IL-1 Cytokine Family Research Articles

STAT3 Signaling in Breast Cancer: Multicellular Actions and Therapeutic Potential.

Simple SummaryMany signaling pathways are overactive in breast cancer, and among them is the STAT3 signaling pathway. STAT3 is activated by secreted factors within the breast tumor, many of which are elevated and correlate to advanced disease and poor survival outcomes. This review examines how STAT3 signaling is activated in breast cancer by the proinflammatory, gp130 cytokines, interleukins 6 and 11. We evaluate how this signaling cascade functions in the various cells of the tumor microenvironment to drive disease progression and metastasis. We discuss how our understanding of these processes may lead to the development of novel therapeutics to tackle advanced disease.Interleukin (IL)-6 family cytokines, such as IL-6 and IL-11, are defined by the shared use of the gp130 receptor for the downstream activation of STAT3 signaling and the activation of genes which contribute to the “hallmarks of cancer”, including proliferation, survival, invasion and metastasis. Increased expression of these cytokines, or the ligand-specific receptors IL-6R and IL-11RA, in breast tumors positively correlate to disease progression and poorer patient outcome. In this review, we examine evidence from pre-clinical studies that correlate enhanced IL-6 and IL-11 mediated gp130/STAT3 signaling to the progression of breast cancer. Key processes by which the IL-6 family cytokines contribute to the heterogeneous nature of breast cancer, immune evasion and metastatic potential, are discussed. We examine the latest research into the therapeutic targeting of IL-6 family cytokines that inhibit STAT3 transcriptional activity as a potential breast cancer treatment, including current clinical trials. The importance of the IL-6 family of cytokines in cellular processes that promote the development and progression of breast cancer warrants further understanding of the molecular basis for its actions to help guide the development of future therapeutic targets.

TSLP up-regulates inflammatory responses through induction of autophagy in T cells.

Thymic stromal lymphopoietin (TSLP), a type I cytokine belonging to the IL-2 cytokine family, promotes Th2-mediated inflammatory responses. The aim of this study is to investigate whether TSLP increases inflammatory responses via induction of autophagy using a murine T cell lymphoma cell line, EL4 cells, and lipopolysaccharide (LPS)-injected mice. TSLP increased expression levels of autophagy-related factors, such as Beclin-1, LC3-II, p62, Atg5, and lysosome associated membrane protein 1/2, whereas these factors increased by TSLP disappeared by neutralization of TSLP in EL4 cells. TSLP activated JAK1/JAK2/STAT5/JNK/PI3K, while the blockade of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways reduced the expression levels of Beclin-1, LC3-II, and p62 in TSLP-stimulated EL4 cells. In addition, TSLP simultaneously increased levels of inflammatory cytokines via induction of autophagy by activation of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways. In an LPS-induced acute liver injury (ALI) mouse model, exogenous TSLP increased expression levels of Beclin-1 and LC3-II, whereas functional deficiency of TSLP by TSLP siRNA resulted in lower expression of Beclin-1, LC3-II, and inflammatory cytokines, impairing their ability to form autophagosomes in ALI mice. Thus, our findings show a new role of TSLP between autophagy and inflammatory responses. In conclusion, regulating TSLP-induced autophagy may be a potential therapeutic strategy for inflammatory responses.

Paradoxical role of interleukin-33/suppressor of tumorigenicity 2 in colorectal carcinogenesis: Progress and therapeutic potential.

Colorectal cancer (CRC) is presently the second most prevalent global mortality-inducing cancer. CRC carcinogenesis is a multifactorial process involving internal genetic mutations and the external environment. In addition, non-neoplastic cell activities within tumor microenvironments for CRC development have been established. However, interleukin (IL)-33, secreted by such cell types, plays a pivotal role in cancer progression due to interaction with cellular constituents within the tumor-inflammation microenvironment. IL-33 belongs to the IL-1 cytokine family and acts as binding attachments for the suppressor of tumorigenicity (ST)2 receptor. Therefore, how to coordinate tumor microenvironment, design and optimize treatment strategies suitable for CRC, based on IL-33/ST2 signal is a challenge. Even though it has established influences upon immunity-linked conditions, IL-33 effects on CRC progression and prevention and related mechanisms are still controversial. Our review depicts controversial activities for IL-33/ST2 within carcinogenesis and cancer prevention. Moreover, IL-33/ST2 signaling is a potential therapeutic target for CRC.

IL-6ファミリーサイトカインは、ポドサイトにおいて共通してSTAT3を活性化させるが、リガンド特異的な作用を示す

IL-6ファミリーサイトカインは、ポドサイトにおいて共通してSTAT3を活性化させるが、リガンド特異的な作用を示す

Interleukin 25 and its biological features and function in intestinal diseases.

Interleukin 25 (IL-25), also known as IL-17E, is a member of the IL-17 cytokine family and an important regulator of the type 2 immune response. Accumulating evidence suggests that IL-25 interacts with diverse immune as well as non-immune cells and plays a rather complicated role in different backgrounds of multiple organs. IL-25 has been studied in the physiology and pathology of the intestine to some extent. With epithelial cells being an important source in the intestine, IL-25 plays a key role in intestinal immune responses and is associated with inappropriate allergic reactions, autoimmune diseases, and cancer tumorigenesis. In this review, we discuss the emerging comprehension of the biology of IL-25, as well as its cellular sources, targets, and signaling transduction. In particular, we discuss how IL-25 participates in the development of intestinal diseases including helminth infection, inflammatory bowel diseases, food allergy and colorectal cancer, as well as its underlying role in future therapy.

The Immunological Impact of IL-1 Family Cytokines on the Epidermal Barrier.

The skin barrier would not function without IL-1 family members, but their physiological role in the immunological aspects of skin barrier function are often overlooked. This review summarises the role of IL-1 family cytokines (IL-1α, IL-1β, IL-1Ra, IL-18, IL-33, IL-36α, IL-36β, IL-36γ, IL-36Ra, IL-37 and IL-38) in the skin. We focus on novel aspects of their interaction with commensals and pathogens, the important impact of proteases on cytokine activity, on healing responses and inflammation limiting mechanisms. We discuss IL-1 family cytokines in the context of IL-4/IL-13 and IL-23/IL-17 axis-driven diseases and highlight consequences of human loss/gain of function mutations in activating or inhibitory pathway molecules. This review highlights recent findings that emphasize the importance of IL-1 family cytokines in both physiological and pathological cutaneous inflammation and emergent translational therapeutics that are helping further elucidate these cytokines.

Acute Effect of Caffeine on the Synthesis of Pro-Inflammatory Cytokines in the Hypothalamus and Choroid Plexus during Endotoxin-Induced Inflammation in a Female Sheep Model.

This study was designed to determine the effect of acute caffeine (CAF) administration, which exerts a broad spectrum of anti-inflammatory activity, on the synthesis of pro-inflammatory cytokines and their receptors in the hypothalamus and choroid plexus (ChP) during acute inflammation caused by the injection of bacterial endotoxin—lipopolysaccharide (LPS). The experiment was performed on 24 female sheep randomly divided into four groups: control; LPS treated (iv.; 400 ng/kg of body mass (bm.)); CAF treated (iv.; 30 mg/kg of bm.); and LPS and CAF treated. The animals were euthanized 3 h after the treatment. It was found that acute administration of CAF suppressed the synthesis of interleukin (IL-1β) and tumor necrosis factor (TNF)α, but did not influence IL-6, in the hypothalamus during LPS-induced inflammation. The injection of CAF reduced the LPS-induced expression of TNF mRNA in the ChP. CAF lowered the gene expression of IL-6 cytokine family signal transducer (IL6ST) and TNF receptor superfamily member 1A (TNFRSF1) in the hypothalamus and IL-1 type II receptor (IL1R2) in the ChP. Our study on the sheep model suggests that CAF may attenuate the inflammatory response at the hypothalamic level and partly influence the inflammatory signal generated by the ChP cells. This suggests the potential of CAF to suppress neuroinflammatory processes induced by peripheral immune/inflammatory challenges.

Interleukin-1 in COVID-19 Infection: Immunopathogenesis and Possible Therapeutic Perspective.

The newfound coronavirus disease 2019 (COVID-19), initiated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an international public health concern, threatening the lives of millions of people worldwide. The virus seems to have a propensity to infect older males, especially those with underlying diseases. The cytokine storm following hyperactivated immune responses due to SARS-CoV-2 infection is probably the crucial source of severe pneumonia that leads to acute lung injury, systemic inflammatory response syndrome, or acute respiratory distress syndrome, and finally multiple organ dysfunction syndromes, as well as death in many cases. Several studies revealed that interleukin (IL)-1β levels were elevated during COVID-19 infection. In addition, the IL-1 cytokine family has a pivotal role in the induction of cytokine storm due to uncontrolled immune responses in COVID-19 infection. This article reviews the role of IL-1 in inflammation and utilization of IL-1 inhibitor agents in controlling the inflammatory outcomes initiated by SARS-CoV-2 infection.

An inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation

Glaucoma is a chronic and progressive neurodegenerative disease of the optic nerve resulting in loss of retinal ganglion cells (RGCs) and vision. The most prominent glaucoma risk factor is increased intraocular pressure (IOP), and most models focus on reproducing this aspect to study disease mechanisms and targets. Yet, current models result in IOP profiles that often do not resemble clinical glaucoma. Here we introduce a new model that results in a gradual and sustained IOP increase over time. This approach modifies a circumlimbal suture method, taking care to make the sutures ‘snug’ instead of tight, without inducing an initial IOP spike. This approach did not immediately affect IOPs, but generated gradual ocular hypertension (gOHT) as the sutures tighten over time, in comparison to loosely sutured control eyes (CON), resulting in an average 12.6 mmHg increase in IOP at 17 weeks (p < 0.001). Corresponding characterization revealed relevant retinal and optic nerve pathology, such as thinning of the retinal nerve fiber layer, decreased optokinetic response, RGC loss, and optic nerve head remodeling. Yet, angles remained open, with no evidence of inflammation. Corresponding biochemical profiling indicated significant increases in TGF-β2 and 3, and IL-1 family cytokines in gOHT optic nerve tissues compared to CON, with accompanying microglial reactivity, consistent with active tissue injury and repair mechanisms. Remarkably, this signature was absent from optic nerves following acute ocular hypertension (aOHT) associated with intentionally tightened sutures, although the resulting RGC loss was similar in both methods. These results suggest that the pattern of IOP change has an important impact on underlying pathophysiology.

Interleukin-36 Cytokines in Infectious and Non-Infectious Lung Diseases.

The IL-36 family of cytokines were identified in the early 2000’s as a new subfamily of the IL-1 cytokine family, and since then, the role of IL-36 cytokines during various inflammatory processes has been characterized. While most of the research has focused on the role of these cytokines in autoimmune skin diseases such as psoriasis and dermatitis, recent studies have also shown the importance of IL-36 cytokines in the lung inflammatory response during infectious and non-infectious diseases. In this review, we discuss the biology of IL-36 cytokines in terms of how they are produced and activated, as well as their effects on myeloid and lymphoid cells during inflammation. We also discuss the role of these cytokines during lung infectious diseases caused by bacteria and influenza virus, as well as other inflammatory conditions in the lungs such as allergic asthma, lung fibrosis, chronic obstructive pulmonary disease, cystic fibrosis and cancer. Finally, we discuss the current therapeutic advances that target the IL-36 pathway and the possibility to extend these tools to treat lung inflammatory diseases.

Abstract 13647: Genetic Deletion of Interleukin-22 Prevents Angiotensin II-Induced Cardiac Diastolic Dysfunction in Mouse

Introduction: Interleukin-22 (IL-22) is a member of the IL-10 cytokine family, which promotes STAT3 activation in targets cells. Although it has been shown that persistent activation of STAT3 causes myocardial hypertrophy and fibrosis, little is known about the effect of IL-22 in the pathogenesis of cardiac diastolic dysfunction. Hypothesis: We hypothesized that IL-22 would be a factor that cardiac diastolic dysfunction. Methods and Results: We used angiotensin II (AngII) infusion mouse model, which has been reported to increase serum IL-22 levels, to cause cardiac diastolic dysfunction. We first investigated the effect of IL-22 deletion to cardiac function. Wild-type (WT) mice and IL-22 deficient (IL-22 KO) mice were compared cardiac function after 2 weeks AngII infusion. Echocardiographic analysis showed no decrease in systolic function as indicated by EF in both groups. However, In WT mice, E/e' was significantly increased compared to before AngII infusion. In contrast to WT mice, E/e' was not increased in IL-22KO mice by AngII infusion. These results suggested that AngII- induced cardiac diastolic dysfunction was prevented in IL-22KO mice. Next, we analyzed the effect of IL-22 deletion to histological changes. Compared to WT mice, ventricular weight to body weight ratio was significantly smaller in IL-22KO mice after 2 weeks AngII infusion. Echocardiographic analysis also showed that ventricular wall thickness was suppressed in IL-22KO mice. Sirius red staining revealed no difference in myocardial fibrosis between WT mice and IL-22KO mice after 2weeks AngII infusion. Conclusions: These results suggest that IL-22 plays an important role in the pathogenesis of AngII- induced cardiac diastolic dysfunction and cardiac hypertrophy.

Murine Oncostatin M Has Opposing Effects on the Proliferation of OP9 Bone Marrow Stromal Cells and NIH/3T3 Fibroblasts Signaling through the OSMR.

The IL-6 family cytokine Oncostatin M (OSM) is involved in cell development, growth, hematopoiesis, inflammation, and cancer. Intriguingly, OSM has proliferative and antiproliferative effects depending on the target cell. The molecular mechanisms underlying these opposing effects are not fully understood. Previously, we found OSM upregulation in different myeloproliferative syndromes. However, OSM receptor (OSMR) expression was detected on stromal cells but not the malignant cells themselves. In the present study, we, therefore, investigated the effect of murine OSM (mOSM) on proliferation in stromal and fibroblast cell lines. We found that mOSM impairs the proliferation of bone marrow (BM) stromal cells, whereas fibroblasts responded to mOSM with increased proliferation. When we set out to reveal the mechanisms underlying these opposing effects, we detected increased expression of the OSM receptors OSMR and LIFR in stromal cells. Interestingly, Osmr knockdown and Lifr overexpression attenuated the OSM-mediated effect on proliferation in both cell lines indicating that mOSM affected the proliferation signaling mainly through the OSMR. Furthermore, mOSM induced activation of the JAK-STAT, PI3K-AKT, and MAPK-ERK pathways in OP9 and NIH/3T3 cells with differences in total protein levels between the two cell lines. Our findings offer new insights into the regulation of proliferation by mOSM.

Analysis of Il36a induction by C/EBP\u03b2 via a half-CRE\u2022C/EBP element in murine macrophages in dependence of its CpG methylation level

Interleukin-36α is a novel member of the IL-1 cytokine family that is highly expressed in epithelial tissues and several myeloid-derived cell types after induction. The transcription factor (TF) C/EBPβ binds specifically to an essential half-CRE•C/EBP motif in the Il36a promoter to induce Il36a expression upon LPS stimulation. C/EBPs regulate gene expression by binding to recognition sequences that can contain 5′-cytosine-phosphate-guanine-3′ dinucleotides (CpG), whose methylation can influence TF binding and gene expression. Herein we show that the half-CRE•C/EBP element in the Il36a promoter is differentially methylated in the murine RAW264.7 macrophage cell line and in primary murine macrophages. We demonstrate that C/EBPβ binding to the half-CRE•C/EBP element in the Il36a promoter following LPS stimulation is insensitive to CpG methylation and that methylation of the CpG in the half-CRE•C/EBP element does not alter LPS-induced Il36a promoter activity which correlated with similar Il36a mRNA copy numbers and pro-IL-36α protein amount in both cell types. Taken together, our data indicate that C/EBPβ binding to the half-CRE•C/EBP element and subsequent gene activation occurs independently of the CpG methylation status of the half-CRE•C/EBP motif and underlines the potential of C/EBPs to recognize methylated as well as unmethylated motifs.

Roles of IL-1 and IL-10 family cytokines in the progression of systemic lupus erythematosus: Friends or foes?

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology that can affect nearly every organ system in the body. Besides genetic and environmental factors, unbalanced pro-inflammatory and anti-inflammatory cytokines contribute to immune dysregulation, trigger an inflammatory response, and induce tissue and organ damage. Inflammatory responses in SLE can be promoted and/or maintained by the availability of cytokines that are overproduced systemically and/or in local tissues. Several key cytokines have been considered potential targets for the reduction of chronic inflammation in SLE. Recent studies indicated that dysregulated production of several cytokines, including those of the IL-1 family and IL-10 family, orchestrate immune activation and self-tolerance, play critical roles in the pathogenesis of SLE. Among IL-1 family cytokines, IL-1, IL-18, IL-33, IL-36, IL-37, and IL-38 had been the most thoroughly investigated in SLE. Additionally, IL-10 family cytokines, IL-10, IL-20, IL-22, IL-26, IL-28, and IL-29 are dysregulated in SLE. Therefore, a better understanding of the initiation and progression of SLE may provide suitable novel targets for therapeutic intervention. In this review, we discuss the involvement of inflammation in the pathogenesis of SLE, with a focus on IL-1 family and IL-10 family cytokines, and highlight pathophysiological approaches and therapeutic potential for treating SLE.

Interleukin 37 Levels in Relation to Serum Vitamin D Levels Among Ain Shams University Medical Students

Abstract Background The extraskeletal role of vitamin D is being increasingly recognized. This has important clinical implications, as vitamin D deficiency has reached epidemic proportions worldwide. Vitamin D has proposed anti-inflammatory properties as recent data suggests that low vitamin D concentrations are associated with increased levels of inflammatory markers. Interleukin-37(IL-37) is an IL1 family cytokine discovered in recent years and has 5 different isoforms. As an immunosuppressive factor, IL-37 can suppress excessive immune response .IL37 plays a role in protecting the body against endotoxin shock, ischemia reperfusion injury, autoimmune diseases, and cardiovascular diseases. In addition, IL-37 has a potential antitumor effect. IL-37 and its receptors may serve as novel targets for the study, diagnosis, and treatment of immune-related diseases and tumors. Aim of the Work The aim of this study is to determine the relation between the level of interleukin-37 and 25-hydroxy Vitamin D among Ain Shams University medical students. Subjects and Methods The study was conducted at Clinical Pathology Department, Ain Shams University Hospitals. Ninety individuals, from medical students of Ain Shams University who participated in the Nutritional Assessment of Ain Shams University Medical Students (NAMESASU) Project, were selected to be in the study. The study included 2 groups: Group I: included 45 subjects selected from the NAMES-ASU project with deficient vitamin D serum levels. Group II: included 45 subjects selected from the NAMES-ASU project with sufficient vitamin D serum levels. Results There was a highly significant difference between the two groups regarding vitamin D levels. Serum IL-37 levels were significantly higher in group I subjects compared to group II subjects. No significant difference was observed between group I and group II regarding BMI, BFM, PBF and hsCRP. No significant difference was observed between the two subgroups regarding IL-37 levels and hsCRP levels. A highly significant negative correlation was observed between vitamin D levels and IL-37. A significant negative correlation was observed between hsCRP and vitamin D levels. However, no correlation was observed between hsCRP and IL-37 levels. Conclusion Data from our study showed that present study denote that in case of vitamin D deficiency, irrespective of BMI, a subclinical state of inflammation may be present as reflected by the increased hsCRP levels and this state of inflammation might induce an increase in IL-37, an anti-inflammatory cytokine, in an attempt to reduce the inflammation.

347 IL-33 deficiency protects skin from ulcer formation in ischemia-reperfusion-induced decubitus mouse model

Decubitus ulcers are serious problems in elderly long-term bedridden patients. Currently, there are no evidence-based treatment in the early phase decubitus to prevent the development of skin ulcers, except for reducing body weight load, by changing position or using cushions. Ischemia- reperfusion (I/R) injury is characterized by the reperfusion of blood to previously ischemic tissue, which induces cellular injury. I/R injury is associated with vascular infarction or vasospasm in various organs such as the brain, heart, liver, and kidneys, and there is also increasing evidence that cutaneous I/R injury is also associated with the development of decubitus. Interleukin-33 (IL- 33) is a member of IL-1 cytokine family that enhance Th2 immune reaction. IL-33 is one of danger signals to elicit inflammation upon tissue damage. We speculated that abundant IL-33 would be released in decubitus ulcer formation (I/R injury), thus we sought to determine if IL-33 acted an important role in the decubitus ulcer formation following I/R and investigate the mechanism. Ulcer area was reduced in IL-33KO mice and sST2 Tg mice compared to WT mice. Anti-IL-33 or anti-ST2L neutralizing antibody reduced the I/R-induced ulceration in WT mice. The number of infiltrating M2 macrophages was larger in IL-33KO mice at day8 I/R ulceration but that of mast cells and neutrophils was less. Real time (RT)-PCR results showed that expression of IL-1β was suppressed, but that of CCL17, related to M2 macrophage differentiation, was upregulated in IL-33KO mice compared to WT mice. In vitro study showed that macrophages from IL-33KO mice was able to produce IL-1β with IL-33 stimulation. These results indicate that blocking of IL-33 signaling would prevent or reduce the decubitus ulcer formation, by reducing mast cells and neutrophil infiltration and increasing M2 macrophage infiltration. We propose that blocking of IL-33 signal would have a great potential in prevention and treatment of early phase decubitus ulcer, which would tremendously contribute to clinical medicine.

Comprehensive Immunologic Evaluation of Bronchoalveolar Lavage Samples from Human Patients with Moderate and Severe Seasonal Influenza and Severe COVID-19.

Infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or seasonal influenza may lead to respiratory failure requiring intubation and mechanical ventilation. The pathophysiology of this respiratory failure is attributed to local immune dysregulation, but how the immune response to viral infection in the lower airways of the human lung differs between individuals with respiratory failure and those without is not well understood. We used quantitative multiparameter flow cytometry and multiplex cytokine assays to evaluate matched blood and bronchoalveolar lavage (BAL) samples from control human subjects, subjects with symptomatic seasonal influenza who did not have respiratory failure, and subjects with severe seasonal influenza or SARS-CoV-2 infection with respiratory failure. We find that severe cases are associated with an influx of nonclassical monocytes, activated T cells, and plasmablast B cells into the lower airways. Cytokine concentrations were not elevated in the lower airways of moderate influenza patients compared with controls; however, 28 of 35 measured cytokines were significantly elevated in severe influenza, severe SARS-CoV-2 infection, or both. We noted the largest elevations in IL-6, IP-10, MCP-1, and IL-8. IL-1 family cytokines and RANTES were higher in severe influenza infection than severe SARS-CoV-2 infection. Interestingly, only the concentration of IP-10-correlated between blood and BAL during severe infection. Our results demonstrate inflammatory immune dysregulation in the lower airways during severe viral pneumonia that is distinct from lower airway responses seen in human patients with symptomatic, but not severe, illness and suggest that measurement of blood IP-10 concentration may predict this unique dysregulation.

Serum Expression of IL-33 and ST2 in Patients with Psoriasis Vulgaris.

Psoriasis vulgaris (PsV) is an immune-mediated skin disease of unknown mechanism. Interleukin 33 (IL-33) is a member of IL-1 cytokine family and suppression of tumorigenicity 2 (ST2) is the specific ligand of IL-33. It has been found that IL-33 and ST2 are increased in psoriatic lesions, but the expression levels in serum and their relationship to clinical features are still unclear. The aim of this study is to assess IL-33, ST2, IL-17 and IL-5 serum levels as well as serum concentration of blood glucose and blood lipids in PsV patients and their relationship with clinical characteristics. Sixty-eight PsV samples and 60 healthy individuals were recruited. Serum levels of IL-33, ST2, IL-17 and IL-5 were measured by enzyme-linked immunosorbent assay and blood glucose and blood lipid were assayed by automatic biochemical analyzer. Serum levels of IL-33, ST2, IL-17 and IL-5 were increased significantly in PsV patients compared with controls (P<0.01). Cytokines were overexpressed in PsV patients during active stages compared with controls (P<0.05). Expression levels of IL-33, ST2 and IL-17 confirmed a significance in different severity groups of PsV patients (P<0.05). Serum concentration of triglyceride (TG) was also increased compared with controls (P=0.024). IL-33 levels were positively correlated with total cholesterol (TC) levels (r=0.319, P=0.008). IL-33/ST2 could generally reflect the activity and disease severity in PsV patients, which indicates that the IL-33/ST2 signaling pathway plays an important role in the pathogenesis of PsV.

LB809 IL-33 contributes to skin ulcer formation in ischemia-reperfusion-induced decubitus mouse model

Decubitus ulcers are injuries to skin and underlying tissue resulting from prolonged pressure on the skin, which become serious problems in aging long-term bedridden patients. Currently, there is no effective treatment or efficient prevention method in early phase of decubitus. Ischemia-reperfusion (I/R) injury is associated with vascular infarction or vasospasm in various organs and decubitus ulcers are considered as cutaneous I/R injury. Interleukin-33 (IL-33) is a member of IL-1 cytokine family that enhance Th2 immune reaction.

The IL-33-ILC2 pathway protects from amebic colitis

Entamoeba histolytica is a pathogenic protozoan parasite that causes intestinal colitis, diarrhea, and in some cases, liver abscess. Through transcriptomics analysis, we observed that E. histolytica infection was associated with increased expression of IL-33 mRNA in both the human and murine colon. IL-33, the IL-1 family cytokine, is released after cell injury to alert the immune system of tissue damage. Treatment with recombinant IL-33 protected mice from amebic infection and intestinal tissue damage; moreover, blocking IL-33 signaling made mice more susceptible to amebiasis. IL-33 limited the recruitment of inflammatory immune cells and decreased the pro-inflammatory cytokine IL-6 in the cecum. Type 2 immune responses were upregulated by IL-33 treatment during amebic infection. Interestingly, administration of IL-33 protected RAG2–/– mice but not RAG2−/−γc−/− mice, demonstrating that IL-33-mediated protection required the presence of innate lymphoid cells (ILCs). IL-33 induced recruitment of ILC2 but not ILC1 and ILC3 in RAG2−/− mice. At baseline and after amebic infection, there was a significantly higher IL13+ILC2s in C57BL/J mice, which are naturally resistant to amebiasis, than CBA/J mice. Adoptive transfer of ILC2s to RAG2−/−γc−/− mice restored IL-33-mediated protection. These data reveal that the IL-33-ILC2 pathway is an important host defense mechanism against amebic colitis.