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Cells Nov 2021Interleukin (IL)-4 and IL-13 belong to the T helper 2 (Th2) cytokine family, along with IL-3, IL-5, and IL-9. These cytokines are key mediators of allergic inflammation.... (Review)
Review
Interleukin (IL)-4 and IL-13 belong to the T helper 2 (Th2) cytokine family, along with IL-3, IL-5, and IL-9. These cytokines are key mediators of allergic inflammation. They have important immunomodulatory activities and exert influence on a wide variety of immune cells, such as B cells, eosinophils, basophils, monocytes, fibroblasts, endothelial cells, airway epithelial cells, smooth muscle cells, and keratinocytes. Recent studies have implicated IL-4 and IL-13 in the development of various autoimmune diseases. Additionally, these cytokines have emerged as potential players in pathogenesis of inflammatory arthritis. Recent findings suggest that the IL-4 and IL-13 might play a significant role in the downregulation of inflammatory processes underlying RA pathology, and beneficially modulate the course of the disease. This review summarizes the biological features of the IL-4 and IL-13 and provides current knowledge regarding the role of these cytokines in inflammatory arthritis.
Topics: Animals; Arthritis; Bone and Bones; Disease Models, Animal; Humans; Inflammation; Interleukin-13; Interleukin-4
PubMed: 34831223
DOI: 10.3390/cells10113000 -
Immunity Oct 2018Regulatory T (Treg) cell responses and apoptotic cell clearance (efferocytosis) represent critical arms of the inflammation resolution response. We sought to determine...
Regulatory T (Treg) cell responses and apoptotic cell clearance (efferocytosis) represent critical arms of the inflammation resolution response. We sought to determine whether these processes might be linked through Treg-cell-mediated enhancement of efferocytosis. In zymosan-induced peritonitis and lipopolysaccharide-induced lung injury, Treg cells increased early in resolution, and Treg cell depletion decreased efferocytosis. In advanced atherosclerosis, where defective efferocytosis drives disease progression, Treg cell expansion improved efferocytosis. Mechanistic studies revealed the following sequence: (1) Treg cells secreted interleukin-13 (IL-13), which stimulated IL-10 production in macrophages; (2) autocrine-paracrine signaling by IL-10 induced Vav1 in macrophages; and (3) Vav1 activated Rac1 to promote apoptotic cell engulfment. In summary, Treg cells promote macrophage efferocytosis during inflammation resolution via a transcellular signaling pathway that enhances apoptotic cell internalization. These findings suggest an expanded role of Treg cells in inflammation resolution and provide a mechanistic basis for Treg-cell-enhancement strategies for non-resolving inflammatory diseases.
Topics: Animals; Apoptosis; Cell Line; Cells, Cultured; Humans; Inflammation; Interleukin-10; Interleukin-13; Jurkat Cells; Lipopolysaccharides; Lung Diseases; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Peritonitis; Phagocytosis; T-Lymphocytes, Regulatory; Zymosan
PubMed: 30291029
DOI: 10.1016/j.immuni.2018.07.015 -
Archives of Dermatological Research Mar 2020Skin fibrosis, characterized by excessive fibroblast proliferation and extracellular matrix deposition in the dermis, is the histopathologic hallmark of dermatologic... (Review)
Review
Skin fibrosis, characterized by excessive fibroblast proliferation and extracellular matrix deposition in the dermis, is the histopathologic hallmark of dermatologic diseases such as systemic sclerosis, hypertrophic scars, and keloids. Effective anti-scarring therapeutics remain an unmet need, underscoring the complex pathophysiologic mechanisms of skin fibrosis. The Th2 cytokines interleukin (IL)-4 and IL-13 have been implicated as key mediators in the pathogenesis of fibroproliferative disorders. The goal of this article is to summarize the current understanding of the role of the IL-4/IL-13 axis in wound healing and skin fibrosis. We conducted a literature search to identify research studies investigating the roles of IL-4 and IL-13 in fibrotic skin diseases. While transforming growth factor-beta has long been regarded as the main driver of fibrotic processes, research into the cellular and molecular biology of wound healing has revealed other pathways that promote scar tissue formation. IL-4 and IL-13 are important mediators of skin fibrosis, supported by evidence from in vitro data, animal models of fibrosis, and clinical studies. Overactive signaling of the IL-4/IL-13 axis contributes to the initiation and perpetuation of fibrotic skin diseases. Further insights into the IL-4/IL-13 axis may reveal potential targets for the development of novel therapies that prevent or treat fibrotic skin diseases.
Topics: Cicatrix; Fibrosis; Gene Expression Regulation; Humans; Interleukin-13; Interleukin-4; Skin
PubMed: 31493000
DOI: 10.1007/s00403-019-01972-3 -
Frontiers in Immunology 2018Interleukin (IL)-4 and IL-13 are related cytokines that regulate many aspects of allergic inflammation. They play important roles in regulating the responses of... (Review)
Review
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.
Topics: Humans; Hypersensitivity; Immunity, Cellular; Interleukin-13; Interleukin-13 Receptor alpha1 Subunit; Interleukin-4; Interleukin-4 Receptor alpha Subunit; Lymphocytes; Myeloid Cells; Receptors, Interleukin-13; Signal Transduction
PubMed: 29930549
DOI: 10.3389/fimmu.2018.00888 -
Blood Dec 2022Myelofibrosis (MF) is a disease associated with high unmet medical needs because allogeneic stem cell transplantation is not an option for most patients, and JAK...
Myelofibrosis (MF) is a disease associated with high unmet medical needs because allogeneic stem cell transplantation is not an option for most patients, and JAK inhibitors are generally effective for only 2 to 3 years and do not delay disease progression. MF is characterized by dysplastic megakaryocytic hyperplasia and progression to fulminant disease, which is associated with progressively increasing marrow fibrosis. Despite evidence that the inflammatory milieu in MF contributes to disease progression, the specific factors that promote megakaryocyte growth are poorly understood. Here, we analyzed changes in the cytokine profiles of MF mouse models before and after the development of fibrosis, coupled with the analysis of bone marrow populations using single-cell RNA sequencing. We found high interleukin 13 (IL-13) levels in the bone marrow of MF mice. IL-13 promoted the growth of mutant megakaryocytes and induced surface expression of transforming growth factor β and collagen biosynthesis. Similarly, analysis of samples from patients with MF revealed elevated levels of IL-13 in the plasma and increased IL-13 receptor expression in marrow megakaryocytes. In vivo, IL-13 overexpression promoted disease progression, whereas reducing IL-13/IL-4 signaling reduced several features of the disease, including fibrosis. Finally, we observed an increase in the number of marrow T cells and mast cells, which are known sources of IL-13. Together, our data demonstrate that IL-13 is involved in disease progression in MF and that inhibition of the IL-13/IL-4 signaling pathway might serve as a novel therapeutic target to treat MF.
Topics: Mice; Animals; Interleukin-13; Interleukin-4; Neoplasms; Myeloproliferative Disorders; Primary Myelofibrosis; Signal Transduction; Fibrosis; Disease Progression
PubMed: 36283106
DOI: 10.1182/blood.2022017326 -
Cold Spring Harbor Perspectives in... Jan 2018Mucosal surfaces are lined by epithelial cells. In the intestine, the epithelium establishes a selectively permeable barrier that supports nutrient absorption and waste... (Review)
Review
Mucosal surfaces are lined by epithelial cells. In the intestine, the epithelium establishes a selectively permeable barrier that supports nutrient absorption and waste secretion while preventing intrusion by luminal materials. Intestinal epithelia therefore play a central role in regulating interactions between the mucosal immune system and luminal contents, which include dietary antigens, a diverse intestinal microbiome, and pathogens. The paracellular space is sealed by the tight junction, which is maintained by a complex network of protein interactions. Tight junction dysfunction has been linked to a variety of local and systemic diseases. Two molecularly and biophysically distinct pathways across the intestinal tight junction are selectively and differentially regulated by inflammatory stimuli. This review discusses the mechanisms underlying these events, their impact on disease, and the potential of using these as paradigms for development of tight junction-targeted therapeutic interventions.
Topics: Animals; Humans; Immunity, Mucosal; Interleukin-13; Intestinal Mucosa; Mucous Membrane; Myosin-Light-Chain Kinase; Permeability; Tight Junctions; Zonula Occludens-1 Protein
PubMed: 28507021
DOI: 10.1101/cshperspect.a029314 -
International Immunopharmacology Aug 2022Ferroptosis is closely associated with respiratory diseases; however, the relationship between ferroptosis and neutrophilic asthma remains unknown. This study...
BACKGROUND AND PURPOSE
Ferroptosis is closely associated with respiratory diseases; however, the relationship between ferroptosis and neutrophilic asthma remains unknown. This study investigated whether Liproxstatin-1 (Lip-1) affects the progression of neutrophilic asthma by inhibiting ferroptosis and inflammatory response, while dissecting the underlying molecular mechanisms.
METHODS
The bronchial epithelial cells (16HBE and BEAS-2B) were administered with lipopolysaccharide (LPS) and interleukin-13 (IL-13) to generate a cell injury model. This cell model was employed to examine the effect of Lip-1 on airway epithelial-associated inflammation and ferroptosis as well as the underlying molecular mechanism. Meanwhile, we evaluated the effects of Lip-1 on neutrophilic asthma and ferroptosis by using the ovalbumin (OVA)/LPS-induced mouse model.
RESULTS
Lip-1 reversed the altered expression of ferroptotic regulators (glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11) and prostaglandin-endoperoxide synthase 2 (PTGS2)), attenuated lipid reactive oxygen species (lipid ROS) and ameliorated cell viability in HBE and BEAS-2B cells administered with LPS and IL-13. Moreover, Lip-1 treatment led to a marked reduction in the expression of IL-33, TSLP, IL-8, IL-6, and HMGB1 in the HBE and BEAS-2B cells. In the meantime, administration with Lip-1 markedly relieved OVA/LPS-induced neutrophilic asthma, as indicated by significant improvement in lung pathological changes, airway mucus secretion, inflammation, and ferroptosis.
CONCLUSION
This study provides data suggesting that Lip-1 alleviates neutrophilic asthma in vivo and in vitro through inhibiting ferroptosis, perhaps providing a new strategy for neutrophilic asthma treatment.
Topics: Animals; Asthma; Epithelial Cells; Ferroptosis; Inflammation; Interleukin-13; Lipopolysaccharides; Mice; Ovalbumin; Quinoxalines; Spiro Compounds
PubMed: 35483233
DOI: 10.1016/j.intimp.2022.108770 -
Nature Communications May 2021Allergic asthma is characterized by elevated levels of IgE antibodies, type 2 cytokines such as interleukin-4 (IL-4) and IL-13, airway hyperresponsiveness (AHR), mucus...
Allergic asthma is characterized by elevated levels of IgE antibodies, type 2 cytokines such as interleukin-4 (IL-4) and IL-13, airway hyperresponsiveness (AHR), mucus hypersecretion and eosinophilia. Approved therapeutic monoclonal antibodies targeting IgE or IL-4/IL-13 reduce asthma symptoms but require costly lifelong administrations. Here, we develop conjugate vaccines against mouse IL-4 and IL-13, and demonstrate their prophylactic and therapeutic efficacy in reducing IgE levels, AHR, eosinophilia and mucus production in mouse models of asthma analyzed up to 15 weeks after initial vaccination. More importantly, we also test similar vaccines specific for human IL-4/IL-13 in mice expressing human IL-4/IL-13 and the related receptor, IL-4Rα, to find efficient neutralization of both cytokines and reduced IgE levels for at least 11 weeks post-vaccination. Our results imply that dual IL-4/IL-13 vaccination may represent a cost-effective, long-term therapeutic strategy for the treatment of allergic asthma as demonstrated in mouse models, although additional studies are warranted to assess its safety and feasibility.
Topics: Animals; Asthma; Bacterial Proteins; Chronic Disease; Disease Models, Animal; Female; Humans; Injections, Intramuscular; Interleukin-13; Interleukin-4; Mice; Mice, Transgenic; Vaccination; Vaccines, Conjugate
PubMed: 33976140
DOI: 10.1038/s41467-021-22834-5 -
Science (New York, N.Y.) Aug 2019Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to...
Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to allergens remain poorly understood. T follicular helper (T) cells direct the affinity and isotype of antibodies produced by B cells. Although T cell-derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13-producing T cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These "T13" cells have an unusual cytokine profile (IL-13IL-4IL-5IL-21) and coexpress the transcription factors BCL6 and GATA3. T13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking T13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.
Topics: Adolescent; Anaphylaxis; Animals; Child; GATA3 Transcription Factor; Guanine Nucleotide Exchange Factors; Humans; Immunoglobulin E; Interleukin-13; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Proto-Oncogene Proteins c-bcl-6; T-Lymphocytes, Helper-Inducer
PubMed: 31371561
DOI: 10.1126/science.aaw6433 -
Nature Communications Apr 2023T helper 9 (T9) cells promote allergic tissue inflammation and express the type 2 cytokines, IL-9 and IL-13, as well as the transcription factor, PPAR-γ. However, the...
T helper 9 (T9) cells promote allergic tissue inflammation and express the type 2 cytokines, IL-9 and IL-13, as well as the transcription factor, PPAR-γ. However, the functional role of PPAR-γ in human T9 cells remains unknown. Here, we demonstrate that PPAR-γ drives activation-induced glycolysis, which, in turn, promotes the expression of IL-9, but not IL-13, in an mTORC1-dependent manner. In vitro and ex vivo experiments show that the PPAR-γ-mTORC1-IL-9 pathway is active in T9 cells in human skin inflammation. Additionally, we find dynamic regulation of tissue glucose levels in acute allergic skin inflammation, suggesting that in situ glucose availability is linked to distinct immunological functions in vivo. Furthermore, paracrine IL-9 induces expression of the lactate transporter, MCT1, in T cells and promotes their aerobic glycolysis and proliferative capacity. Altogether, our findings uncover a hitherto unknown relationship between PPAR-γ-dependent glucose metabolism and pathogenic effector functions in human T9 cells.
Topics: Humans; Glucose; Glycolysis; Inflammation; Interleukin-13; Interleukin-9; PPAR gamma; T-Lymphocytes, Helper-Inducer
PubMed: 37120582
DOI: 10.1038/s41467-023-38233-x