Our data suggest that individuals with low erythrocyte CR1 are less equipped to mop up these ICs than individuals with high erythrocyte CR1 and are more likely to develop complications as a result. This is complicated further

by the fact that individuals afflicted by some of these diseases develop low CR1 levels as a result of the infection [16,17,24]. In addition, we have Bortezomib reported that the level of CR1 can vary with age, and young children aged from 6 to 24 months have the lowest levels of CR1 [15,21]. This population is at greatest risk from complications due to Plasmodium falciparum infection [29]. Young children are known to produce more TNF-α during malaria infection than older children, regardless of the level of parasitaemia [30], and differential capacity to remove ICs during malaria infection may be one potential explanation. We have provided evidence for a unique role of red cells in the stimulation of TNF-α production by presenting ICs and cross-linking Fcγ receptors on macrophages. This phenomenon may be important whenever slow circulation allows close contact between erythrocytes and monocyte/macrophages, such as in the liver and the spleen, leading to local production of proinflammatory cytokines. In the setting of P. falciparum malaria,

this could also happen in capillaries of the brain and other tissues where infected erythrocytes tend to adhere to the endothelium and sequester, slowing down the circulation. This is the pathognomonic feature

of cerebral Opaganib malaria, one of the deadliest complications of this infection. In these capillaries, local production of TNF-α has been documented by immunohistochemistry [31]. We propose that presentation of ICs to monocytes/macrophages by red cells is one possible mechanism for the localized production of proinflammatory cytokines in sequestered capillaries. In addition, IC-loaded red cells in microhaemorrhages of patients with CM could stimulate microglial cells, resident macrophages that express Fcγ receptors [32]. Differential expression of CR1 on red cells is an appealing explanation for the increased susceptibility to cerebral malaria of older children compared to young children [16]. However, our Dichloromethane dehalogenase data do not support that differences in CR1 expression level can lead to differences in the ability of red cells to stimulate macrophages. In conclusion, we have demonstrated that erythrocytes can play a dual role in immune regulation, removing ICs from circulation to prevent inflammation and at the same time being capable of stimulating an inflammatory response by presenting ICs to macrophages. Our findings justify further exploration of the role of these mechanisms in the pathology of IC-mediated diseases such as malaria. This work was supported by NIH grant HL71502 (Principle Investigator José A. Stoute). We are grateful to individuals who participated in the study.

e. able to induce full T-cell differentiation 27, 38, 39. BALB/c ByJ and OT-I TCR-transgenic (Charles Rivers), C57BL/6J (Janvier), and ubiquitin–GFP-expressing mice 23 (Jackson) were housed and bred FDA approved Drug Library purchase in our SPF animal facility. Unless otherwise specified in the legend of the figures, wt C57BL/6 mice were used in the experiments. This study was carried out in strict accordance with the recommendations in the Guide

for the Care and Use of Laboratory Animals of the Commitee of Animal Care and Use of the Regional Cote d’Azur. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Institut de Pharmacologie Moléculaire et Cellulaire (Permit Number: B-06-152-5, delivered by the Veterinary Services of the Alpes-Maritimes Prefecture) and by the animal use committees at the Albert Einstein

College of Medicine. All efforts were made to minimize suffering and provide humane treatment to the animals included in the study. We used the L. monocytogenes 10403s background strain in all experiments, either wt or deleted in the secA2 gene, expressing or not GFP 16. Wt Lm-OVA was a kind gift from Hao Shen (University of Pennsylvania, PA, USA). For infections, Lm were grown to log phase (OD600∼0.05–0.15) in broth heart infusion (BHI) medium (Sigma-Aldrich), diluted in PBS and injected in the lateral tail vein. For Lm titers, organs were this website dissociated on metal screens (water 0.1% Triton X-100), and serial dilutions plated onto broth heart infusion plates. Spleens were digested 20 min at 37°C in HBSS (Invitrogen) containing 4000 U/mL collagenase I (Invitrogen) and 0.1 mg/mL

DNase I (Roche). Red blood cells were lysed for 5 min in 170 mM NH4Cl, 17 M Tris-HCl and pH 7.4. All fluorochrome-labeled mAbs are listed in the Supporting Information Table S1. PE-conjugated LLO91-99/H2-Kd Interleukin-2 receptor tetramers were obtained from the NIH tetramer core facility. Splenocytes were stained with the specified antibodies in PBS containing 0.5% BSA (FACS buffer). For surface staining, cells were incubated for 20 min on ice. For intracellular staining, splenocytes were incubated for 4 h at 37°C, 5% CO2 in RPMI1640 (Invitrogen) 5% FBS, 2 μg/mL Golgi Plug (BD) with or without 100 nM LLO91–99 peptide (Mimotopes), fixed in 1% paraformaldehyde/FACS buffer 10 min, incubated 20 min in 1× Perm/Wash (BD). Cells were analyzed on a FACSCalibur cytofluorometer (BD). When indicated, cells were sorted on a FACSVantage SE cell sorter (BD). Organs were homogenized in PBS containing a complete protease inhibitor cocktail (Roche), centrifuged 10 min 12 000×g. The supernatants were incubated with the BD Cytometric Bead Assay Flex Sets and analyzed using a FACS Array (BD).

In control CD47−/− and WT mice fed

PBS, a similar frequency of adoptively transferred cells was found in MLN (Fig. 2a). Three days after feeding OVA, the fraction of DO11.10 T cells that had entered division was reduced by 50% in the MLN of CD47−/− mice, when compared with WT mice (Fig. 2b,c). However, intravenous OVA administration did not affect proliferation of DO11.10 T cells in the spleen of CD47−/− mice (Fig. 2d). Addition of CT did not alter the reduced proliferation NVP-BKM120 of DO11.10 T cells in MLN (data not shown) or PP of CD47−/− mice (Fig. 2e,f). These experiments show that CD47−/− mice have a reduced ability to induce proliferation of CD47-expressing CD4+ T cells in GALT after feeding OVA in the presence or absence of an adjuvant. However, the expansion of CD4+ T cells in CD47−/− mice is not compromised after parenteral immunization. We next assessed the capability of CD47−/− mice to induce oral tolerance. CD47−/− and WT mice were fed 50 mg OVA or PBS. Two weeks later, mice were challenged subcutaneously with OVA + IFA, and 1 week later draining LN were harvested. The antigen-specific proliferative response of LN cells was then determined in vitro after re-stimulation with OVA. The OVA-fed CD47−/− and WT mice Sotrastaurin concentration exhibited a similar capacity to inhibit the

OVA-specific proliferative response in vitro (approximately 75% suppression; Fig. 3a). As feeding a high dose of OVA may conceal differences in the efficacy of tolerance induction between mouse strains, the experiment was repeated using a 10-fold lower dose of OVA. This reduced antigen dose resulted in efficient tolerance induction in CD47−/− mice that was not significantly not different from what was seen in WT mice (Fig. 3b). These results show that although

CD47−/− mice have a reduced frequency of CD11b+ DC in LP and MLN, and a reduced capacity to induce T cell proliferation in the MLN following OVA feeding, they maintain the capacity to induce oral tolerance. CD4+ T cell help is required for the generation of antigen-specific antibodies following oral immunization with CT.1,2 As feeding OVA + CT resulted in reduced proliferation of OVA-specific CD4+ T cells in PP of CD47−/− mice, we next assessed OVA-specific antibody titres in intestinal tissues and serum after three oral immunizations with OVA + CT. CD47−/− mice generated significantly lower intestinal anti-OVA IgA titres than WT mice (Fig. 4a), whereas total intestinal IgA and OVA-specific serum IgA and IgG titres did not differ between CD47−/− and WT mice (Fig. 4b–d). In support of this, the frequency of OVA-specific IgA-producing cells in the intestine is reduced in CD47−/− mice following immunization with OVA and CT (531 ± 102/1 × 106 cells in WT and 219 ± 49/1 × 106 cells in CD47−/− mice, n = 10 and P < 0·05).

In this process, phenomena described following observational buy Metformin studies in humans drives hypotheses to be tested in animal experiments.

Animal experimentation in turn refines hypotheses that can then be tested in humans. This in turn leads to further questions and more productive animal experimentation. In this iterative approach, studies in humans and animals complement each other and can synergize to move our understanding of disease forward. That being said, my bias is that a good animal is not meant to primarily replicate all of what happens in humans, nor is it meant to be directly transferable. A well-working model generates logical and testable hypotheses that are consistent first foremost with existing data in the animal, and possibly in humans as well. The drive for those who primarily use animal models should be to ‘know thy model’, able to communicate

it effectively to others, and to generate productive integrative and iterative study. In studies in humans, several properties are taken into consideration to determine the appropriateness of the group of patients accessed for a study. These properties may be related to certain demographics or to CH5424802 purchase prevalence of disease. When considering animal models to study adverse pregnancy outcomes, several issues come to mind. With decreasing funding through federal and other sources, PLEKHM2 cost may play a large role in the choice of mode. Larger animal

models are likely more costly and research based on these models is receiving less support.[1] However, certain strains of genetically manipulated mice are also very expensive (http://jaxmice.jax.org). The animal welfare regulatory requirements for non-human primate work are increasingly stringent as is the administrative oversight. Another constraint is the ability to deal with the public relations issues necessary to utilize primate models. Only certain institutions have the capacity, specialized facilities, and highly trained veterinary staff. Depending on the species, there are some zoonotic disease issues that require a very rigorous occupational health program. Another practical issue related to choice of animal models is the presence of experts working with that model. Just as it is often better to watch a relative cooking a family tradition, rather than relying on a recipe, there are likely to be small bits of ‘inside’ or not widely published information about the model that are more easily obtained by direct contact with the investigator utilizing the model. Current thinking would refute the notion that the placenta is just a passive membrane between mother and fetus. Early studies of nutrient uptake suggest that most of the resources delivered to the uterus are utilized by this organ. The placenta is selfish.

13 However, the growth cycle can be slowed or arrested depending on intracellular nutrient availability, leading to bacterial persistence within host cells.14,15 This is a key survival feature of these organisms and is a major determinant of disease pathogenesis as discussed more fully in the following sections. C. abortus typically causes reproductive failure and abortion in ruminants and swine and has a world-wide distribution, with the exception of Australia and New Zealand. C. abortus is also a well-recognized and potentially

fatal zoonosis, presenting a major hazard to pregnant women who come in contact with livestock, particularly at lambing.16 Although OEA is a reproductive disease, the principal route of transmission to naïve sheep is thought to be via an oro-nasal route, most likely from heavily infected placentas from ewes that have aborted and contaminate the environment.17,18 A typical example VX-770 ic50 of a placenta with characteristic thickened Ceritinib in vitro membranes from an ewe that aborted as a result of OEA is shown in Fig. 2. Abortion is thought to be because of inappropriate inflammatory cytokine and chemokine production in the placenta that leads to placentitis.18,19 The success of C. abortus as a reproductive pathogen in a species that is only pregnant for 5 months

and only gives birth once a year is because of its ability to establish a persistent, subclinical infection in non-pregnant sheep.20 Thus, when naïve, non-pregnant sheep are infected, protective immunity does not develop. Ewes then abort in the subsequent pregnancy. Sheep that have aborted do develop strong protective immunity (but not necessarily sterile immunity) and reproduce normally in subsequent pregnancies.20,21 The http://www.selleck.co.jp/products/Vorinostat-saha.html epidemiology and pathogenesis of OEA both indicate that a systemic phase of infection occurs after the primary infection of the oro-nasal mucosa. Neither the site of persistence of C. abortus nor the timing or duration of the systemic phase of infection has been identified. Therefore, the paradigms relating to reproductive immunology and to host immune control of intracellular bacteria are useful frameworks for addressing questions regarding

the pathogenesis of OEA. Furthermore, in addressing these paradigms in sheep, we can test their predictions and assess their relevance for a species other than mouse or human. In doing so, we should advance our knowledge of comparative immunology and reproduction. The first description of helper T-cell clones expressing distinctive cytokine profiles was made by Tim Mosmann, Robert Coffman and co-workers22 in 1986 in a paper that has had a profound impact on our understanding of how CD4+ve T cells orchestrate and regulate immune responses. They discovered that mitogen-activated murine CD4+ve T-cell clones were mutually exclusive in their expression of IL-2/IFN-γ (TH1) and what we now know to be IL-4 (TH2), whereas both sets of clones made IL-3.

mansoni actin 1.1 gene (23) was constructed and transfected into schistosomes

by electroporation of larval stages together with mRNAs encoding the piggyBac transposase. The activity of piggyBac was determined by plasmid excision assays, and the recovery of excised plasmids from tissues of transformed schistosomules in these assays indicated that piggyBac was Y-27632 chemical structure active in the worm. Southern blot hybridization analysis of genomic DNAs from populations of schistosomules transformed with donor constructs plus helper transposase mRNA detected numerous variable length luciferase-positive signals. These findings further indicated piggyBac transposon insertions into the schistosome chromosomes. piggyBac integration sites were detected by a PCR technique. Numerous piggyBac integrations were detected and, after cloning, the fragments sequenced

ranged in size from approximately 1·5 to 4 kb. Sequence analysis indicated that integration of piggyBac took place at numerous loci in the schistosome genome at target TTAA sites. The discovery of sequence-specific click here gene silencing in response to double-stranded RNAs (dsRNA) has had an enormous impact on molecular biology by uncovering an unsuspected layer of gene regulation. The process, also known as RNA interference (RNAi) or RNA silencing, involves complementary pairing of dsRNAs with their homologous messenger RNA targets, thereby preventing their expression, and leading ultimately to their degradation, or interfering with protein translation (33). Since its discovery, RNAi technology has been used widely as a reverse genetics tool in C. elegans, Drosophila and many other organisms, including zebrafish, plants, human, mouse and mammalian cell culture. The ability to inhibit gene activity on a post-transcriptional

level allows generation Baricitinib of loss-of-function mutants to study gene function, or identification and validation of novel therapeutic targets [reviewed in ref. (34)]. In C. elegans, silencing was found to have high potency and specificity, and was activated throughout the treated animal (35,36), even in cells that did not encounter the double-stranded RNA. It has now been revealed that a complex protein machinery is involved in the transport of the silencing signal. This raises the possibility that animals can communicate gene-specific silencing information between cells (37). In schistosomes, the presence of transcripts encoding dicer and RISC-associated proteins (piwi/argonaute orthologs) was relatively recently described (6,38,39). SmDicer was later shown to contain all domains that are characteristic of metazoan dicers including an amino terminal helicase domain, DUF283, a PAZ domain, two RNAse III domains and an RNA binding domain. An examination of the available S.

39 Collectively, an anti-sense E7 also can inhibit the expression of both E6 and E7 proteins simultaneously and can completely block COX-2 production. We attempted to determine whether IL-32, when coupled with COX-2, would

Doramapimod research buy function as a pro-inflammatory cytokine, exerting HPV-16 E7-mediated regulatory effects in cervical cancer cells. The significant induction of IL-32 and COX-2 promoter activities by HPV-16 E7 was inhibited by E7 knock-down in cervical cancer cells. As COX-2 is induced in response to an inflammatory factor40 and IL-32 also exerts immune/cancer effects,41 we identified the relationship between IL-32 and COX-2 induced by HPV-16 E7. As suggested by Figs 1 and 2(b), and also by Subbaramaiah and Dannenberg,22,24 the use of the COX-2 inhibitor NS398 results in lower expressions of IL-32 (RT-PCR and Western blot) and E7 genes (RT-PCR) (Fig. 3b). As shown in Figs 1 and 2(a), E7 expression is directly coupled to IL-32 expression. Hence, the results shown in Fig. 3 could also be interpreted as NS398 decreasing E7 expression for unknown reasons and therefore the expression of IL-32,

without COX-2 being involved. Taken together these results indicate that IL-32 expression levels were enhanced in COX-2-over-expressing SiHa and CaSki LY2157299 cells, and treatment with the COX-2 selective inhibitor blocks E7-mediated IL-32 stimulation. The E7-mediated production of PGE2 was also suppressed by NS398 in a dose-dependent fashion. These results demonstrate that IL-32 affects the regulation of COX-2 in response to HPV-16 E7 in cervical cancer cells. To determine the effects of IL-32 on the regulation of E7-mediated COX-2 and COX-2-derived PGE2 production, IL-32 was

over-expressed and knocked-down in SiHa and CaSki cells. IL-32 over-expression was shown to inhibit the activation of E7-mediated COX-2 and E7 expression in a feedback-based manner. Furthermore, PGE2 levels were reduced in culture media by IL-32 over-expression, whereas those levels were increased in the IL-32 knock-down cell supernatants. We confirmed that E7-mediated IL-32 activation is profoundly correlated with Montelukast Sodium the expression of other proinflammatory cytokines, such as IL-1β, TNF-α, and IL-18, in HPV-expressing cervical cancer cells, thereby indicating that they were induced by IL-32 over-expression, and down-regulated by IL-32 knock-down. It was previously demonstrated that HPV-16 E7 inhibits IL-18-induced IFN-γ production in human peripheral blood mononuclear and natural killer cells.10 Over-expression of IL-32 inhibited E7 oncogene expression, whereas IL-18 expression was enhanced. This suggests that the E7-mediated inhibition of IL-18 expression would be recovered via the suppression of E7, or that IL-18 could be directly induced by IL-32.

Results 

The administration of melatonin did not disturb the circadian rhythm of melatonin concentration. The ovarian graft lifespan was prolonged at 200 mg/kg/day melatonin (P < 0.001). However, in doses of higher than 20 mg/kg/day melatonin, the proportion of healthy follicles and ovary size decreased. Th1 cytokines levels were reduced dose dependently. However, the effect of melatonin on Th2 cytokines was not pronounced. IgM and IgG2a decreased in recipients receiving 200 mg/kg/day melatonin in comparison with non-treated group (P < 0.001), while this variables were significantly increased at the dose of 50 mg/kg/day (P < 0.001). Conclusion  Melatonin at 200 mg/kg/day has an immunosuppresent effect and produce prolongation of graft survival. However, the associated reduction in healthy follicles suggests that melatonin in doses of higher than 20 mg/kg/day has no preventative ischemic LY294002 action. “
“The clinical efficacy of peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists in cell-mediated autoimmune diseases results from down-regulation of inflammatory cytokines and autoimmune effector cells. T cell islet autoimmunity has been demonstrated to be common in patients

with phenotypic type 2 diabetes mellitus (T2DM) and islet-specific T cells (T+) to be correlated positively with more severe beta cell dysfunction. We hypothesized that the beneficial effects of the PPAR-γ agonist, rosiglitazone, therapy in autoimmune T2DM patients is due, in part, to the immunosuppressive properties on the islet-specific T cell responses. Twenty-six Cobimetinib cost phenotypic T2DM patients positive for T cell islet autoimmunity (T+) were identified and randomized to rosiglitazone (n = 12) or glyburide (n = 14). Beta cell function,

islet-specific T cell responses, interleukin (IL)-12 and interferon (IFN)-γ responses and islet autoantibodies were followed for 36 months. Patients treated with rosiglitazone demonstrated significant (P < 0·03) down-regulation very of islet-specific T cell responses, although no change in response to tetanus, a significant decrease (P < 0·05) in IFN-γ production and significantly (P < 0·001) increased levels of adiponectin compared to glyburide-treated patients. Glucagon-stimulated beta cell function was observed to improve significantly (P < 0·05) in the rosiglitazone-treated T2DM patients coinciding with the down-regulation of the islet-specific T cell responses. In contrast, beta cell function in the glyburide-treated T2DM patients was observed to drop progressively throughout the study. Our results suggest that down-regulation of islet-specific T cell autoimmunity through anti-inflammatory therapy may help to improve beta cell function in autoimmune phenotypic T2DM patients. Peroxisome proliferator-activated receptor-gamma (PPAR-γ) mediates important immune regulatory functions in conventional T cells, macrophages and dendritic cells [1-7].

27. During long-term exposure to the antigen, leading to a chronic lung inflammation, the number of eosinophils and monocytes were significantly upregulated. The lack of Thy-1 resulted in decreased infiltration of eosinophils and monocytes into the lung during acute as well as chronic

inflammation, indicating a key role of Thy-1 GDC-0941 order in airway inflammation induced by OVA. Thus, investigating different inflammation models in Thy-1−/− mice, we could prove the physiological relevance of Thy-1 in the control of the recruitment of leukocytes at sites of inflammation in vivo. Due to strong expression of Thy-1 on TCs in mice, Thy-1 was investigated previously in mouse models with respect to the role of Thy-1 for development and function of TCs 14, 28, 29. Beissert et al. showed that Thy-1 deficiency in mice led to reduced contact hypersensitivity responses and a decreased irritant dermatitis, which were suggested to be due to a defective fine tuning of TC functions 14. In the light of our data, the impaired cutaneous immune responses in Thy-1−/− mice might, in addition to affected TC responses, also be caused by the lack of Thy-1 as an adhesion receptor on EC, mediating

the extravasation of leukocytes during inflammation. Considering the high expression of Thy-1 on murine TCs 29, 14 and the pathogenic role of TCs in OVA-induced lung inflammation 21, we excluded that the reduced lung inflammation in Thy-1−/− mice was dependent of the

different Thy-1 expression levels on TCs. In Thy-1 BM chimera, the Thy-1-expression was detectable on 70% of TCs. Although Thy-1−/− BM Selleck Rapamycin chimera expressed Thy-1 on TCs and Thy-1−/− mice did not, airway inflammation was similarly reduced in both. In addition, BM transfer did not result in the incorporation of Thy-1-positive EC progenitor cells into the vessels, as Thy-1 staining of lungs revealed that Docetaxel cell line vessels did not express Thy-1 in the BM chimeras. Thus, we can conclude that reduced extravasation of eosinophils and monocytes during airway inflammation in Thy-1-deficient mice is independent of Thy-1 expression on TCs and relies on the Thy-1 expression on activated ECs. Gerwin et al. used the approach of generating BM chimera to exclude effects of TCs in an inflammation model in ICAM-2−/− mice. Accordingly, they also showed that the lack of ICAM-2 on ECs was responsible for the decreased eosinophil emigration during lung inflammation 30. As expected, the infiltration of leukocytes to the BAL fluid or into the peritoneal cavity was not completely inhibited in Thy-1−/− mice, suggesting a functional impact of further adhesion molecules. For example, ICAM-1−/− mice showed strongly decreased leukocyte infiltration in an OVA-induced inflammation model 31, as well as in a murine model of toluene diisocyanate-induced lung inflammation 32.

CD73-deficient mice display enhanced leukocyte extravasation at sites of inflammation in several ischemia-reperfusion models, and also the vascular permeability is increased in the absence of CD73 27. It has been firmly established that these effects are largely mediated by diminished adenosine production in these mice. However, the other enzymes involved in the inactivation and/or transphosphorylation of ATPADPAMP, and further degradation of RG-7204 AMP into adenosine and inosine have not been previously studied in the CD73-deficient mice. Here, we confirmed that CD73 was expressed both in a subpopulation of CD4+ and CD8+ T lymphocytes. T cells had significantly increased ATPase and ADPase

activities in the CD73-deficient mice. This suggests that the extracellular levels of proinflammatory ATP and procoagulant ADP molecules are lower in these mice. However, since extracellular AMP hydrolysis is also largely blocked in the absence of CD73, the concentration of extracellular adenosine, which is an anti-inflammatory molecule, is actually also decreased in the absence of CD73. Thus, the net effect of CD73 deficiency may be

to tilt the balance of purinergic signaling towards a state in ABT-263 ic50 which AMP accumulates in the body. The tumor microenvironment is capable of diverting the inflammatory reaction in a way that paradoxically enhances tumor growth. Intratumoral infiltration of Tregs and intratumoral differentiation of type 1 macrophages into type 2 macrophages are two key events in this immune evasion process 23, 30–33. Our findings indicate that Molecular motor the altered purinergic balance in the absence of CD73 inhibits this detrimental process, inasmuch the

tumors in CD73-deficient mice had specific decrease in the numbers of intratumoral Tregs and MR+ macrophages when compared with the WT mice. Interestingly, type 2 macrophages also show altered expression of purinergic receptors, which may link the CD73 and altered NTPDase activities to the observed phenotype 34. Moreover, tumor-infiltrating leukocytes in CD73-deficient mice showed increased IFN-γ synthesis. Since the transcription factor T-bet was actually down-regulated in tumor-infiltrating leukocytes in CD73-deficient mice, we speculate that IFN-γ is mainly produced by CD8+ cells, which in contrast to CD4+ and NK cells do not require T-bet for IFN-γ production 35. IFN-γ inhibits tumor formation and drives macrophage polarization into classically activated type 1, which show multiple anti-tumoral properties 30, 36. Notably, increased IFN-γ synthesis has also been recently reported in CD73-deficient mice during allograft rejection and in gastritis 37, 38. Interestingly, adenosine prevents IFN-γ-induced STAT phosphorylation and macrophage activation 39, and ATP has been reported to impair IFN-γ secretion in blood cells 35.