Role Of IL-4 Research Articles

The Role of IL-25 and IL-35 in Amoebiasis

Bacground: Amoebiasis is a protazon infection of the human intestine spread through the world the mostprevelant form of the disease is amebic dysenterywhich characterizes acute diarrhoea with observable bloodand mucus in stools.Aims: This article aimed to detects the role of IL-25 and IL-35 in the immune response against amebicdysentery.Methods: This study was conducted in Thi-Qar province-Al-Nasiriyah city in Muhammad Al-MousawiHospital for Children, the study included collection of (60)blood samples from amebiasis patients and (30)apparently healthy children at a period from September 2019 to March 2020 with the age less than oneyear to 15 years that divides to four age groups, the levels of IL-25 and IL-35 were determined by ELISAtechnique.Results:The results indicate that the IL-25 and IL-35 concentrations in serum samples from amoebiasispatients were significantly higher when compared with that from healthy controls. The highest level of IL-25was recordsin the third age group of patients with level 1677.2 ± 867.2ng /ml,compare with the high level inthe third age group of control with level 450.40 ± 97.31ng /ml.Also, the findings indicates the highest levelof IL-35 records35 in the second age group of patients with level 291.0 ± 62.3ng /ml, while the high levelrecorded in the first age group of control with level 8.246± 0.60 ng /ml.

The Role of IL-13, IL-15 and Granulysin in the Pathogenesis of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis.

Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are Severe Cutaneous Adverse Reactions (SCARS) characterized by fever and mucocutaneous lesions leading to necrosis and sloughing of the epidermis. Conjunctival lesions are reported in 85% of patients. The pathogenesis of SJS/TEN/SCARS is not completely understood. It is hypothesized that IL-13, IL-15 and Granulysin expressed in plasma and skin may play a role. We measured the circulating levels of these cytokines in the plasma using ELISA and their expression in the skin using immunofluorescence microscopy. A total of 12 SJS/TEN skin biopsy samples (8 SJS, 2 SJS/TEN overlap and 2 TEN) were analyzed. Biopsy samples from patients with Lichen Planus (an inflammatory condition of the skin and mucous membranes) served as controls. Studies were also performed in human corneal epithelial cells where expression of these cytokines were measured following a challenge with TNF-α (0, 1, 10 and 100 ng/ml). The intensity of immunofluorescence was measured Using Imaris® software. The results showed significantly increased expression of these cytokines in the skin biopsy samples as measured by the average intensities of IL-13 (6.1 x 133.0 ± 4.231 x 10^8), and Granulysin (4.2 x 123.0 ± 4.231 x 10^8) compared to Lichen planus control (3.0 x 123.0 ±1.62 x 10^5). Increased expression of IL-13 and IL-15 were noted in cell culture studies and in the plasma samples when compared to Normal Human Plasma as controls. It is concluded that IL-13, IL-15 and Granulysin play a role in the pathogenesis of SJS/TEN.

T2 asthma and T2-associated diseases: a consolidated approach to biological therapy

This article is dedicated to the main characteristics of severe bronchial asthma (SBA) and its heterogeneity. In particular, it describes T2 asthma and the role of the main cytokines involved in T2 inflammation. It focuses on the role of IL-4 and IL-13 in the pathogenesis of asthma and other T2-associated diseases, as key cytokines in the initiation and maintenance of T2 inflammation. The article presents the results of experimental studies proving that the activation of IL-4/IL-13 can cause significant hyperresponsiveness of the human airway smooth muscles and the combined blockade of the activity of these cytokines using a human monoclonal antibody against the common IL-4/13 receptor-subunit-dupilumab-determines the clinical efficacy not only in relation to exacerbations and control of asthma symptoms, but also an improvement of the lung function and a reduction in bronchial hyperresponsiveness. When type 2 helper cells (Th2) interact with antigen-presenting cells, IL-4 and IL-13 are simultaneously released, therefore, blocking IL-4Ris more effective than blocking each of the ligands separately, which explains the high efficacy of dupilumab not only in T2 asthma, but also other T2-associated diseases: atopic dermatitis and chronic rhinosinusitis with nasal polyps. In addition to asthma and atopic dermatitis, a new indication for dupilumab, chronic rhinosinusitis with nasal polyps, has recently been approved.
 According to the recommendations of the European Academy of Allergy and Clinical Immunology (EAACI) for the biological therapy of SBA 2020, dupilumab is recommended as an add-on maintenance therapy in adults and children aged 1217 years old with uncontrolled severe T2 asthma, including asthma with the allergic and eosinophilic phenotype, as well as mixed (when there are signs of both phenotypes) and steroid-dependent asthma. At the same time, dupilumab is well tolerated.

Characterization of IL-19, -20, and -24 in acute and chronic kidney diseases reveals a pro-fibrotic role of IL-24

BackgroundRecently, the role of IL-19, IL-20 and IL-24 has been reported in renal disorders. However, still little is known about their biological role.MethodsLocalization of IL-20RB was determined in human biopsies and in the kidneys of mice that underwent unilateral ureteral obstruction (UUO). Renal Il19, Il20 and Il24 expression was determined in ischemia/reperfusion, lipopolysaccharide, streptozotocin, or UUO induced animal models of kidney diseases. The effects of H2O2, LPS, TGF-β1, PDGF-B and IL-1β on IL19, IL20 and IL24 expression was determined in peripheral blood mononuclear cells (PBMCs). The extents of extracellular matrix (ECM) and α-SMA, Tgfb1, Pdgfb, and Ctgf expression were determined in the kidneys of Il20rb knockout (KO) and wild type (WT) mice following UUO. The effect of IL-24 was also examined on HK-2 tubular epithelial cells and NRK49F renal fibroblasts.ResultsIL-20RB was present in the renal biopsies of patients with lupus nephritis, IgA and diabetic nephropathy. Amount of IL-20RB increased in the kidneys of mice underwent UUO. The expression of Il19, Il20 and Il24 increased in the animal models of various kidney diseases. IL-1β, H2O2 and LPS induced the IL19, IL20 and IL24 expression of PBMCs. The extent of ECM, α-SMA, fibronectin, Tgfb1, Pdgfb, and Ctgf expression was lower in the kidney of Il20rb KO compared to WT mice following UUO. IL-24 treatment induced the apoptosis and TGF-β1, PDGF-B, CTGF expression of HK-2 cells.ConclusionsOur data confirmed the significance of IL-19, IL-20 and IL-24 in the pathomechanism of renal diseases. Furthermore, we were the first to demonstrate the pro-fibrotic effect of IL-24.

Distinct expression profiles and overlapping functions of IL-4/13A and IL-4/13B in grass carp (Ctenopharyngodon idella)

Abstract In mammals, interleukin (IL)-4 and IL-13 are important cytokines involved in the immune response of the host defence against pathogens and play critical roles in the polarization of monocytes/macrophages (MO/Mϕs). However, in teleost fish, the role of IL-4/13 homologues in the polarization of MO/Mϕ remains unknown. In this paper, we identified a second isoform of IL-4/13 (CiIL-4/13A) from grass carp (Ctenopharyngodon idella) in addition to the IL-4/13 homologue previously reported and comparatively studied their expression profiles and functions. The two CiIL-4/13 transcripts were constitutively expressed in tissues but displayed distinct expression patterns. Infection with Flavobacterium columnare or grass carp reovirus II (GCRV-Ⅱ) resulted in the alteration of expression levels of both IL-4/13 isoforms. Furthermore, in the primary head kidney cells, the recombinant CiIL-4/13A and B could up-regulate the expression of IL-10, inducible nitric oxide synthase (iNOS) and M2 macrophage marker gene (KLF4, kruppel like factor 4), whilst down-regulate the expression of IL-1β and M1 macrophage marker gene (MARCO, macrophage receptor with collagenous structure). The results suggest that the CiIL-4/13A and B play similar roles in regulating inflammation and differentiation of MO/Mϕs in grass carp.

IL-4 Receptor α Chain Protects the Kidney Against Tubule-Interstitial Injury Induced by Albumin Overload.

Increasing evidence has highlighted the role of tubule-interstitial injury (TII) as a vital step in the pathogenesis of acute kidney injury (AKI). Incomplete repair of TII during AKI could lead to the development of chronic kidney disease. Changes in albumin endocytosis in proximal tubule epithelial cells (PTECs) is linked to the development of TII. In this context, interleukin (IL)-4 has been shown to be an important factor in modulating recovery of TII. We have studied the possible role of IL-4 in TII induced by albumin overload. A subclinical AKI model characterized by albumin overload in the proximal tubule was used, without changing glomerular function. Four groups were generated: (1) CONT, wild-type mice treated with saline; (2) BSA, wild-type mice treated with 10 g/kg/day bovine serum albumin (BSA); (3) KO, IL4Rα–/– mice treated with saline; and (4) KO + BSA, IL4Rα–/– mice treated with BSA. As reported previously, mice in the BSA group developed TII without changes in glomerular function. The following parameters were increased in the KO + BSA group compared with the BSA group: (1) tubular injury score; (2) urinary γ-glutamyltransferase; (3) CD4+ T cells, dendritic cells, macrophages, and neutrophils are associated with increases in renal IL-6, IL-17, and transforming growth factor β. A decrease in M2-subtype macrophages associated with a decrease in collagen deposition was observed. Using LLC-PK1 cells, a model of PTECs, we observed that (1) these cells express IL-4 receptor α chain associated with activation of the JAK3/STAT6 pathway; (2) IL-4 alone did not change albumin endocytosis but did reverse the inhibitory effect of higher albumin concentration. This effect was abolished by JAK3 inhibitor. A further increase in urinary protein and creatinine levels was observed in the KO + BSA group compared with the BSA group, but not compared with the CONT group. These observations indicate that IL-4 has a protective role in the development of TII induced by albumin overload that is correlated with modulation of the pro-inflammatory response. We propose that megalin-mediated albumin endocytosis in PTECs could work as a sensor, transducer, and target during the genesis of TII.

IL-4 controls activated neutrophil FcγR2b expression and migration into inflamed joints

Neutrophils are the most abundant immune cells found in actively inflamed joints of patients with rheumatoid arthritis (RA), and most animal models for RA depend on neutrophils for the induction of joint inflammation. Exogenous IL-4 and IL-13 protect mice from antibody-mediated joint inflammation, although the mechanism is not understood. Neutrophils display a very strong basal expression of STAT6, which is responsible for signaling following exposure to IL-4 and IL-13. Still, the role of IL-4 and IL-13 in neutrophil biology has not been well studied. This can be explained by the low neutrophil surface expression of the IL-4 receptor α-chain (IL-4Rα), essential for IL-4- and IL-13-induced STAT6 signaling. Here we identify that colony stimulating factor 3 (CSF3), released during acute inflammation, mediates potent STAT3-dependent neutrophil IL-4Rα up-regulation during sterile inflammatory conditions. We further demonstrate that IL-4 limits neutrophil migration to inflamed joints, and that CSF3 combined with IL-4 or IL-13 results in a prominent neutrophil up-regulation of the inhibitory Fcγ receptor (FcγR2b). Taking these data together, we demonstrate that the IL-4 and CSF3 pathways are linked and play important roles in regulating proinflammatory neutrophil behavior.

Role of IL-24 in the mucosal remodeling of children with coeliac disease

BackgroundRecently, involvement of IL-19, IL-20 and IL-24 has been reported in inflammatory diseases associated with tissue remodeling. However, their impact on the pathomechanism of coeliac disease (CD) is still completely unknown.MethodsExpression of IL19, IL20 and IL24 was measured by real-time RT-PCR, protein amount of IL-24, α smooth muscle actin (α-SMA) and fibronectin (FN) was determined by Western-blot analysis in the duodenal biopsies of therapy naive children with CD and controls. Localization of IL-24 and IL-20RB was investigated by immunofluorescent staining in the duodenal mucosa. Effect of recombinant IL-1β, TNF-α, TGF-β and IL-17 treatment on the expression of IL19, IL20, IL24 and their receptors was investigated by real-time RT-PCR in small intestinal epithelial cells (FHs74Int), in primary duodenal myofibroblasts (pdMFs) and in peripheral blood mononuclear cells (PBMCs). Effect of IL-24 on H2O2 treated FHs74Int cells and on pdMFs was measured by MTT, LDH, Annexin V assays, real-time RT-PCR and by fluorescent microscopy.ResultsWe found increased level of IL-24 (3.3×, p < 0.05), α-SMA (2.4×, p < 0.05) and FN (2.3×, p < 0.05) in the duodenal mucosa and increased expression of IL19 (3.6×, p < 0.05) and IL24 (5.2×, p < 0.05) in the PBMCs of children with CD compared to that of controls. IL-1β was a strong inducer of IL24 expression of FHs74Int cells (9.9×, p < 0.05), pdMFs (552.9×, p < 0.05) or PBMCs (17.2×, p < 0.05), as well. IL-24 treatment reduced the number of apoptotic cells (0.5×, p < 0.05) and decreased the expression of inflammatory factors, including IL1A, IL6 and TNF of H2O2-treated FHs74Int cells. IL-24 decreased the proliferation (0.6×, p < 0.05) of PDGF-B treated pdMFs. Moreover, IL-24 treatment altered the morphology of pdMFs by influencing the size of the angles between stress fibers and the longitudinal axis of the cells (2.0×, p < 0.05) and the expression of cytoskeletal components, including ACTA2, ACTB, VIM, SNAI1 and SNAI2.ConclusionOur results suggest that IL-24 plays a significant role in the maintenance of duodenal mucosal integrity in CD.

IL-5 overexpression attenuates aortic dissection by reducing inflammation and smooth muscle cell apoptosis

As an inflammation-related cytokine, interleukin (IL)-5 has been reported to be involved in the development of cardiovascular diseases, such as chronic heart failure and atherosclerosis. However, the role of IL-5 in acute aortic dissection (AAD) has barely been explored. Aortic tissue samples from normal donors and patients with AAD were collected, and the expression and localization of IL-5 in aortic tissue were analyzed. In addition, a mouse AAD model was established by administering angiotensin II (Ang II) to β-aminopropionitrile (BAPN)-treated mice. Morphological examinations and histopathologic analyses were performed to evaluate the effects of IL-5 overexpression on the occurrence of AAD. IL-5 expression was significantly decreased in aorta samples from AAD patients compared to those from donors, and macrophages were the main source of IL-5. In addition, IL-5 expression was decreased in plasma and aortic tissue samples from AAD mice. IL-5 overexpression markedly attenuated the occurrence of AAD in mice and produced corresponding decreases in the inflammatory response and cell apoptosis. In cocultures of macrophages and smooth muscle cells (SMCs), IL-5 overexpression in the macrophages significantly reduced Ang II-induced SMC apoptosis. IL-5 overexpression suppresses the development of AAD by reducing inflammation and SMC apoptosis. These results suggest that IL-5 is a potential therapeutic target in AAD.

Abstract #4318 Immunization with mycobacterium vaccae enhances immunoregulation in the CNS: A role for IL-4 in mitigation of stress-induced microglial priming, alarmins and anxiety-like behavior

Abstract #4318 Immunization with mycobacterium vaccae enhances immunoregulation in the CNS: A role for IL-4 in mitigation of stress-induced microglial priming, alarmins and anxiety-like behavior

Lower serum levels of IL-13 is associated with increased carotid intima-media thickness in old age subjects

Cardiovascular diseases due to atherosclerosis represent the major cause of disability and mortality in old age subjects. The atherosclerotic process is linked to a low grade of systemic inflammation with the involvement of many cytokines and inflammatory proteins. Among them, evidence from animal studies suggests that IL-13 has a protective property. However, the role of IL-13 in the pathogenesis of atherosclerosis in humans is still unknown. With this study, we aim to investigate a potential association between IL-13 and carotid intima-media thickness (IMT) in old age subjects. This is a retrospective study conducted among 79 old age subjects (over 75years old). All subjects underwent IMT assessment by high-resolution B-mode ultrasonography and IL-13 measurement in serum by ELISA. Subjects (41M/38F) had a mean age of 81.0 ± 4.5years and were mostly overweight. Stratifying the whole cohort by IMT thickness (IMT ≤ 0.9, n = 17; IMT ≥ 1 and ≤ 1.3, n = 50; IMT ≥ 1.4, n = 12) among the main variables explored, only BMI and triglycerides differed among groups, having subjects with higher IMT significantly higher BMI and lower triglycerides. Serum IL-13 levels significantly differed among groups having subjects with IMT ≥ 1.4 lower levels as compared to other groups (p < 0.0001). In all sample population, IMT values significantly correlate with IL-13 levels (r = - 0.454, p < 0.0001). Indeed, a linear regression analysis showed that independent of age, gender, body mass index, triglycerides, systolic blood pressure, statin use and smoking habit, lower IL-13 serum levels were associated with higher IMT values. IL-13, an anti-inflammatory cytokine, may have a protective role in the human atherosclerotic process. It could be used as an effective and promising novel therapeutic target development.

Common and different roles of IL-4 and IL-13 in skin allergy and clinical implications.

This review summarizes the mode of action of IL-4 and IL-13 in skin allergy, upcoming therapeutics and depicts key outcomes of the latest clinical trials. Atopic dermatitis is considered to be one of the most common inflammatory skin disease in industrialized countries. Accompanied by strong pruritus, atopic dermatitis has a significant impact on quality of life in severely affected individuals. Aside from unspecific immunosuppressant medications, therapeutics targeting the key cytokines IL-4 and IL-13 and their downstream mediators are under development or have been approved just recently with outstanding potential. The recent development of several biologics and small compounds has the potential to revolutionize the treatment of atopic dermatitis, and applying this set of state-of-the-art drugs will provide a unique chance to gain insights into this skin disorder, patient subgroups, and key inflammatory mediators.

Interleukin‐13: Targeting an underestimated cytokine in atopic dermatitis

Atopic dermatitis (AD) is a common inflammatory skin condition that has traditionally been considered a paradigmatic type 2 immunity (T2)-driven disease. Interleukin (IL)-4 and IL-13 are both pivotal cytokines involved in the generation of allergic diseases. Currently, besides dupilumab, which blocks the binding of both cytokines to their receptors, a number of new pharmacologic entities have been designed to target both T2 cytokines and/or their receptors and/or receptor-associated signal transduction machinery such as Janus kinases. Recently, IL-13 has been suggested to be the key T2 cytokine driving inflammation in the periphery, while IL-4 may merely have a central effect. There is increasing evidence that this concept holds true for the inflammatory reaction underlying AD, where IL-13 is overexpressed locally and has a significant impact on skin biology, including the recruitment of inflammatory cells, the alteration of the skin microbiome, and the decrease in the epidermal barrier function. This review provides an update on the role of IL-13 in AD and discusses the different strategies aimed at interfering with its biologic activity as well as their potential in a precision medicine approach in the management of AD.

Th2 cytokines and specific donor alloantigen activated CD4+CD25+T cells reverse chronic rejection: role of IL-4 and IL-5 in promoting antigen-specific Treg

Abstract Naïve CD4+CD25+Foxp3+T regulatory cells (tTreg) activated by specific alloantigen (Ag) and IL-4 express IL-5Ralpha. We examined if IL-5 treatment activated alloAg specific Treg to prevent chronic rejection in F344 rats grafted with Lewis hearts. 5000units rIL-5 (rIL-5Rx) was given daily from 7d after grafting when rejection had started. Changes in CD4+CD25+T cells were assessed by FACS, RT-PCR of Il5ra and response to alloAg in MLC. Sham Rx rats fully rejected their grafts by 28d while IL-5Rx for 10d reversed rejection and grafts survived 60d (p&amp;lt;0.01). There were rejection episodes after stopping IL-5 but continued IL-5Rx reduced this. Pre-treatment with anti-CD25 or anti-IL-4 mAb abolished the benefit of rIL-5Rx, all grafts rejected by 28d. IL-5 treated hosts had increased CD4+CD25+T cells, 6–8% vs 3–4% in controls. After 10d of rIL-5Rx, host CD4+CD25+T cells responded to Lewis but not to F344 or third-party PVG alloAg in MLC, showing activation of alloAg-specific Treg. CD4+CD25+T cells from rats treated for 50d with rIL-5 had more il5ra, remained FOXP3+ and in MLC rIL-5 enhanced responses to Lewis but not other alloAg. These findings are consistent with IL-4 and alloAg activating tTreg to induce Ag-specific Treg that suppress rejection. To demonstrate rIL-4 and specific alloantigen activated naïve tTreg to suppress rejection, these cells were prepared ex vivo. 5×106 of these IL-4 alloAg activated tTreg, given after rejection commenced, reversed rejection. 5×106 fresh naïve tTreg or 5×106 tTreg activated by third-party PVG alloAg had no effect on rejection. IL-5 prevented heart graft rejection through hosts’ CD25+Treg that had been activated by alloAg and IL-4. IL-5 therapy may have potential to prevent chronic allograft rejection.

The role of interleukin-13 in chronic inflammatory intestinal disorders.

Interleukin (IL)-13 is a cytokine playing a pivotal role in T helper (Th)2 immune response supposed to be implicated in some intestinal disorders. IL-13 is produced by Th2 cells, natural killer T cell, innate lymphoid cells and innate immune cells, which contribute to trigger and maintain a chronic idiopathic intestinal inflammation. In murine models IL-13 exerts pleiotropic functions, playing either pathogenic or protective roles according to the different experimental conditions. As regards celiac disease, IL-13 is considered to be involved mostly in the refractory phase rather than at uncomplicated stage. Discrepancies have been observed in the role of IL-13 upon the inflammation and fibrosis in ulcerative colitis (UC) and in Crohn's disease, respectively. Failure of the anti-IL-13 monoclonal antibodies tralokinumab and anrukinzumab in UC patients in clinical trials support the absence of a role for IL-13 in UC. This review deals with IL-13 in several experimental colitis models -such as oxazolone-, trinitrobenzene sulfonic acid- or dextran sodium sulphate-induced colitis- and chronic intestinal inflammatory disorders -including celiac disease, UC and Crohn's disease-, and it also highlights the attempts to modulate IL-13 as therapeutic tool.

A role of IL-25, a sibling of IL-17, in triggering psoriatic skin inflammation.

A role of IL-25, a sibling of IL-17, in triggering psoriatic skin inflammation.

Biological Properties and the Role of IL-25 in Disease Pathogenesis.

The interleukin- (IL-) 17 superfamily, a T cell-derived cytokine, consists of 6 ligands (IL-17A–IL-17F) and 5 receptors (IL-17RA–IL-17RE). IL-17A, a prototype member of this family, is involved in the pathogenesis of allergies, autoimmune diseases, allograft transplantations, and malignancies. By contrast, IL-17B is reported to be closely related to certain diseases, particularly tumors such as breast cancer, gastric cancer, and pancreatic cancer. Recently, the biological function of IL-17E (also called IL-25) in disease, particularly airway diseases, has attracted the attention of researchers. However, studies on IL-25 are scant. In this review, we detail the structural characteristics, expression patterns, responder cells, biological properties, and role of IL-25 in disease pathogenesis.

GM-CSF and IL-4 are not involved in IVIG-mediated amelioration of ITP in mice: a role for IL-11 cannot be ruled out.

Previously, we have reported that interleukin (IL)-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-11, but not IL-33, are up-regulated in two strains of mice with immune thrombocytopenia (ITP) that are responsive to intravenous immunoglobulin (IVIg) treatment. Previously, IL-4 was ruled out in the mechanism of IVIg; however, other publications have suggested this cytokine as a major player in the mechanism of IVIg action. Thus, we sought to further investigate a role for IL-4 and, in addition, GM-CSF and IL-11 in the mechanism of action of IVIg using a murine model of ITP. A passive platelet antibody model was used to generate ITP in IL-4 receptor knock-out (IL-4R-/- ), IL-11 receptor knock-out (IL-11Rα-/- ) and GM-CSF knock-out (Csf2-/- ) mice. We also used a neutralizing antibody to IL-11 and recombinant human IL-11 (rhIL-11) in addition to depleting basophils in vivo to study the effect of IVIg to ameliorate ITP. Our results showed that basophils, IL-4 and GM-CSF were unimportant in both ITP induction and its amelioration by IVIg. The role of IL-11 in these processes was less clear. Even though IL-11Rα-/- mice with ITP responded to IVIg similarly to wild-type (WT) mice, treatment of ITP WT mice with rhIL-11 instead of IVIg showed an increase in platelet numbers and WT mice administered anti-IL-11 showed a significant reduction in the ability of IVIg to ameliorate the ITP. Our findings indicate that neither IL-4, basophils or GM-CSF have roles in IVIg amelioration of ITP; however, a role for IL-11 requires further study.

Tuning the Cytokine Responses: An Update on Interleukin (IL)-4 and IL-13 Receptor Complexes

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.

ILC2-derived IL-13 likely promotes development of peanut allergy

Abstract Background Peanut (PN) allergies are life-long diseases that cause severe anaphylactic responses to affected individuals. Allergic immune responses are typically mediated by CD4+ T cells producing type 2 cytokines. However, there is little information available regarding the immunological mechanisms that initiate the development of PN allergen-specific T cells and production of PN specific-IgE (PN-IgE). Goal The goal of this study was to elucidate the mechanisms involved in initiation of peanut allergy. Results Naïve BALB/c mice (wt) chronically exposed intranasally (i.n.) to PNf developed PN allergy as demonstrated by increased serum levels of PN-IgE as well as acute anaphylactic response when challenged intraperitoneally with PN extract. Acute i.n. exposure of naïve mice to PNf increased the lung levels of IL-13. By using IL-13eGFP reporter mice, we found that group 2 innate lymphoid cells (ILC2s) produce IL-13 when mice are exposed to PNf. Further, IL-13−/− mice showed significant decrease in the numbers of follicular helper T cells in dLNs and serum levels of PN-IgE relative to wild type (wt) mice. When naïve mice were exposed daily to PNf for 2 days, wt mice showed a significant increase in the numbers of dendritic cells (DCs) in the lung dLN; in contrast, overall dLN cellularity as well as number of DCs was decreased in IL-13−/− mice. Furthermore, there were fewer CD11c+ MHC2+ DCs in dLN of IL-13−/− mice, indicating a role for IL-13 in maturation of DCs. Conclusions Our findings show that airway exposure to PN induces allergy sensitization by mechanisms involving ILC2-derived IL-13 that mediate the migration and maturation of lung DCs to the dLN. The interplay between ILC2s and DCs are likely critical for development of peanut allergy.