Epigenetic regulation is involved in traffic-related PM2.5 aggravating allergic airway inflammation in rats.

Increasing fine particulate matter (PM2.5) and epigenetic modifications are closely associated with the pathogenesis of asthma, but the definite mechanism remains unclear. The traffic-related PM2.5 exposure aggravated pulmonary inflammation and changed the methylation level of interferon gamma (Ifng) and interleukin (Il)4 genes, and then altered levels of affiliated cytokines of IFN-γ and IL-4 in rats with allergic airway inflammation. It also increased the level of miR146a and decreased the level of miR31. In addition, transcription factors of nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 6 (Stat6) rose; forkhead box P3 (Foxp3) and signal transducer and activator of transcription 4 (Stat4) lowered. The traffic-related PM2.5 altered epigenetic modifications in allergic airway inflammation of rats leading to inflammation exacerbation through impaired regulatory T (Treg) cells function and T-helper type 1 (Th1)/Th2 cells imbalance, which provided a new target for the treatment and control of asthma.

Early-Life Stress Regulates Cardiac Development through an IL-4-Glucocorticoid Signaling Balance.

Stressful experiences early in life can increase the risk of cardiovascular diseases. However, it remains largely unknown how stress influences susceptibility to the disease onset. Here, we show that exposure to brain-processed stress disrupts myocardial growth by reducing cardiomyocyte mitotic activity. Activation of the glucocorticoid receptor (GR), the primary stress response pathway, reduces cardiomyocyte numbers, disrupts trabecular formation, and leads to contractile dysfunction of the developing myocardium. However, a physiological level of GR signaling is required to prevent cardiomyocyte hyperproliferation. Mechanistically, we identify an antagonistic interaction between the GR and the cytokine interleukin-4 (IL-4) as a key player in cardiac development. IL-4 signals transcription of key regulators of cell-cycle progression in cardiomyocytes via signal transducer and activator of transcription 3 (Stat3). GR, on the contrary, inhibits this signaling system. Thus, our findings uncover an interplay between stress and immune signaling pathways critical to orchestrating physiological growth of the heart.

Eosinophils regulate adipose tissue inflammation and sustain physical and immunological fitness in old age.

Adipose tissue eosinophils (ATEs) are important in the control of obesity-associated inflammation and metabolic disease. However, the way in which ageing impacts the regulatory role of ATEs remains unknown. Here, we show that ATEs undergo major age-related changes in distribution and function associated with impaired adipose tissue homeostasis and systemic low-grade inflammation in both humans and mice. We find that exposure to a young systemic environment partially restores ATE distribution in aged parabionts and reduces adipose tissue inflammation. Approaches to restore ATE distribution using adoptive transfer of eosinophils from young mice into aged recipients proved sufficient to dampen age-related local and systemic low-grade inflammation. Importantly, restoration of a youthful systemic milieu by means of eosinophil transfers resulted in systemic rejuvenation of the aged host, manifesting in improved physical and immune fitness that was partially mediated by eosinophil-derived IL-4. Together, these findings support a critical function of adipose tissue as a source of pro-ageing factors and uncover a new role of eosinophils in promoting healthy ageing by sustaining adipose tissue homeostasis.

Role of IL-4 in bone marrow driven dysregulated angiogenesis and age-related macular degeneration.

Age-associated sterile inflammation can cause dysregulated choroidal neovascularization (CNV) as age-related macular degeneration (AMD). Intraocular fluid screening of 234 AMD patients identified high levels of IL-4. The purpose of this study was to determine the functional role of IL-4 in CNV formation using murine CNV model. Our results indicate that the IL-4/IL-4 receptors (IL4Rs) controlled tube formation and global proangiogenic responses of bone marrow cells. CCR2+ bone marrow cells were recruited to form very early CNV lesions. IL-4 rapidly induces CCL2, which enhances recruitment of CCR2+ bone marrow cells. This in vivo communication, like quorum-sensing, was followed by the induction of IL-4 by the bone marrow cells during the formation of mature CNVs. For CNV development, IL-4 in bone marrow cells are critically required, and IL-4 directly promotes CNV formation mainly by IL-4R. The IL-4/IL-4Rα axis contributes to pathological angiogenesis through communications with bone marrow cells leading to retinal degeneration.

Activation of the IL-4/STAT6 Signaling Pathway Promotes Lung Cancer Progression by Increasing M2 Myeloid Cells.

Emerging evidence shows that signal transducer and activator of transcription 6 (STAT6) plays critical roles in tumor development. We previously found high-level expression of STAT6 in human lung adenocarcinoma and squamous cell carcinoma, specifically in infiltrated immune cells located in the lung interstitium. Nevertheless, the role of STAT6 signaling in lung carcinogenesis and lung cancer proliferation and its underlying mechanisms remain unclear. This study aimed to investigate the role of STAT6 and the interaction between STAT6 and the tumor microenvironment in pulmonary tumorigenesis. We established a murine model of primary lung carcinogenesis in STAT6-deficient (STAT6-/-) and STAT6 wild-type (WT) BALB/c mice using the carcinogen urethane. Two-month-old male mice were intraperitoneally injected with urethane (1 g/kg) dissolved in phosphate buffered saline (PBS). Primary tumors were monitored in vivo by positron emission tomography scanning. At 4, 6, and 9 months after urethane injection, lung tumors were harvested from the STAT6-/- and WT mice for analysis. Small interfering RNA was used to downregulate the expression of STAT6 in tumor cells. Fluorescence activated cell sorting analysis was used to analyze fluorescence-conjugated cell markers. Transwell assays were used in coculturing experiments. STAT6 protein expression was detected by Western blotting, immunohistochemistry, and immunofluorescence. STAT6 mRNA expression was detected by quantitative real time-polymerase chain reaction. Cell Counting Kit-8 and colony formation assays were performed to evaluate cell proliferation. We detected high expression of STAT6 in CD11b+ cells of lung carcinoma. Our results indicate that STAT6 deficiency inhibits carcinogen-induced tumor growth and improves prognosis. STAT6 deficiency also decreased the mobilization and differentiation of CD11b+ cells. STAT6 deficiency in CD11b+ cells but not tumor cells decreased interleukin (IL)-4 secretion and the differentiation of CD11b+ cells into M2 macrophage cells. In conclusion, our findings indicate that IL-4/STAT6 signaling in CD11b+ cells promotes lung cancer progression by triggering an IL-4 positive feedback loop and increasing M2 myeloid cells. STAT6 may be a new therapeutic target for the prevention and treatment of lung cancer.

The interleukin-4/PPARγ signaling axis promotes oligodendrocyte differentiation and remyelination after brain injury.

The repair of white matter damage is of paramount importance for functional recovery after brain injuries. Here, we report that interleukin-4 (IL-4) promotes oligodendrocyte regeneration and remyelination. IL-4 receptor expression was detected in a variety of glial cells after ischemic brain injury, including oligodendrocyte lineage cells. IL-4 deficiency in knockout mice resulted in greater deterioration of white matter over 14 d after stroke. Consistent with these findings, intranasal delivery of IL-4 nanoparticles after stroke improved white matter integrity and attenuated long-term sensorimotor and cognitive deficits in wild-type mice, as revealed by histological immunostaining, electron microscopy, diffusion tensor imaging, and electrophysiology. The selective effect of IL-4 on remyelination was verified in an ex vivo organotypic model of demyelination. By leveraging primary oligodendrocyte progenitor cells (OPCs), microglia-depleted mice, and conditional OPC-specific peroxisome proliferator-activated receptor gamma (PPARγ) knockout mice, we discovered a direct salutary effect of IL-4 on oligodendrocyte differentiation that was mediated by the PPARγ axis. Our findings reveal a new regenerative role of IL-4 in the central nervous system (CNS), which lies beyond its known immunoregulatory functions on microglia/macrophages or peripheral lymphocytes. Therefore, intranasal IL-4 delivery may represent a novel therapeutic strategy to improve white matter integrity in stroke and other brain injuries.

Cardiotrophin-1 is an anti-inflammatory cytokine and promotes IL-4-induced M2 macrophage polarization.

Macrophages play a central role in tissue remodeling, repair, and resolution of inflammation. Macrophage polarization to M1 or M2 activation status may determine the progression or resolution of the inflammatory response. We have previously reported that cardiotrophin-1 (CT-1) displays both cytoprotective and metabolic activities. The role of CT-1 in inflammation remains poorly understood. Here, we employed recombinant CT-1 (rCT-1) and used CT-1-null mice and myeloid-specific CT-1 transgenic mice to investigate whether CT-1 might play a role in the modulation of the inflammatory response. We observed that CT-1 deficiency was associated with enhanced release of inflammatory mediators and with stronger activation of NF-κB in response to LPS, whereas the inflammatory response was attenuated in CT-1 transgenic mice or by administering rCT-1 to wild-type animals prior to LPS challenge. We found that CT-1 promoted IL-6 expression only by nonhematopoietic cells, whereas LPS up-regulated IL-6 expression in both hematopoietic and nonhematopoietic cells. Notably, rCT-1 inhibited LPS-mediated soluble IL-6R induction. Using IL-6-/- mice, we showed that rCT-1 inhibited LPS-induced TNF-α and IFN-γ response in an IL-6-independent manner. Importantly, we demonstrated that CT-1 primes macrophages for IL-4-dependent M2 polarization by inducing IL-4 receptor expression. Mechanistic analyses showed that the signal transducer and activator of transcription 3-suppressor of cytokine signaling 3 axis mediates this effect. Our findings support the notion that CT-1 is a critical regulator of inflammation and suggest that rCT-1 could be a molecule with potential therapeutic application in inflammatory conditions.-Carneros, D., Santamaría, E. M., Larequi, E., Vélez-Ortiz, J. M., Reboredo, M., Mancheño, U., Perugorria, M. J., Navas, P., Romero-Gómez, M., Prieto, J., Hervás-Stubbs, S., Bustos, M. Cardiotrophin-1 is an anti-inflammatory cytokine and promotes IL-4-induced M2 macrophage polarization.

IL-4 receptor engagement in human neutrophils impairs their migration and extracellular trap formation.

BACKGROUND: Type 2 immunity serves to resist parasitic helminths, venoms, and toxins, but the role and regulation of neutrophils during type 2 immune responses are controversial. Helminth models suggested a contribution of neutrophils to type 2 immunity, whereas neutrophils are associated with increased disease severity during type 2 inflammatory disorders, such as asthma. OBJECTIVE: We sought to evaluate the effect of the prototypic type 2 cytokines IL-4 and IL-13 on human neutrophils. METHODS: Human neutrophils from peripheral blood were assessed without or with IL-4 or IL-13 for (1) expression of IL-4 receptor subunits, (2) neutrophil extracellular trap (NET) formation, (3) migration toward CXCL8 in vitro and in humanized mice, and (4) CXCR1, CXCR2, and CXCR4 expression, as well as (5) in nonallergic versus allergic subjects. RESULTS: Human neutrophils expressed both types of IL-4 receptors, and their stimulation through IL-4 or IL-13 diminished their ability to form NETs and migrate toward CXCL8 in vitro. Likewise, in vivo chemotaxis in NOD-scid-Il2rg-/- mice was reduced in IL-4-stimulated human neutrophils compared with control values. These effects were accompanied by downregulation of the CXCL8-binding chemokine receptors CXCR1 and CXCR2 on human neutrophils on IL-4 or IL-13 stimulation in vitro. Ex vivo analysis of neutrophils from allergic patients or exposure of neutrophils from nonallergic subjects to allergic donor serum in vitro impaired their NET formation and migration toward CXCL8, thereby mirroring IL-4/IL-13-stimulated neutrophils. CONCLUSION: IL-4 receptor signaling in human neutrophils affects several neutrophil effector functions, which bears important implications for immunity in type 2 inflammatory disorders.

Th2 cytokines orchestrate the secretion of MUC5AC and MUC5B in IL-5-positive chronic rhinosinusitis with nasal polyps.

BACKGROUND: Mucin over-secretion is a significant characteristic of chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to investigate the relationship between Th2 cytokines and MUC5AC or MUC5B, and the mechanism of mucin over-secretion in the type-2 inflammatory endotype of CRSwNP. METHODS: Main Th-cell cytokines, associated mediators, and mucins were determined in the homogenates of nasal polyp samples from 21 CRSwNP patients and inferior turbinate samples from 8 controls, by ELISA or UniCAP system. Secretion of MUC5AC and MUC5B was measured in the supernatants of IL-5, IL-4, or IL-13 primed nasal polyp fragments. Co-localization of MUC5AC, MUC5B, and IL-4 receptor α (IL-4Rα) in CRSwNP and controls was evaluated by immunohistochemistry. Gene expression of IL-4Rα in the samples was measured by real-time reverse transcription-polymerase chain reaction. RESULTS: Baseline protein levels of the Th2-cytokines IL-4, IL-5, and IL-13, and mucins MUC5AC and MUC5B were significantly higher in the IL-5(+) CRSwNP group, compared to control and IL-5(-) CRSwNP groups. MUC5AC and MUC5B secretions were significantly increased in IL-4- or IL-13-primed, but not IL-5-primed fragments of nasal polyps. Immuno-stained serial sections demonstrated that IL-4Rα was widely expressed in the epithelium and submucosal glands in control and nasal polyp tissues. Gene expression of IL-4Rα was elevated in nasal polyp tissues, specifically in the IL-5(+) CRSwNP group. CONCLUSIONS: In type-2 inflammatory nasal polyps, characterized by the tissue expression of IL-5, MUC5AC and MUC5B are overexpressed. Both IL-4 and IL-13 may upregulate mucin expression via IL-4Rα, which is also overexpressed in IL-5(+) CRSwNP.

A preliminary study of the relation between IL-4 and hypertension in type II diabetes mellitus.

Clinical outcome of T2DM can be influenced by a polymorphism of different cytokines. The aim of this study was to evaluate the effect of genetic variation and gene expression of IL-4 in T2DM patients. This study was carried out on type II diabetic patients and healthy people served as controls. All subjects were submitted to estimation of IL-4 gene polymorphism using VNTR PCR method and gene expression by real-time PCR. There was a significant decrease of IL-4 gene expression and serum IL4 levels in subjects with B2B2 genotypes. A significant positive correlation was found between IL-4 gene expression and the HDL-c levels and negative correlation between serum IL4 levels and LDLc. Also, a negative correlation was found between serum IL4 and gene expression with both systolic and diastolic blood pressure levels in patients group. It can be concluded that IL-4 gene expression and serum IL4 reduction in patients with B2B2 genotypes has a relation to dyslipidemia and hypertension in the patient with type 2 diabetes mellitus.

PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism.

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPARγ ligand, in a PPARγ-dependent manner. Moreover, PPARγ is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARγ dramatically affects the oxidation of glutamine. Both glutamine and PPARγ have been implicated in alternative activation (AA) of macrophages, and PPARγ was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPARγ contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPARγ functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPARγ expression is itself markedly increased by IL4. This suggests that PPARγ functions at the center of a feed-forward loop that is central to AA of macrophages.

A malaria protein factor induces IL-4 production by dendritic cells via PI3K-Akt-NF-κB signaling independent of MyD88/TRIF and promotes Th2 response.

Dendritic cells (DC) and cytokines produced by DC play crucial roles in inducing and regulating pro-/anti-inflammatory and Th1/Th2 responses. DC are known to produce a Th1-promoting cytokine, interleukin (IL)-12, in response to malaria and other pathogenic infections, but it is thought that DC do not produce Th2-promoting cytokine, IL-4. Here, we show that a protein factor of malaria parasites induces IL-4 responses by CD11chiMHCIIhiCD3ϵ-CD49b-CD19-FcϵRI- DC via PI3K-Akt-NF-κB signaling independent of TLR-MyD88/TRIF. Malaria parasite-activated DC induced IL-4 responses by T cells both in vitro and in vivo, favoring Th2, and il-4-deficient DC were unable to induce IL-4 expression by T cells. Interestingly, lethal parasites, Plasmodium falciparum and Plasmodium berghei ANKA, induced IL-4 response primarily by CD8α- DC, whereas nonlethal Plasmodium yoelii induced IL-4 by both CD8α+ and CD8α- DC. In both P. berghei ANKA- and P. yoelii-infected mice, IL-4-expressing CD8α- DC did not express IL-12, but a distinct CD8α- DC subset expressed IL-12. In P. berghei ANKA infection, CD8α+ DC expressed IL-12 but not IL-4, whereas in P. yoelii infection, CD8α+ DC expressed IL-4 but not IL-12. These differential IL-4 and IL-12 responses by DC subsets may contribute to different Th1/Th2 development and clinical outcomes in lethal and nonlethal malaria. Our results for the first time demonstrate that a malaria protein factor induces IL-4 production by DC via PI3K-Akt-NF-κB signaling, revealing signaling and molecular mechanisms that initiate and promote Th2 development.

The IL-4/STAT6/PPARγ signaling axis is driving the expansion of the RXR heterodimer cistrome, providing complex ligand responsiveness in macrophages.

Retinoid X receptor (RXR) is an obligate heterodimeric partner of several nuclear receptors (NRs), and as such a central component of NR signaling regulating the immune and metabolic phenotype of macrophages. Importantly, the binding motifs of RXR heterodimers are enriched in the tissue-selective open chromatin regions of resident macrophages, suggesting roles in subtype specification. Recent genome-wide studies revealed that RXR binds to thousands of sites in the genome, but the mechanistic details how the cistrome is established and serves ligand-induced transcriptional activity remained elusive. Here we show that IL-4-mediated macrophage plasticity results in a greatly extended RXR cistrome via both direct and indirect actions of the transcription factor STAT6. Activation of STAT6 leads to chromatin remodeling and RXR recruitment to de novo enhancers. In addition, STAT6 triggers a secondary transcription factor wave, including PPARγ. PPARγ appears to be indispensable for the development of RXR-bound de novo enhancers, whose activities can be modulated by the ligands of the PPARγ:RXR heterodimer conferring ligand selective cellular responses. Collectively, these data reveal the mechanisms leading to the dynamic extension of the RXR cistrome and identify the lipid-sensing enhancer sets responsible for the appearance of ligand-preferred gene signatures in alternatively polarized macrophages.

[Pathogenesis of atopic dermatitis]. / Pathogenese des atopischen Ekzems.

Atopic dermatitis (AD) is one of the most common chronic inflammatory diseases and is also one of the most frequent reasons to consult a dermatologist. Over the past few years there has been a rapidly growing understanding of the cellular, molecular and immunological relationships as well as genetic variations, which leads to a better comprehension of the disease. Consequently, there are innovative targeted therapies in clinical studies or already approved for therapy. To make reasonable use of the new targeted therapies a good understanding of the pathogenesis is very important. In the future, stratification of patients with AD and the resulting personalized therapies will gain in importance. This review depicts the up to date state of knowledge on the complex pathogenesis of AD.

The modulatory role of cytokines IL-4 and IL-17 in the functional activity of phagocytes in diabetic pregnant women.

The study investigated the role of cytokines IL-4 and IL-17 in the modulation of the functional activity of mononuclear phagocytes in diabetic pregnant women with hyperglycemia. Sixty pregnant women were assigned to the following groups: nondiabetic (ND), mild gestational hyperglycemia (MGH), gestational diabetes mellitus (GDM), or type 2 diabetes mellitus (DM2). The functional activity of phagocytes from maternal blood, cord blood, and colostrum was assessed by determining their superoxide release, phagocytosis, microbicidal activity, and intracellular Ca2+ release. Irrespective of glycemic status, colostrum and blood cells treated with IL-4 and IL-17 increased superoxide release in the presence of enteropathogenic Escherichia coli (EPEC). The highest phagocytosis rate was observed in cells from the DM2 group treated with IL-4. In all the groups, phagocytes from colostrum, maternal blood, and cord blood exhibited higher microbicidal activity against EPEC when treated with cytokines. IL-17 increased intracellular Ca2+ release by colostrum phagocytes in diabetic groups. The results indicate that the IL-4 and IL-17 modulate the functional activity of phagocytes in the maternal blood, cord blood, and colostrum of diabetic mother. The natural immunity resulting from the interaction between the cells and cytokines tested may be an alternative procedure to improve the prognosis of maternal and newborn infections.

Anti-inflammatory (M2) macrophage media reduce transmission of oligomeric amyloid beta in differentiated SH-SY5Y cells.

Neuroinflammation plays an influential role in Alzheimer's disease (AD), although the mechanisms underlying this phenomenon remain largely unknown. Microglia are thought to be responsible for the majority of these effects and can be characterized into resting (M0), proinflammatory (M1), or anti-inflammatory (M2) functional phenotypes. We investigated the effects of conditioned macrophage media, as an analogue to microglia, on the transfer of oligomeric amyloid beta (oAß) between differentiated SH-SY5Y cells. We also investigated how the different inflammatory environments related to intercellular and intracellular changes. We demonstrate that M2 products decrease interneuronal transfer of oAß, while recombinant interleukin (IL)-4, IL-10, and IL-13 increase transfer. There were no alterations to the mRNA of a number of AD-related genes in response to the combination of oAß and M0, M1, or M2, but several intracellular proteins, some relating to protein trafficking and the endosomal/lysosomal system, were altered. Stimulating microglia to an M2 phenotype may thus slow down the progression of AD and could be a target for future therapies.

IL-4/5 signalling plays an important role during Litomosoides sigmodontis infection, influencing both immune system regulation and tissue pathology in the thoracic cavity.

Approximately 100 million people suffer from filarial diseases including lymphatic filariasis (elephantiasis), onchocerciasis (river blindness) and loiasis. These diseases are amongst the most devastating of the neglected tropical diseases in terms of social and economic impact. Moreover, many infection-induced immune mechanisms in the host, their relationship to disease-related symptoms and the development of pathology within the site of infection remain unclear. To improve on current drug therapies or vaccines, further studies are necessary to decipher the mechanisms behind filaria-driven immune responses and pathology development, and thus the rodent model of Litomosoides sigmodontis can be used to unravel host-filaria interactions. Interestingly, BALB/c mice develop a patent state (release of microfilariae, the transmission life-stage, into the periphery) when exposed to L. sigmodontis. Thus, using this model, we determined levels of host inflammation and pathology development during a L. sigmodontis infection in vivo for the first known time. Our study reveals that after 30days p.i., inflammation and pathology began to develop in infected wild type BALB/c mice between the lung and diaphragm, close to the site of infection - the thoracic cavity. Interestingly, infected IL-4Rα/IL-5-/- BALB/c mice had accentuated inflammation of the pleural lung and pleural diaphragm, and higher parasite burdens. Corresponding to the pleural inflammation, levels of IP-10, MIP-1α, MIP-1ß, MIP-2 and RANTES were significantly elevated in the thoracic cavity fluid of infected IL-4Rα/IL-5-/- mice compared with wild type controls. Moreover, upon L. sigmodontis antigen stimulation, IFN-γ and IL-17A secretions by cells isolated from draining lymph nodes of IL-4Rα/IL-5-/- mice were significantly elevated, whereas secretion of IL-5, IL-13 and IL-10 was reduced. Elevated filaria-specific IFN-γ secretion was also observed in spleen-derived CD4+ T cell co-cultures from IL-4Rα/IL-5-/- mice. In summary, this study unravels the essential role of IL-4/IL-5 signalling in controlling immunity against filarial infections and demonstrates the requirement of this pathway for the host to control ensuing pathology and inflammation.

Growth Differentiation Factor 15 Mediates Systemic Glucose Regulatory Action of T-Helper Type 2 Cytokines.

T-helper type 2 (Th2) cytokines, including interleukin (IL)-13 and IL-4, produced in adipose tissue, are critical regulators of intra-adipose and systemic lipid and glucose metabolism. Furthermore, IL-13 is a potential therapy for insulin resistance in obese mouse models. Here, we examined mediators produced by adipocytes that are responsible for regulating systemic glucose homeostasis in response to Th2 cytokines. We used RNA sequencing data analysis of cultured adipocytes to screen factors secreted in response to recombinant IL-13. Recombinant IL-13 induced expression of growth differentiation factor 15 (GDF15) via the Janus kinase-activated STAT6 pathway. In vivo administration of α-galactosylceramide or IL-33 increased IL-4 and IL-13 production, thereby increasing GDF15 levels in adipose tissue and in plasma of mice; however, these responses were abrogated in STAT6 knockout mice. Moreover, administration of recombinant IL-13 to wild-type mice fed a high-fat diet (HFD) improved glucose intolerance; this was not the case for GDF15 knockout mice fed the HFD. Taken together, these data suggest that GDF15 is required for IL-13-induced improvement of glucose intolerance in mice fed an HFD. Thus, beneficial effects of Th2 cytokines on systemic glucose metabolism and insulin sensitivity are mediated by GDF15. These findings open up a potential pharmacological route for reversing insulin resistance associated with obesity.

Types of External Root Resorption of Replanted Teeth: Analysis of the Clinical Aspects and of Interleukin-4 Gene Polymorphisms Involvement.

INTRODUCTION: The absence or presence of root resorption on the surface of a replanted tooth indicates an immune-inflammatory reaction. Recent research even suggests the participation of host predominant immunologic profile on types of resorptions detected on the root surface. Because interleukin 4 (IL-4) is an important anti-inflammatory cytokine, this study aimed to investigate the association of clinical variables and polymorphisms in IL4 with types of resorption of replanted teeth after 1 year of follow-up. METHODS: One hundred twenty-seven avulsed teeth that were replanted were selected. Periapical radiographs were taken after replantation and for 1 year to detect the types of root resorption. Real-time polymerase chain reaction was used to genotype IL4 polymorphisms. The χ2 and Z tests were performed to verify the association of clinical and genetic variables with the outcomes of replanted teeth (P < .05). RESULTS: An association was observed of extra-alveolar time, storage medium, and development of the root (P < .05), but not of IL4 polymorphisms, with the outcomes of replanted teeth (P > .05). CONCLUSIONS: Extraoral time, storage medium, and development of the root, but not IL4 polymorphisms, may influence the types of resorption of avulsed and replanted teeth in the first year after trauma.