLR10-DN had no effect on PDG reduction in trophoblast IL-6 secretion.

We performed neutralizing assays on patient sera using coxsackievirus type B viruses (B1 through B6) before assessing by ELISA. We chose patient sera which showed a high level of CVB3 neutralized Selleckchem Torin 1 antibody. This assay is the first to use detection of a CVB3-induced IgG antibody in patient serum for diagnostic purposes. The coxsackieviruses are members of the genus Enterovirus of the family Picornaviridae and are known to be the most common cause of myocarditis [13, 15]. Modrow

and Dorsch attempted to detect parvovirus B19 in patient sera [16]; however, IgM antibodies against this virus are detectable for only around 2–10 weeks after acute infection. There is still no effective diagnostic method for CVB3 in human patients Z-VAD-FMK concentration with fulminant myocarditis. Positive viral serology does not necessarily indicate myocarditis, suggesting that assessing the presence of the virus is not a particularly good diagnostic tool on its own. Reverse transcriptase PCR analysis of EMB is positive

in only 4% of patients with myocarditis who have serological evidence of infection with CVB3 [6, 17]. However, we found that anti-virus antibodies in patient sera were associated with entero-VP1-positive immunohistochemical staining in an EMB specimen. These results confirm that our new synthetic peptide ELISA system based on the VP2 peptide specifically identifies anti-CVB3 antibodies produced in response to CVB3 infection. Some patients showed low titers of anti-virus antibodies, probably attributable to individual differences in immune activity. However, the levels of detection were sufficient to allow a diagnosis of myocarditis. Our newly developed enterovirus diagnostic system can detect

anti-CVB3 antibodies in mice and humans with CVB3 infection. The sensitivity and accuracy of the assay are acceptable for its diagnostic use in clinical samples. However, thus far the amounts of anti-CVB3 Tyrosine-protein kinase BLK antibodies in patient sera have been too low to measure. In this report, we have shown that a peptide-based ELISA system can be used to detect CVB3-infection-induced IgG antibodies in mice and CVB3 infection of patients with fulminant myocarditis. This is the first successful attempt to develop a CVB3 serological diagnosis system. We believe that this method will allow rapid and accurate diagnosis of infection in humans. In addition, this system may become a useful diagnostic tool for the identification of enterovirus in human patients in the future. This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A2008640) and Samsung Biomedical Research Institute (#SBRI C-B0-232-2). The authors have no conflicts of interest. “
“Superantigens have been implicated in a number of diseases including Kawasaki disease (KD), a multi-system vasculitis resulting in coronary artery aneurysms.

Cell culture and stimulation.  PBMCs were cultured in complete RPMI-1640 culture medium supplemented with 7.5% heat-inactivated foetal calf serum (Sigma-Aldrich, St. Louis, MO, USA) and plated on 24-well plates. For stimulation, cells were incubated with

anti-CD3/anti-CD28-coated beads (Invitrogen Dynal AS, Oslo, Norway) at a bead:cell ratio of 1.0. Proliferation assay.  For cell proliferation assay, PBMCs were labelled with carboxyfluorescein diacetate (CFSE) (Molecular Probes, Inc., Eugene, OR, USA) according to the manufacturers recommendations. At the end of the culture period, the CFSE labelled cells were stained with anti-CD4-APC, anti-CD8-PerCP and anti-CD25-APC-Cy7 monoclonal antibodies (mAbs) (BD Pharmingen, San Diego, CA, USA), R788 solubility dmso washed and then run immediately on the flow cytometer. The BD FACS Aria (Becton-Dickinson, Franklin Lakes,

NJ, USA) was used for all measurements of our study. Cell death assay.  Cells Selleck PD0325901 were stained with anti-CD4-PE-Cy7, anti-CD25-FITC and anti-CD8 APC-Cy7 mAbs (BD Pharmingen). After 10 min of incubation in dark, propidium iodide was added and samples were incubated for 10 more min. The samples were then analysed immediately on flow cytometer. Intracellular FoxP3 assay for the identification of Tregs.  For analysis of Foxp3, cells were first stained for the expression of CD4 and CD25 surface molecules with anti-CD4 APC and anti-CD25 FITC mAbs (both BD PharMingen). Cells were fixed and permeabilized based on the manufacturer’s recommendations (Fixation/Permeabilization solution,

Permeabilization solution, eBioscience, San Diego, CA, USA). Anti-Foxp3 PE mAb (eBioscience) was then used for intracellular staining (40 min at 4 °C), and corresponding isotype control was also included. Cells were washed once and analysed immediately on flow cytometer. Surface markers of T lymphocytes.  To determine Atazanavir the activation, maturation markers and Th1/Th2 polarization of CD4+ and CD8+ lymphocytes, the following mAbs were used in combinations: anti-CD4 PE-Cy7, anti-CD8 APC-Cy7, anti-CXCR3 APC (Th1), anti-CCR4 PE (Th2), anti-CD62L PE-Cy5, anti-CD25 FITC, anti-CD69 APC, anti-CD45RO PE, anti-HLA-DR PerCP, anti-CD45RA FITC (all purchased from BD Pharmingen). The cells were incubated with mAbs for 20 min in dark, washed once and analysed on flow cytometer. Statistical analysis.  Median [range] of the variables is reported. Hettmansperger–Norton trend test was applied to investigate the trend of the changes with increasing hyperoxia time [18]. P values <0.05, two tailed, were considered significant. We did not correct for multiplicity. Mann–Whitney U test was used for comparison of two groups. Data are summarized in Table 1 for cell cultures without T cell stimulation and in Table 2 for experiments with anti-CD3/CD28 bead stimulation.

7 to 47.8 Mbp of chromosome 17. The Ncf1 mutation impairs the function of the Ncf1 gene as described earlier 2, 52. Transgenic mice containing the MHC class II Aq β (Abq)

chain gene under the human CD68 promoter, CD68-Abq (Macrophage A β Q, abbreviated MBQ), were developed as follows: the coding sequence from the Abq gene was amplified from first strand cDNA. This cDNA was modified to contain cloning sites in the 5′ and 3′ ends and the Kozak sequence 53 was optimized on the Abq sequence. DNA was inserted downstream of human CD68 promoter and the splice signal flanking the first intron of the CD68 gene and upstream of a poly-A addition site 8. The transgene was excised from the bacterial selleck chemical vector and introduced into pronuclei from (B10.PxC3H.NB)F2. The MBQ transgenic mice were backcrossed to B10.P (>10n) to create the B10.P.MBQ strain. Screening for Abq, Abp and

the MBQ transgene was performed by PCR; to screen for the Ncf1 mutation, PCR was combined with pyrosequencing (Biotage) as previously described 2. B10.P.MBQ heterozygous and this website homozygous mice were both used in some of the experiments shown, other experiments were performed with only homozygous mice; no differences between these mice were observed. Expression of Aq was confirmed by flow cytometry using the Aq-specific antibody PCQ6 12. All animal experiments were approved by the Malmö/Lund ethical committee (license no. M70/04 and M107/07). CIA was induced by injecting 100 μg of rat type II collagen (CII), prepared as described earlier 54, emulsified in complete Freund’s adjuvant (CFA; Difco) at the base of the tail. After 35 days, mice were boosted with 50 μg of CII in incomplete Freund’s adjuvant (IFA; Difco) at the same site. Arthritis development was scored blindly using a macroscopic scoring system; one point was given for each swollen or red toe or joint and five points for a swollen ankle, adding up to a max score of 60 points per mouse. Blood for serum was taken at day 42 and when sacrificed. To stain cells for flow cytometry, Baricitinib the following antibodies were used:

FITC anti-mouse CD11b (M1/70), APC anti-mouse Gr-1 (RB6-8C5), APC anti-mouse CD11c (N4.18), FITC anti-mouse CD19 (1D3) (all from BD Biosciences, Pharmingen) and biotinylated PCQ6 directed against H2-Aq 12 detected with Streptavidin-PE (Pharmingen). CII was isolated from Swarm rat chondrosarcoma by pepsin or lathyritic digestion as described before 55, 56. Lathryritic CII was used in in vitro assays to avoid contamination of pepsin known to lead to unwanted T-cell responses 57. Spleens were conferred to single cell suspension and hemolysed: 106 cells per well were plated in cell culture 96-well plates (Nunc) and cultured for 24 h in DMEM (GIBCO) with addition of 10% of heat-inactivated fetal bovine serum (PAA), 10 mM Hepes, penicillin/streptomycin. Cells were stimulated with IFN-γ (BD Pharmingen) or nothing.

Our data are consistent with this hypothesis and we show that these SCH772984 clinical trial types of interchromosomal translocations reflect interchromosomal CSR based on our findings

that AID activity is required. It should be noted, however, that in our VV29 transgenic mice, interchromosomal translocations can occur in vitro, whereas in Δ3′RR transgenic mice interchromosomal translocations can only be detected in vivo. As the VV29 transgene does not contain either the 3′RR or all the Igh locus sequences downstream the Cμ gene, translocation to the endogenous Igh locus is the only CSR mechanism to repair transgene Sμ AID-induced DNA damage. On the other hand, in the Δ3′RR transgene the presence of all of Igh locus S regions together with their surrounding sequences might lead to abortive downstream intrachromosomal CSR processes that compete with the interchromosomal translocation. Based on our findings, together with the previous studies, and the fact that the frequencies of in vitro interchromosomal translocation in the VV29 B cells are orders of

magnitude higher than c-myc/Igh translocation Tyrosine Kinase Inhibitor Library frequencies 17 yet comparable to the frequencies of interallelic CSR among endogenous Igh loci 2, we conclude that interchromosomal translocations involving the Igh locus occur by an AID-medicated CSR mechanism and occur more often between chromosomes that share Igh-associated regulatory elements. It would be interesting to determine whether the presence of a switch region or Igh enhancer elements near the c-myc gene would

increase the frequency of translocations to the Igh locus. In VV29 B cells that are undergoing CSR, we can find only VV29 VDJ regions expressed with the VV29 transgenic Cμ gene and not the endogenous Cμ gene although we can easily detect the expression of the VV29 region with endogenous Cγ regions. These results indicate that Glycogen branching enzyme VV29 transgene translocations into the Igh locus do not involve trans-switching between the transgene Sμ and the endogenous Sμ regions, implying that Sμ regions may be differentially regulated from downstream S regions, perhaps to give directionality to the CSR machinery. One source of regulation may be chromosomal looping that associates the intronic Eμ enhancer with the downstream 3′RR enhancers during CSR 28. It is possible that DNA looping or protein complexes block Sμ regions from recombining with their chromosomal homologues. On the other hand, the DNA looping structure could leave downstream S regions more exposed to participate in interchromosomal recombination. To our knowledge, this is the first study that has indicated that two homologous Sμ regions do not recombine via trans-switching.

“
“Tufted astrocytes (TAs) in progressive supranuclear palsy (PSP) and astrocytic plaques (APs) in corticobasal degeneration (CBD) have been regarded as the pathological hallmarks of major sporadic 4-repeat tauopathies. To better define the astrocytic inclusions in PSP and CBD and to outline the pathological features of each disease,

we reviewed 95 PSP cases and 30 CBD cases https://www.selleckchem.com/products/Vorinostat-saha.html that were confirmed at autopsy. TAs exhibit a radial arrangement of thin, long, branching accumulated tau protein from the cytoplasm to the proximal processes of astrocytes. APs show a corona-like arrangement of tau aggregates in the distal portions of astrocytic processes and are composed of fuzzy,

short processes. Immunoelectron microscopic examination using quantum dot nanocrystals revealed filamentous tau accumulation of APs located in the immediate vicinity of the synaptic structures, which suggested synaptic dysfunction by APs. The pathological subtypes of PSP and CBD have been proposed to ensure that the clinical phenotypes are in accordance with the pathological distribution and degenerative changes. The pathological features of PSP are divided into 3 representative subtypes: typical PSP type, pallido-nigro-luysian type (PNL type), and Omipalisib research buy CBD-like type. CBD is divided into three pathological subtypes: typical CBD type, basal ganglia- predominant type, and PSP-like type. TAs are found exclusively in PSP, while APs are exclusive to CBD, regardless of the pathological subtypes, although some morphological variations exist, especially with regard to TAs. The overlap of the pathological distribution of PSP and CBD makes their clinical diagnosis complicated, although the presence of TAs and APs differentiate these two diseases. The characteristics of tau accumulation in both neurons and glia suggest a different underlying mechanism with

regard Bumetanide to the sites of tau aggregation and fibril formation between PSP and CBD: proximal-dominant aggregation of TAs and formation of filamentous NFTs in PSP in contrast to the distal-dominant aggregation of APs and formation of less filamentous pretangles in CBD. “
“The role of chemokines and their receptors, which regulate trafficking and homing of leucocytes to inflamed organs in human or murine autoimmune neuritis, has not yet been elucidated in detail, Therefore, the role of the chemokine receptors CXCR4 and CXCR7 and their ligand CXCL12 was studied in autoimmune-mediated inflammation of the peripheral nervous system. CXCL12/CXCR4 and/or CXCL12/CXCR7 interactions were specifically inhibited by the compounds AMD3100 or CCX771, respectively, in experimental autoimmune neuritis (EAN) of C57BL/6J mice immunized with P0106–125 peptide.

[76] In one study, the ligation of CD40 with anti-CD40 mAb retrieved the activity of NF-κB and induced the destruction of tumour cells.[94] In another investigation,

the treatment with CD40 mAb resulted in the up-regulation of MHC-II and co-stimulatory molecule CD86 in macrophages, and elevated serum levels of IL-12, TNF-α and IFN-γ, positively correlating with the regression of pancreatic carcinoma in humans and mice.[95] The tumour repression effect of anti-CD40 selleck screening library mAb is also attributed to the release of CD40′s suppression effect on TLR9 because anti-CD40 mAb promoted TLR9 to respond to CpG-ODN in macrophages.[96] In fact, the synergy of CpG-ODN with agonistic anti-CD40 mAb reversed TAMs toward the M1 phenotype, and augmented the apoptogenic effects of macrophages against tumour cells.[25, 96] However, it should be noted that the activation of the NF-κB pathway does not solely facilitate the M1-phenotype of TAMs.[76] For instance, Hagemann et al.[97] found that NF-κB JAK inhibitor participated in pro-tumoral functions of TAMs, and the inhibition of NF-κB activity significantly re-polarized TAMs to M1 tumoricidal

phenotype and promoted the regression of mouse ovarian cancers. Moreover, TNF-α and other cytokines involved in NF-κB activation are reported to act positively in the metastasis of certain tumours, such as Lewis lung carcinoma, and these cytokines can protect TAMs and tumour cells from apoptosis.[98-100] In addition, Chlormezanone NF-κB promotes, in some experiments, the transcription of HIF-1α, which in turn promotes tumour angiogenesis.[101] Hence, it is currently still difficult to envisage a broad applicability of NF-κB mediators to re-educate TAMs, further exploration and evaluation are essential. Like the NF-κB pathway, the STAT1 pathway is generally targeted to reverse TAMs to an M1 transcriptome.[6] The natural agonist of STAT1 is IFN. IFN-α and IFN-β have long been known for their anti-tumour potential and have been approved by the US Food and Drug Administration for treatment of

several human cancers, including hairy-cell leukaemia and AIDS-related Kaposi sarcoma.[102] Experimental studies indicate that the effects of IFN-α/-β on the inhibition of tumour growth is likely to be based on targeting haematopoietic cells rather than tumour cells per se.[103] The role of IFN-γ in reversing immunosuppressive and pro-tumoral properties of human TAMs has also been observed.[104] It was proposed that IFNs trigger the activation of STAT1 and then the transcription of the genes encoding pro-inflammatory cytokines, such as IL-12, nitric oxide synthase 2 (NOS2) and CXCL-10, in TAMs.[105] In this regard, IFNs and IFN-mimics may contribute to TAM-education. However, the STAT1 pathway, similar to NF-κB, also displays pro-tumoral capacity in certain tumours.