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Abstract Objectives This study investigated gene polymorphisms in the interleukin-4 (IL-4) and its receptor alpha (IL-4Rα) gene regions in human hosts with uncomplicated malaria. Data description Blood samples were obtained from a case-control study conducted at the Sogakope district hospital in the Volta region of Ghana. Thick blood films were made and used to detect the presence and levels of parasitaemia in the patient samples. Genotyping of IL-4 (150 C/T) and the IL-4Rα (Pro-478-Ser) polymorphisms in the promoter regions and receptor gene was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) after DNA extraction. The data are useful in determining genetic polymorphisms (allele and genotypic frequencies) of IL-4 and its alpha receptor. In addition, they are useful when comparing levels of parasite density and haematological parameters between genotypic variants of IL-4 and IL-4Rα. These data contribute to our understanding of the genetic basis of malaria susceptibility, particularly in the population of the Volta region of Ghana.

Objectives: This study investigated gene polymorphisms in the interleukin-4 (IL-4) and its receptor alpha (IL-4Rα) gene regions in human hosts with uncomplicated malaria. Data description: Blood samples were obtained from a case-control study conducted at the Sogakope district hospital in the Volta region of Ghana. Thick blood films were made and used to detect the presence and levels of parasitaemia in the patient samples. Genotyping of IL-4 (150 C/T) and the IL-4Rα (Pro-478-Ser) polymorphisms in the promoter regions and receptor gene was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) after DNA extraction. The data are useful in determining genetic polymorphisms (allele and genotypic frequencies) of IL-4 and its alpha receptor. In addition, they are useful when comparing levels of parasite density and haematological parameters between genotypic variants of IL-4 and IL-4Rα. These data contribute to our understanding of the genetic basis of malaria susceptibility, particularly in the population of the Volta region of Ghana. [ABSTRACT FROM AUTHOR]

Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly a type 2 inflammatory disease associated with type 2 (T2) cell responses and epithelial barrier, mucociliary, and olfactory dysfunction. The inflammatory cytokines interleukin (IL)-4, IL-13, and IL-5 are key mediators driving and perpetuating type 2 inflammation. The inflammatory responses driven by these cytokines include the recruitment and activation of eosinophils, basophils, mast cells, goblet cells, M2 macrophages, and B cells. The activation of these immune cells results in a range of pathologic effects including immunoglobulin E production, an increase in the number of smooth muscle cells within the nasal mucosa and a reduction in their contractility, increased deposition of fibrinogen, mucus hyperproduction, and local edema. The cytokine-driven structural changes include nasal polyp formation and nasal epithelial tissue remodeling, which perpetuate barrier dysfunction. Type 2 inflammation may also alter the availability or function of olfactory sensory neurons contributing to loss of sense of smell. Targeting these key cytokine pathways has emerged as an effective approach for the treatment of type 2 inflammatory airway diseases, and a number of biologic agents are now available or in development for CRSwNP. In this review, we provide an overview of the inflammatory pathways involved in CRSwNP and describe how targeting key drivers of type 2 inflammation is an effective therapeutic option for patients. [ABSTRACT FROM AUTHOR]

Abstract Dupilumab demonstrated high efficacy and tolerable safety profiles in moderate‐to‐severe atopic dermatitis (AD) patients in clinical trials; however, certain patients suffer from facial redness, while obtaining good responses on the trunk and limbs to dupilumab in the real‐world setting. In our study, we investigated the effectiveness of tacrolimus ointment on facial lesions refractory to topical corticosteroid in patients with AD receiving dupilumab. This study included Japanese adult patients with moderate‐to‐severe AD who developed facial lesions during dupilumab treatment and whose facial lesions became refractory to topical corticosteroid treatment. Nine patients (one female, eight males) were included in this study. One patient newly developed facial erythema after initiating dupilumab. Facial lesions were refractory to dupilumab treatment in the other patients. Five of the nine patients showed improvement in EASI scores of head and neck by switching the facial treatment from topical corticosteroid to tacrolimus ointment. The patient who developed newly facial erythema showed improvement after applying tacrolimus ointment. Although we explored the predictors of effectiveness of tacrolimus ointment in patients with facial lesions during dupilumab treatment, no significant differences were observed in age, duration of dupilumab prior treatment, or prior head and neck EASI between patients who showed improvement after changing to tacrolimus and those who did not. Tacrolimus ointment is worth trying if facial lesions are refractory to topical corticosteroid.

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been demonstrated to deliver therapeutic drugs in preclinical studies. However, their use is limited, as they lack the ability to specifically deliver drugs to tumor tissues in vivo. In the present study, we propose the use of a targeting peptide, IL-4R-binding peptide (IL4RPep-1), to specifically deliver intravenously (i.v.) infused EVs to thyroid tumors. In vivo, a xenograft tumor model was treated with either the control peptide (NSSSVDK) or IL4RPep-1-Flamma; mice were fluorescently imaged (FLI) using an in vivo imaging system at 0–3 h post-treatment. EVs (labeled with DiD dye) were conjugated with IL4RPep-1 through a DOPE-NHS linker and administered to mice intravenously. FLI was performed 0–24 h post-injection, and the animals were sacrificed for further experiments. The morphology and size of EVs, the presence of EV markers such as CD63 and ALIX, and the absence of the markers GM130 and Cyto-C were confirmed. In vivo, FLI indicated an accumulation of i.v. injected IL4RPep-1-Flamma at the tumor site 90 min post-injection. No accumulation of NSSSVDK-Flamma was detected. In vivo, IL4RPep-1-EVs targeted the Cal-62 tumor 2 h post-injection. NSSSVDK-EVs were not even detected in the tumor 24 h post-injection. The quantification of FLI showed a significant accumulation of MSC-EVs in the tumor 2 h, 3 h, and 24 h post-injection. Furthermore, ex vivo imaging and an IF analysis confirmed the in vivo findings. Our results demonstrate the use of the IL4RPep-1 peptide as a targeting moiety of EVs for IL-4R-expressing anaplastic thyroid tumors. [ABSTRACT FROM AUTHOR]

Corrado Pelaia,1 Nicola Lombardo,2 Maria Teresa Busceti,1 Giovanna Piazzetta,2 Claudia Crimi,3 Cecilia Calabrese,4 Alessandro Vatrella,5 Girolamo Pelaia1 1Department of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy; 2Department of Medical and Surgical Sciences, Magna Graecia University of Catanzaro, Catanzaro, Italy; 3Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; 4Department of Translational Medical Sciences, Luigi Vanvitelli University of Campania, Naples, Italy; 5Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, ItalyCorrespondence: Corrado PelaiaDepartment of Health Sciences, Magna Graecia University of Catanzaro, Catanzaro, ItalyTel + 39 0961 364-7007Email pelaia.corrado@gmail.comBackground: Having been approved for biological treatment of atopic dermatitis, dupilumab has also been recently licensed as add-on therapy for severe asthma and nasal polyposis. With regard to the latter diseases, few real-life clinical investigations have been carried out to date.Objective: The primary end point of this single-center observational study was to evaluate in a real-life setting the short-term therapeutic effects of dupilumab in patients with severe asthma and nasal polyposis.Methods: At baseline and after 4 weeks of add-on therapy with dupilumab, several clinical and functional parameters were assessed in 20 patients with severe asthma and nasal polyposis, including both allergic and nonallergic subjects.Results: After 4 weeks of treatment with dupilumab, all patients experienced remarkable improvement in both severe asthma and nasal polyposis. In particular, asthma-control test and sinonasal outcome test 22 scores had significantly increased (p< 0.0001) and decreased (p< 0.0001), respectively. Oral corticosteroid intake got to zero within 4 weeks (p< 0.0001). Moreover, in week 4, significant increases were detected with regard to both prebronchodilator forced expiratory volume in the first second (p< 0.01) and forced vital capacity (FVC; p< 0.05). At the same time point, dupilumab had significantly reduced residual volume (p< 0.0001) and total lung capacity (p< 0.001), whereas it had enhanced forced midexpiratory flow of 25%– 75% FVC (p< 0.01) and peak expiratory flow (p< 0.01). After 4 weeks of treatment, dupilumab had also lowered levels of fractional exhaled nitric oxide (p< 0.0001).Conclusion: The results of this real-life study suggest that dupilumab can be utilized in both allergic and nonallergic patients with severe asthma and nasal polyposis as a valuable add-on biological therapy with rapid onset of action.Keywords: severe asthma, nasal polyposis, interleukin 4 receptor, dupilumab

Dupilumab demonstrated high efficacy and tolerable safety profiles in moderate‐to‐severe atopic dermatitis (AD) patients in clinical trials; however, certain patients suffer from facial redness, while obtaining good responses on the trunk and limbs to dupilumab in the real‐world setting. In our study, we investigated the effectiveness of tacrolimus ointment on facial lesions refractory to topical corticosteroid in patients with AD receiving dupilumab. This study included Japanese adult patients with moderate‐to‐severe AD who developed facial lesions during dupilumab treatment and whose facial lesions became refractory to topical corticosteroid treatment. Nine patients (one female, eight males) were included in this study. One patient newly developed facial erythema after initiating dupilumab. Facial lesions were refractory to dupilumab treatment in the other patients. Five of the nine patients showed improvement in EASI scores of head and neck by switching the facial treatment from topical corticosteroid to tacrolimus ointment. The patient who developed newly facial erythema showed improvement after applying tacrolimus ointment. Although we explored the predictors of effectiveness of tacrolimus ointment in patients with facial lesions during dupilumab treatment, no significant differences were observed in age, duration of dupilumab prior treatment, or prior head and neck EASI between patients who showed improvement after changing to tacrolimus and those who did not. Tacrolimus ointment is worth trying if facial lesions are refractory to topical corticosteroid. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-4 and IL-13 are the main effectors of innate lymphoid cells (ILC2) of the type 2 innate immune response, which can carry out specific signal transmission between multiple cells in the tumor immune microenvironment. IL-4 and IL-13 mediate signal transduction and regulate cellular functions in a variety of solid tumors through their shared receptor chain, the transmembrane heterodimer interleukin-4 receptor alpha/interleukin-13 receptor alpha-1 (type II IL-4 receptor). IL-4, IL-13, and their receptors can induce the formation of a variety of malignant tumors and play an important role in their progression, growth, and tumor immunity. In order to explore possible targets for lung cancer prediction and treatment, this review summarizes the characteristics and signal transduction pathways of IL-4 and IL-13, and their respective receptors, and discusses in depth their possible role in the occurrence and development of lung cancer.

Abstract Background Kawasaki disease (KD) is a systemic vasculitis which may be associated with coronary artery aneurysms. A notable risk factor for the development of coronary artery aneurysms is resistance to intravenous immunoglobulin (IVIG) therapy, which comprises standard treatment for the acute phase of KD. The cause of IVIG resistance in KD is largely unknown; however, the contribution of genetic factors, especially variants in immune-related genes, has been suspected. Methods To explore genetic variants related to IVIG-unresponsiveness, we designated KD patients who did not respond to both first and second courses of IVIG therapy as IVIG-unresponsive patients. Using genomic DNA from 30 IVIG-unresponsive KD patients, we performed pooled genome sequencing targeting 39 immune-related cytokine receptor genes. Results The single nucleotide variant (SNV), rs563535954 (located in the IL4R locus), was concentrated in IVIG-unresponsive KD patients. Individual genotyping showed that the minor allele of rs563535954 was present in 4/33 patients with IVIG-unresponsive KD, compared with 20/1063 individuals in the Japanese genome variation database (odds ratio = 7.19, 95% confidence interval 2.43–21.47). Furthermore, the minor allele of rs563535954 was absent in 42 KD patients who responded to IVIG treatment (P = 0.0337), indicating that a low-frequency variant, rs563535954, is associated with IVIG-unresponsiveness in KD patients. Although rs563535954 is located in the 3′-untranslated region of IL4R, there was no alternation in IL4R expression associated with the mior allele of rs563535954. However, IVIG-unresponsive patients that exhibited the minor allele of rs563535954 tended to be classified into the low-risk group (based on previously reported risk scores) for prediction of IVIG-resistance. Therefore, IVIG-unresponsiveness associated with the minor allele of rs563535954 might differ from IVIG-unresponsiveness associated with previous risk factors used to evaluate IVIG-unresponsiveness in KD. Conclusion These findings suggest that the SNV rs563535954 could serve as a predictive indicator of IVIG-unresponsiveness, thereby improving the sensitivity of risk scoring systems, and may aid in prevention of coronary artery lesions in KD patients.

Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been demonstrated to deliver therapeutic drugs in preclinical studies. However, their use is limited, as they lack the ability to specifically deliver drugs to tumor tissues in vivo. In the present study, we propose the use of a targeting peptide, IL-4R-binding peptide (IL4RPep-1), to specifically deliver intravenously (i.v.) infused EVs to thyroid tumors. In vivo, a xenograft tumor model was treated with either the control peptide (NSSSVDK) or IL4RPep-1-Flamma; mice were fluorescently imaged (FLI) using an in vivo imaging system at 0–3 h post-treatment. EVs (labeled with DiD dye) were conjugated with IL4RPep-1 through a DOPE-NHS linker and administered to mice intravenously. FLI was performed 0–24 h post-injection, and the animals were sacrificed for further experiments. The morphology and size of EVs, the presence of EV markers such as CD63 and ALIX, and the absence of the markers GM130 and Cyto-C were confirmed. In vivo, FLI indicated an accumulation of i.v. injected IL4RPep-1-Flamma at the tumor site 90 min post-injection. No accumulation of NSSSVDK-Flamma was detected. In vivo, IL4RPep-1-EVs targeted the Cal-62 tumor 2 h post-injection. NSSSVDK-EVs were not even detected in the tumor 24 h post-injection. The quantification of FLI showed a significant accumulation of MSC-EVs in the tumor 2 h, 3 h, and 24 h post-injection. Furthermore, ex vivo imaging and an IF analysis confirmed the in vivo findings. Our results demonstrate the use of the IL4RPep-1 peptide as a targeting moiety of EVs for IL-4R-expressing anaplastic thyroid tumors.

Disturbance of epithelial barrier function causes chronic intestinal inflammation such as inflammatory bowel disease. Several studies have reported that Th2 cytokines such as interleukin (IL)-4 and IL-13 play an important role in the regulation of intestinal barrier function. However, the precise role of the IL-4 receptor α subunit (IL-4Rα) in intestinal inflammation remains unclear. Thus, we used an experimental colitis model to investigate the role of IL-4Rα in intestinal inflammation. IL-4Rα-deficient (IL-4Rα-/-) mice and their littermate wild-type (WT) mice were used. Experimental colitis was induced by administration of 3% dextran sulfate sodium (DSS) in the drinking water for seven days. Treatment with DSS caused body weight loss, an increase in the disease activity index and histological abnormalities in WT colitis mice, all of which were significantly attenuated in IL-4Rα-/- colitis mice. Neutrophil infiltration in the colonic mucosa was reduced in IL-4Rα-/- colitis mice compared with WT colitis mice. NADPH oxidase 1 expression and reactive oxygen species production were increased in the colons of IL-4Rα-/- mice. Furthermore, elevated intestinal permeability induced by DSS treatment was suppressed in IL-4Rα-/- colitis mice. These results demonstrate that IL-4Rα-/- mice exhibit reduced susceptibility to DSS-induced colitis. Our present findings suggest that IL-4Rα deficiency enhances intestinal mucosal barrier function through the upregulation of NADPH oxidase 1-dependent reactive oxygen species production, thereby suppressing the development of intestinal inflammation.

Targeted delivery of antitumor drugs is especially important for tumour therapy. Tumour targeting peptides have been shown to be very effective drug carriers for tumour therapy. Interleukin-4 receptor (IL-4R) is overexpressed on the surface of various human solid tumours. To obtain a better targeting peptide, we first designed a novel targeting peptide derived from interleukin-4 (IL-4), ILBP-b. ILBP-b contains the key high-affinity binding residue E9 of IL-4 to IL-4R. Compared with a reported targeting peptide ILBP-a (containing another key high affinity residue R88), ILBP-b was proved to be a better targeting peptide by the fluorescence experiments. Then, we further fused ILBP-b and ILBP-a to increase the multisite-binding ability of ILBP-b and got a better targeting peptide ILBP-ba. ILBP-ba showed a stronger preferential binding ability to IL-4R high-expressing cells than ILBP-a and ILBP-b. Competitive binding experiments demonstrated ILBP-ba specifically targets IL-4R. By fusing ILBP-ba with drug protein trichosanthin (TCS), in vitro drug carrying experiments showed that ILBP-ba could specifically enhance the killing effect of TCS on IL-4R high-expressing tumour cells (more than 10 folds). These results indicated that ILBP-ba has great potential for drug delivery applications targeting IL-4R and will be beneficial for the development of tumour therapeutic agents. [ABSTRACT FROM AUTHOR]

Summary: Signaling by Kit has been extensively studied in hematopoietic cells and is essential for the survival, proliferation and maintenance of hematopoietic stem and progenitor cells. In addition to the activation of intrinsic signaling pathways, Kit has been shown to interact with lineage‐restricted type I cytokine receptors and produce cross signals, e.g. erythropoietin receptor, interleukin‐7 receptor (IL‐7R), IL‐3R. Based on the earlier studies, we hypothesize that Kit activate other type I cytokine receptors in a cell‐specific manner and execute cell‐specific function. To investigate other Kit‐activated receptors, we tested Kit and IL‐4R cross‐receptor activation in murine bone‐marrow‐derived mast cells, which express both Kit and IL‐4R at the surface level. Kit upon activation by Kit ligand (KL), activated IL‐4Rα, γC, and signal transducer and activator of transcription 6 independent of its cognate ligand IL‐4. Though KL and IL‐4 are individually mitogenic, combinations of KL and IL‐4 synergistically promoted mast cell proliferation. Furthermore, inhibition of lipid raft formation by methyl‐β‐cyclodextrin resulted in loss of synergistic proliferation. Together the data suggest IL‐4R as a novel Kit‐activated receptor. Such cross‐receptor activations are likely to be a universal mechanism of Kit signaling in hematopoiesis. [ABSTRACT FROM AUTHOR]

Interleukin-4 (IL-4) receptor (IL-4R) signaling plays a pivotal role in type 2 immune responses. Type 2 immunity ensures several host-protective processes such as defense against helminth parasites and wound repair, however, type 2 immune responses also drive the pathogenesis of allergic diseases. Neutrophil granulocytes (neutrophils) have not traditionally been considered a part of type 2 immunity. While neutrophils might be beneficial in initiating a type 2 immune response, their involvement and activation is rather unwanted at later stages. This is evidenced by examples of type 2 immune responses where increased neutrophil responses are able to enhance immunity, however, at the cost of increased tissue damage. Recent studies have linked the type 2 cytokines IL-4 and IL-13 and their signaling via type I and type II IL-4Rs on neutrophils to inhibition of several neutrophil effector functions. This mechanism directly curtails neutrophil chemotaxis toward potent intermediary chemoattractants, inhibits the formation of neutrophil extracellular traps, and antagonizes the effects of granulocyte colony-stimulating factor on neutrophils. These effects are observed in both mouse and human neutrophils. Thus, we propose for type 2 immune responses that neutrophils are, as in other immune responses, the first non-resident cells to arrive at a site of inflammation or infection, thereby guiding and attracting other innate and adaptive immune cells; however, as soon as the type 2 cytokines IL-4 and IL-13 predominate, neutrophil recruitment, chemotaxis, and effector functions are rapidly shut off by IL-4/IL-13-mediated IL-4R signaling in neutrophils to prevent them from damaging healthy tissues. Insight into this neutrophil checkpoint pathway will help understand regulation of neutrophilic type 2 inflammation and guide the design of targeted therapeutic approaches for modulating neutrophils during inflammation and neutropenia.

Interleukin-4 (IL-4) receptor (IL-4R) signaling plays a pivotal role in type 2 immune responses. Type 2 immunity ensures several host-protective processes such as defense against helminth parasites and wound repair, however, type 2 immune responses also drive the pathogenesis of allergic diseases. Neutrophil granulocytes (neutrophils) have not traditionally been considered a part of type 2 immunity. While neutrophils might be beneficial in initiating a type 2 immune response, their involvement and activation is rather unwanted at later stages. This is evidenced by examples of type 2 immune responses where increased neutrophil responses are able to enhance immunity, however, at the cost of increased tissue damage. Recent studies have linked the type 2 cytokines IL-4 and IL-13 and their signaling via type I and type II IL-4Rs on neutrophils to inhibition of several neutrophil effector functions. This mechanism directly curtails neutrophil chemotaxis toward potent intermediary chemoattractants, inhibits the formation of neutrophil extracellular traps, and antagonizes the effects of granulocyte colony-stimulating factor on neutrophils. These effects are observed in both mouse and human neutrophils. Thus, we propose for type 2 immune responses that neutrophils are, as in other immune responses, the first non-resident cells to arrive at a site of inflammation or infection, thereby guiding and attracting other innate and adaptive immune cells; however, as soon as the type 2 cytokines IL-4 and IL-13 predominate, neutrophil recruitment, chemotaxis, and effector functions are rapidly shut off by IL-4/IL-13-mediated IL-4R signaling in neutrophils to prevent them from damaging healthy tissues. Insight into this neutrophil checkpoint pathway will help understand regulation of neutrophilic type 2 inflammation and guide the design of targeted therapeutic approaches for modulating neutrophils during inflammation and neutropenia. [ABSTRACT FROM AUTHOR]

Interleukin-4 (IL-4) is a potent growth and differentiation factor for B cells which play a vital role in the pathogenesis of myasthenia gravis (MG). IL-4 exerts its function by binding to three types of IL-4 receptor (IL-4R) complexes. IL-4Rα is the key component of the IL-4R complex. We hypothesize that polymorphism of IL-4Rα gene may be associated with the susceptibility and severity of MG. A Chinese cohort of 480 MG patients and 487 healthy controls were recruited. Polymorphisms of IL-4Rα gene were determined with SNPscan™ methods and compared between MG and control groups, as well as among MG subgroups. Rs2107356 and rs1805010 were found to be associated with adult thymoma associated MG, and rs1801275 was found to be associated with adult non-thymoma AChR-Ab positive MG. We did not found association between IL-4Rα polymorphism and the severity of MG. Genetic variations of IL-4Rα were found associated with the susceptibility of MG in Chinese Han population.

Interleukin (IL)-4 and IL-13 are related cytokines that regulate many aspects of allergic inflammation. They play important roles in regulating the responses of lymphocytes, myeloid cells, and non-hematopoietic cells. In T-cells, IL-4 induces the differentiation of naïve CD4 T cells into Th2 cells, in B cells, IL-4 drives the immunoglobulin (Ig) class switch to IgG1 and IgE, and in macrophages, IL-4 and IL-13 induce alternative macrophage activation. This review gives a short insight into the functional formation of these cytokine receptors. I will discuss both the binding kinetics of ligand/receptor interactions and the expression of the receptor chains for these cytokines in various cell types; both of which are crucial factors in explaining the efficiency by which these cytokines induce intracellular signaling and gene expression. Work initiated in part by William (Bill) E. Paul on IL-4 some 30 years ago has now grown into a major building block of our current understanding of basic immunology and the immune response. This knowledge on IL-4 has growing clinical importance, as therapeutic approaches targeting the cytokine and its signal transduction are becoming a part of the clinical practice in treating allergic diseases. Just by reading the reference list of this short review, one can appreciate the enormous input Bill has had on shaping our understanding of the pathophysiology of allergic inflammation and in particular the role of IL-4 in this process.

Interleukin-4 (IL-4) is a potent growth and differentiation factor for B cells which play a vital role in the pathogenesis of myasthenia gravis (MG). IL-4 exerts its function by binding to three types of IL-4 receptor (IL-4R) complexes. IL-4Rα is the key component of the IL-4R complex. We hypothesize that polymorphism of IL-4Rα gene may be associated with the susceptibility and severity of MG. A Chinese cohort of 480 MG patients and 487 healthy controls were recruited. Polymorphisms of IL-4Rα gene were determined with SNPscan™ methods and compared between MG and control groups, as well as among MG subgroups. Rs2107356 and rs1805010 were found to be associated with adult thymoma associated MG, and rs1801275 was found to be associated with adult non-thymoma AChR-Ab positive MG. We did not found association between IL-4Rα polymorphism and the severity of MG. Genetic variations of IL-4Rα were found associated with the susceptibility of MG in Chinese Han population. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-4 and IL-13 are related cytokines that regulate many aspects of allergic inflammation. They play important roles in regulating the responses of lymphocytes, myeloid cells, and non-hematopoietic cells. In T-cells, IL-4 induces the differentiation of naïve CD4 T cells into Th2 cells, in B cells, IL-4 drives the immunoglobulin (Ig) class switch to IgG1 and IgE, and in macrophages, IL-4 and IL-13 induce alternative macrophage activation. This review gives a short insight into the functional formation of these cytokine receptors. I will discuss both the binding kinetics of ligand/receptor interactions and the expression of the receptor chains for these cytokines in various cell types; both of which are crucial factors in explaining the efficiency by which these cytokines induce intracellular signaling and gene expression. Work initiated in part by William (Bill) E. Paul on IL-4 some 30 years ago has now grown into a major building block of our current understanding of basic immunology and the immune response. This knowledge on IL-4 has growing clinical importance, as therapeutic approaches targeting the cytokine and its signal transduction are becoming a part of the clinical practice in treating allergic diseases. Just by reading the reference list of this short review, one can appreciate the enormous input Bill has had on shaping our understanding of the pathophysiology of allergic inflammation and in particular the role of IL-4 in this process. [ABSTRACT FROM AUTHOR]

Adoptive transfer of cytotoxic T lymphocytes (CTLs) has been used as an immunotherapy in melanoma. However, the tumor homing and therapeutic efficacy of transferred CTLs against melanoma remain unsatisfactory. Interleukin-4 receptor (IL-4R) is commonly up-regulated in tumors including melanoma. Here, we studied whether IL-4R-targeted CTLs exhibit enhanced tumor homing and therapeutic efficacy against melanoma. CTLs isolated from mice bearing melanomas were non-genetically engineered with IL4RPep-1, an IL-4R-binding peptide, using a membrane anchor composed of dioleylphosphatidylethanolamine. Compared to control CTLs, IL-4R-targeted CTLs showed higher binding to melanoma cells and in vivo tumor homing. They also exerted a more rapid and robust effector response, including increased cytokine secretion and cytotoxicity against melanoma cells and enhanced reprogramming of M2-type macrophages to M1-type macrophages. Moreover, IL-4R-targeted CTLs efficiently inhibited melanoma growth and reversed the immunosuppressive tumor microenvironment. These results suggest that non-genetically engineered CTLs targeting IL-4R have potential as an adoptive T cell therapy against melanoma. [ABSTRACT FROM AUTHOR]

To quantitatively examine the effect of membrane organization on lateral diffusion, we studied fluorescent carbocyanine lipid analogues and EGFP-tagged, single-pass transmembrane proteins in systems of decreasing complexity: (i) the plasma membrane (PM) of living cells, (ii) paraformaldehyde/dithiothreitol-induced giant plasma membrane vesicles (GPMVs), and (iii) giant unilamellar vesicles (GUVs) under physiological buffer conditions. A truncated, signaling-deficient interleukin-4 receptor subunit, showing efficient accumulation in the plasma membrane, served as a model transmembrane protein. Two-dimensional diffusion coefficients (D) were determined by fluorescence correlation spectroscopy (FCS) either at fixed positions (single-point, spFCS) or while scanning a circular orbit (circular scanning, csFCS). Consistent with a different inclusion sizes in the membrane, lipids diffuse slightly faster than the single-spanning membrane proteins in both membrane systems, GUVs and GPMVs. In GPMVs lipids and proteins consistently experienced a fivefold larger viscosity than in GUVs, reflecting the significant fraction of plasma membrane-derived proteins partitioning into GPMVs. Lipid and protein diffusion in the PM was, respectively, 2 times and 4-5 times slower in comparison to GPMVs. This discrepancy was quantitatively confirmed by csFCS. The similarity of diffusion of receptors and lipids in GPMVs and GUVs and its significant difference in the plasma membrane suggest that protein domains as small as EGFP convey sensitivity to the actin cortex on various length scales. [ABSTRACT FROM AUTHOR]

Abstract Asthma is a complex inflammatory disorder controlled by both genetic and environmental influences. Multiple genetic analyses have identified the T helper type 2 (Th2) cytokine gene cluster on chromosome 5q as a susceptibility locus for asthma. Recently, the Th2 cytokine interleukin-13 has been shown to be a critical mediator of the asthma phenotype in murine models. In this commentary we discuss several recent studies that have identified polymorphisms in the gene encoding interleukin-13. The consistent genetic associations of interleukin-13 with asthma and related traits across diverse ethnic populations in these studies provides strong support for the candidacy of this cytokine as a susceptibility locus for asthma and atopy on chromosome 5q31.

The Th2 cytokines, interleukin (IL)-4 and -13, are structurally and functionally related. They regulate immune responses and the immune microenvironment, not only under normal physiological conditions, but also in cancer. Both cytokines bind to their high-affinity receptors and form various configurations of receptor subtypes. We and others have reported that IL-4 and IL-13 bind to IL-4Rα and IL-13Rα1 chains, forming functional receptors in cancer cells. IL-13 also binds with high affinity to a private chain IL-13Rα2. After forming ligand-receptor complexes, both cytokines initiate signal transduction and mediate biological effects, such as tumor proliferation, cell survival, cell adhesion and metastasis. In certain cancers, the presence of these cytokine receptors may serve as biomarkers of cancer aggressiveness. In a series of studies, we reported that overexpression of IL-4 and IL-13 receptors on cancer cells provides targets for therapeutic agents for cancer therapy. In addition, both of these cytokines and their receptors have been shown to play important roles in modulating the immune system for tumor growth. IL-4, IL-13 and their receptors seem to play a role in cancer stem cells and provide unique targets to eradicate these cells. In this review article, we summarize some of the important attributes of IL-4 and IL-13 receptors in cancer biology and discuss pre-clinical and clinical studies pertaining to recombinant immunotoxins designed to target these receptors. [ABSTRACT FROM AUTHOR]

Chronic glial activation and neuroinflammation induced by the amyloid-β peptide (Aβ) contribute to Alzheimer's disease ( AD) pathology. APOE4 is the greatest AD-genetic risk factor; increasing risk up to 12-fold compared to APOE3, with APOE4-specific neuroinflammation an important component of this risk. This editorial review discusses the role of APOE in inflammation and AD, via a literature review, presentation of novel data on Aβ-induced neuroinflammation, and discussion of future research directions. The complexity of chronic neuroinflammation, including multiple detrimental and beneficial effects occurring in a temporal and cell-specific manner, has resulted in conflicting functional data for virtually every inflammatory mediator. Defining a neuroinflammatory phenotype ( NIP) is one way to address this issue, focusing on profiling the changes in inflammatory mediator expression during disease progression. Although many studies have shown that APOE4 induces a detrimental NIP in peripheral inflammation and Aβ-independent neuroinflammation, data for APOE-modulated Aβ-induced neuroinflammation are surprisingly limited. We present data supporting the hypothesis that impaired apoE4 function modulates Aβ-induced effects on inflammatory receptor signaling, including amplification of detrimental (toll-like receptor 4-p38α) and suppression of beneficial ( IL-4R-nuclear receptor) pathways. To ultimately develop APOE genotype-specific therapeutics, it is critical that future studies define the dynamic NIP profile and pathways that underlie APOE-modulated chronic neuroinflammation. [ABSTRACT FROM AUTHOR]

Background Interleukin-4 (IL-4) and interleukin-13 (IL-13) are anti-inflammatory and immunomodulatory cytokines that play crucial roles in cancer progression. However, the clinical significance of the expression of these cytokines and their receptors (IL-4R) in oral cavity squamous cell carcinoma (OSCC) is unknown. Therefore, we evaluated the expression of IL-4R in OSCC specimens by immunohistochemistry (IHC) and analysed its relationship to recurrence and survival. Methods A total of 186 patients with OSCC were enrolled, and the expression of IL-4Rα and IL-13Rα1 on their primary tumour specimens was evaluated by IHC and correlated to clinicopathologic parameters, recurrence and survival. Findings High expression of IL-4Rα and IL-13Rα1 was observed in 60 (32.3%) and 165 (88.7%) patients, respectively. IL-4Rα expression was inversely correlated with parameters reflecting primary tumour burden, including tumour size, tumour stage and depth of invasion at the initial diagnosis ( P < 0.05). High expression of IL-4Rα also correlated with a greater risk of recurrence ( P = 0.002), but was unrelated to cancer-specific survival (CSS, P = 0.118). Conversely, high IL-13Rα1 expression correlated with reduced recurrence ( P < 0.001) and increased CSS ( P < 0.001) in OSCC patients. Interpretations High expression of IL-4Rα correlated with increased recurrence, while high IL-13Rα1 expression had an inverse relationship to recurrence and CSS in OSCC patients. [ABSTRACT FROM AUTHOR]

Sarcoidosis (SARC) and extrinsic allergic alveolitis (EAA) share certain markers, making a differential diagnosis difficult even with histopathological investigation. In lung tissue, proteinase-activated receptor-2 (PAR-2) is primarily investigated with regard to epithelial and inflammatory perspectives. Varying levels of certain chemokines can be a useful tool for distinguishing EAA and SARC. Thus, in the present study, differences in the levels of transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, interleukin-4 receptor (IL-4R) and PAR-2 in bronchoalveolar lavage fluid (BALF) were compared, using an ELISA method, between 14 patients with EAA and six patients with SARC. Statistically significant higher levels of IL-4R, PAR-2 and the PAR-2/TGF-β1 and PAR-2/TNF-α ratios were observed in EAA patients as compared with SARC patients. Furthermore, the ratios of TNF-α/total protein, TGF-β1/PAR-2 and TNF-α/PAR-2 were significantly lower in EAA patients than in SARC patients. The results indicated a higher detection of PAR-2 in EAA samples in association with TNF-α and TGF-β levels. As EAA and PAR-2 in parallel belong to the Th2-mediated pathway, the results significantly indicated an association between this receptor and etiology. In addition, the results indicated that SARC is predominantly a granulomatous inflammatory disease, thus, higher levels of TNF-α are observed. Therefore, the detection of PAR-2 and investigated chemokines in BALF may serve as a useful tool in the differential diagnosis between EAA and SARC. [ABSTRACT FROM AUTHOR]

Strictinin has been shown to suppress interleukin (IL)-4-induced signal transducer and activator of transcription (STAT)-6 phosphorylation, which is a critical event for IgE class switching. However, it is unclear how strictinin inhibits STAT6 activation. Strictinin inhibited STAT6 phosphorylation by suppressing IL-4 receptor α (IL-4Rα) activation. Strictinin was bound to the cell surface and only localized in non-lipid raft fraction of the cells where IL-4Rα was also located. In addition, strictinin directly bound to IL-4Rα and inhibited binding of IL-4 to IL-4Rα. These results suggest that IL-4Rα locating in non-lipid raft region is a target molecule for strictinin in inhibiting STAT6 activation. [ABSTRACT FROM AUTHOR]