Cytokine Family Research Articles

Immunomodulatory Activity of Granulocyte Colony-Stimulating Factor and its Therapeutic Effect on Liver Failure

Abstract Liver failure is characterized by the rapid deterioration of liver function, often accompanied by ascites, coagulation dysfunction, hepatic encephalopathy, and other critical complications. Owing to the complex multifaceted pathogenesis and consequential clinical manifestations of the disease, liver failure displays poor prognosis and warrants comprehensive clinical treatment and management. Liver transplantation remains the only well-established treatment for liver failure. However, several factors including transplantation cost and low organ donation rates limit the rate of liver transplantation. The development of a suitable therapy for liver failure is a significant challenge and remains a cause of concern for the medical world. Granulocyte colony-stimulating factor (G-CSF), a member of the cytokine family of hematopoietic growth factors, is involved in the migration of hematopoietic stem cells into the damaged liver, and effectuates their dedifferentiation into hepatocytes. Liver regeneration involves a complex crosstalk of multiple cell types, including hepatocytes, endothelial cells, and inflammatory cells. Neutrophils and monocytes/macrophages that present different types of innate immune cells were found to play a crucial role in the progression of inflammation and restoration of the liver tissue. G-CSF, known as the most common used cytokine, may also affect these immune cells by combining G-CSF receptors on their surface. The immunomodulatory activity of G-CSF should be studied and described in order to ascertain its therapeutic effect on liver failure.

The role of interleukin-33 in the pathogenesis, and treatment of severe asthma

Interleukin-33 (IL-33) belongs to the IL-1 family of cytokines, which has 11 members, including IL-1α, IL-1β, IL-1Ra, IL-18, IL-36α, IL-36β, and IL-37. Unlike its family members, IL-33 mediates T helper type-2 (Th2) immune responses, and promotes eosinophilic inflammation, similar to the other epithelial-derived cytokines, such as IL-25, and thymic stromal lymphopoietin (TSLP). Epithelial injury due to viral, and bacterial infections, allergens, chemical irritants, and trauma lead to secretion of alarmin cytokines, including IL-25, IL-33, and TSLP. IL-33 plays an important role in activating Th2 lymphocytes, group 2 innate lymphoid cells, dendritic cells, mast cells, basophils, and eosinophils, which result in secretion of cytokines, such as IL-4, IL-13, and IL-5; chemokines, including CCL2, and CXCL8, and adhesion molecules. The inflammatory mediators promote eosinophilic airway inflammation, airway hyperresponsiveness, and remodeling. IL-33 signaling is via a complex heterodimeric receptor comprising of IL-1 receptor-like 1 (IL-1RL1), and IL-1 receptor accessory protein. Downstream signaling cascade leads to the transcription of multiple cytokines and chemokines, which orchestrate eosinophilic asthma. Treatment of severe eosinophilic asthma include long-acting beta2-agonists, and inhaled corticosteroids, and addition of biologics at GINA step 4/5, such as omalizumab, mepolizumab, dupilumab, and tezepelumab. Currently, there are no anti-IL-33 biologics which have been approved for the treatment of eosinophilic asthma. Etokimab is a first-in-class IgG1 monoclonal antibody which blocks the activity of IL-33, thereby, inhibiting its biological effects. Phase 2a proof-of-concept clinical trial in 25 patient with severe eosinophilic asthma, showed that a single intravenous dose of etokimab (330 mg) resulted in a rapid and sustained improvement in lung function, and reduction in the asthma control questionnaire-5 scores throughout the study period of 64 days. Recently, itepekimab has been shown to improve asthma control, lung function, and quality of life, although the effects of itepekimab were slightly lesser than those observed for dupilumab. The dual therapy of itepekimab plus dupilumab did not achieve optimal outcomes, moreover, treatment with the doublet resulted in minimal change in pre-bronchodilator FEV1 compared with placebo. Dual blockade of interleukins incriminated in the pathogenesis of eosinophilic asthma need further careful studies, because of the immunological consequences in the era of SARS-CoV-2.

Therapeutic Opportunities of IL-22 in Non-Alcoholic Fatty Liver Disease: From Molecular Mechanisms to Clinical Applications.

Nonalcoholic fatty liver disease (NAFLD) represents one of the most common liver disorders and can progress into a series of liver diseases, including nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even liver cancer. Interleukin-22 (IL-22), a member of the IL-10 family of cytokines, is predominantly produced by lymphocytes but acts exclusively on epithelial cells. IL-22 was proven to favor tissue protection and regeneration in multiple diseases. Emerging evidence suggests that IL-22 plays important protective functions against NAFLD by improving insulin sensitivity, modulating lipid metabolism, relieving oxidative and endoplasmic reticulum (ER) stress, and inhibiting apoptosis. By directly interacting with the heterodimeric IL-10R2 and IL-22R1 receptor complex on hepatocytes, IL-22 activates the Janus kinase 1 (JAK1)/ signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK) and extracellular-signal regulated kinase (ERK) pathways to regulate the subsequent expression of genes involved in inflammation, metabolism, tissue repair, and regeneration, thus alleviating hepatitis and steatosis. However, due to the wide biodistribution of the IL-22 receptor and its proinflammatory effects, modifications such as targeted delivery of IL-22 expression and recombinant IL-22 fusion proteins to improve its efficacy while reducing systemic side effects should be taken for further clinical application. In this review, we summarized recent progress in understanding the physiological and pathological importance of the IL-22-IL-22R axis in NAFLD and the mechanisms of IL-22 in the protection of NAFLD and discussed the potential strategies to maneuver this specific cytokine for therapeutic applications for NAFLD.

Specific cytokines of interleukin-6 family interact with S100 proteins

Cytokines of interleukin-6 (IL-6) family are important signaling proteins involved in various physiological and pathological processes. Earlier, we described interactions between IL-11 and S100P/B proteins from the family of S100 proteins engaged in the pathogenesis of numerous diseases. We probed here interactions between seven IL-6 family cytokines (IL-6, IL-11, OSM, LIF, CNTF, CT-1, and CLCF1) and fourteen S100 proteins (S100A1/A4/A6/A7/A8/A9/A10/A11/A12/A13/A14/A15/B/P). Surface plasmon resonance spectroscopy revealed formation of calcium-dependent complexes between IL-11, OSM, CNTF, CT-1, and CLCF1 and distinct subsets of S100A1/A6/B/P proteins with equilibrium dissociation constants of 19 nM – 12 µM. The existence of a network of interactions between Ca2+-loaded S100 proteins and IL-6 family cytokines suggest regulation of these cytokines by the extracellular forms of S100 proteins.

Role of IL-33/ST2 Axis in Chronic Inflammatory Neurological Disorderss

Abstract Interleukin-33 (IL-33) is a member of IL-1 family of cytokines, produced constitutively by fibroblasts, endothelial cells, and epithelial cells. IL-33 can be released passively from cells during tissue damage and cell necrosis, suggesting that it may act as an alarmin. Function of IL-33 is mediated by its interaction with ST2 molecule that is expressed on many immune cells: Th2 lymphocytes, NK, NKT and mast cells, monocytes, dendritic cells and granulocytes. IL-33/ST2 pathway plays, often dual, roles in different physiological and inflammatory processes, mediating both, pathological immune responses and tissue repair. Expression of IL-33 in the central nervous system (CNS) is significantly enhanced during various pathological processes, indicating its important role in the pathogenesis of neurological inflammatory and degenerative diseases. In this review the biological features, expression of IL-33 and its ligand ST2 in CNS, and the role of IL- 33/ST2 pathway in development of Alzheimer’s disease and multiple sclerosis are discussed.

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.

450. Type I Interferon Autoantibodies Are Detected in Those with Critical COVID-19, Including a Young Female Patient

BackgroundApproximately 10-20% of patients with critical COVID-19 harbor neutralizing autoantibodies (auto-Abs) that target type I interferons (IFN), a family of cytokines that induce critical innate immune defense mechanisms upon viral infection. Studies to date indicate that these auto-Abs are mostly detected in men over age 65. MethodsWe screened for type I IFN serum auto-Abs in sera collected < 21 days post-symptom onset in a subset of 103 COVID-19 inpatients and 24 outpatients drawn from a large prospective cohort study of SARS-CoV-2 infected patients enrolled across U.S. Military Treatment Facilities. The mean age of this n = 127 subset of study participants was 55.2 years (SD = 15.2 years, range 7.7 – 86.2 years), and 86/127 (67.7%) were male. ResultsAmong those hospitalized 49/103 (47.6%) had severe COVID-19 (required at least high flow oxygen), and nine subjects died. We detected neutralizing auto-Abs against IFN-α, IFN-ω, or both, in four inpatients (3.9%, 8.2% of severe cases), with no auto-Abs detected in outpatients. Three of these patients were white males over the age of 62, all with multiple comorbidities; two of whom died and the third requiring high flow oxygen therapy. The fourth patient was a 36-year-old Hispanic female with a history of obesity who required mechanical ventilation during her admission for COVID-19.ConclusionThese findings support the association between type I IFN auto-antibody production and life-threatening COVID-19. With further validation, reliable high-throughput screening for type I IFN auto-Abs may inform diagnosis, pathogenesis and treatment strategies for COVID-19, particularly in older males. Our finding of type I IFN auto-Ab production in a younger female prompts further study of this autoimmune phenotype in a broader population. Disclosures David A. Lindholm, MD, American Board of Internal Medicine (Individual(s) Involved: Self): Member of Auxiliary R&D Infectious Disease Item-Writer Task Force. No financial support received. No exam questions will be disclosed ., Other Financial or Material Support David Tribble, M.D., DrPH, Astra Zeneca (Other Financial or Material Support, HJF, in support of USU IDCRP, funded under a CRADA to augment the conduct of an unrelated Phase III COVID-19 vaccine trial sponsored by AstraZeneca as part of USG response (unrelated work)) Simon Pollett, MBBS, Astra Zeneca (Other Financial or Material Support, HJF, in support of USU IDCRP, funded under a CRADA to augment the conduct of an unrelated Phase III COVID-19 vaccine trial sponsored by AstraZeneca as part of USG response (unrelated work))

Interleukin-11 receptor expression on monocytes is dispensable for their recruitment and pathogen uptake during Leishmania major infection.

Interleukin-11 (IL-11) is an important member of the IL-6 family of cytokines. IL-11 activates its target cells via binding to a non-signaling α-receptor (IL-11R), which results in recruitment and activation of a gp130 homodimer. The cytokine was initially described as an anti-inflammatory protein, but has recently gained attention as a potent driver in certain types of cancer and different fibrotic conditions. Leishmania spp. are a group of eukaryotic parasites that cause the disease leishmaniasis. They infect phagocytes of their hosts, especially monocytes recruited to the site of infection, and are able to replicate within this rather harsh environment, often resulting in chronic infections of the patient. However, the molecular mechanisms underlying parasite and host cell interactions and factors of the immune cells that are crucial for Leishmania uptake are so far largely unspecified. Recently, increased IL-11 expression in the lesions of patients with cutaneous leishmaniasis has been reported, but the functional relevance is unknown. In this study, we show that monocytes express IL-11R on their cell surface. Furthermore, using an adoptive transfer model of IL-11R−/− monocytes, we analyze the contribution of IL-11 signaling on monocyte recruitment and monocyte infection in a mouse model of cutaneous leishmaniasis and find that IL-11 signaling is dispensable for monocyte recruitment and pathogen uptake during Leishmania major infection.

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.

A hybrid systems biology and systems pharmacology investigation of Zingerone\u2019s effects on reconstructed human epidermal tissues

BackgroundAs individuals live longer, elderly populations can be expected to face issues. This pattern urges researchers to investigate the aging concept further to produce successful anti-aging agents. In the current study, the effects of Zingerone (a natural compound) on epidermal tissues were analyzed using a bioinformatics approach.MethodsFor this purpose, we chose the GEO dataset GSE133338 to carry out the systems biology and systems pharmacology approaches, ranging from identifying the differentially expressed genes to analyzing the gene ontology, determining similar structures of Zingerone and their features (i.e., anti-oxidant, anti-inflammatory, and skin disorders), constructing the gene–chemicals network, analyzing gene–disease relationships, and validating significant genes through the evidence presented in the literature.ResultsThe post-processing of the microarray dataset identified thirteen essential genes among control and Zingerone-treated samples. The procedure revealed various structurally similar chemical and herbal compounds with possible skin-related effects. Additionally, we studied the relationships of differentially expressed genes with skin-related diseases and validated their direct connections with skin disorders the evidence available in the literature. Also, the analysis of the microarray profiling dataset revealed the critical role of interleukins as a part of the cytokines family on skin aging progress.ConclusionsZingerone, and potentially any constituents of Zingerone (e.g., their similar compound scan functionality), can be used as therapeutic agents in managing skin disorders such as skin aging. However, the beneficial effects of Zingerone should be assessed in other models (i.e., human or animal) in future studies.

Identifying neuroinflammation in omics datasets with a computational biological network model of reactive astrogliosis

Neuroimmune responses by astrocytes and microglia play a key role in the pathogenesis of neurodegenerative diseases. Reactive astrocytes have diverse responses to triggers and can release a wide variety of effector molecules in an insult-specific manner. Identifying key mechanisms of reactive astrogliosis in large datasets is key to finding new therapeutic targets, but the interpretation of such datasets is challenging. Causal biological network (CBNs) models assemble available biological knowledge in a structured computable format that facilitates mechanistic interpretation of molecular data in a well-defined biological context. Here, we present a CBN model of pan-reactive astrogliosis genes as a new tool to explore and quantify the extent of reactive astrogliosis based on transcriptomic data and identify key molecular drivers of the phenotype. Mechanistic knowledge from 133 original publications on astrogliosis were used to build this CBN model. The statements were translated into computational statements using the Biological Expression Language and assembled into a CBN. Biological entities are represented by molecular nodes connected with edges that indicate the causal relationship between these nodes. A collection of these causal relationships were assembled to form a CBN. Information about gene expression regulation by a subset of the nodes was used to build a second scorable layer to infer the activity of the CBN nodes in transcriptomic datasets. The extent of perturbation of the astrogliosis CBN in transcriptomic datasets was quantified with a network perturbation amplitude algorithm. The astrogliosis CBN model is composed of 879 nodes and 1687 edges. Highly connected nodes within the network included the S1PR family of Sphingosine 1-phosphate receptors, extracellular matrix proteins, inflammatory regulator nuclear factor NF-κB complex and the glial fibrillary acidic protein. Assessment of transcriptomic dataset GSE75246 in the context of the CBN showed increased astrogliosis in astrocytes from LPS-treated mice compared with vehicle-treated mouse astrocytes. Increased signaling of the toll-like receptor 4, interferons and interleukin-6 family cytokines and decreased acetylcholine esterase and histone deacetylase activity were inferred as key drivers of LPS-induced astrogliosis in this dataset. The astrogliosis CBN is a novel tool to quantify astrogliosis in transcriptomic datasets and identify insult-specific molecular drivers of the phenotype.

Cancer-Associated Fibroblasts Regulate the Plasticity of Breast Cancer Stemness through the Production of Leukemia Inhibitory Factor

Simple SummaryCancer-associated fibroblasts (CAFs; as components of cancer stroma) use different signaling pathways to promote tumor progression and growth, invasion, and metastasis in diverse cancers. They have crosstalk with cancer cells during tumor progression. To investigate this crosstalk, in this study, a coculture system of CAF cells isolated from breast cancer patients with breast cancer cells was used to investigate leukemia inhibitory factor (LIF) production from CAFs. LIF is a signaling molecule that activates distinct signaling pathways through which cell cycle progression, cell death, adhesion, migration, and tumorigenesis are regulated.Leukemia inhibitory factor (LIF), as a member of the interleukin-6 cytokine family, plays a complex role in solid tumors. However, the effect of LIF as a tumor microenvironment factor on plasticity control in breast cancer remains largely unknown. In this study, an in vitro investigation is conducted to determine the crosstalk between breast cancer cells and fibroblasts. Based on the results, cancer-associated fibroblasts are producers of LIF in the cocultivation system with breast cancer cells. Treatment with the CAF-CM and human LIF protein significantly promoted stemness through the dedifferentiation process and regaining of stem-cell-like properties. In addition, the results indicate that activation of LIFR signaling in breast cancer cells in the existence of CAF-secreted LIF can induce Nanog and Oct4 expression and increase breast cancer stem cell markers CD24−/CD44+. In contrast, suppression of the LIF receptor by human LIF receptor inhibition antibody decreased the cancer stem cell markers. We found that LIF was frequently overexpressed by CAFs and that LIF expression is necessary for dedifferentiation of breast cancer cell phenotype and regaining of cancer stem cell properties. Our results suggest that targeting LIF/LIFR signaling might be a potent therapeutic strategy for breast cancer and the prevention of tumor recurrence.

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.

A novel cytokine consisting of the p40 and EBI3 subunits suppresses experimental autoimmune arthritis via reciprocal regulation of Th17 and Treg cells

ObjectiveThe interleukin (IL)-12 cytokine family is closely related to the development of T helper cells, which are responsible for autoimmune disease enhancement or suppression. IL-12 family members are generally heterodimers and share three α-subunits (p35, p19, and p28) and two β-subunits (p40 and EBI3). However, a β-sheet p40 homodimer has been shown to exist and antagonize IL-12 and IL-23 signaling 1. Therefore, we assumed the existence of a p40-EBI3 heterodimer in nature and sought to investigate its role in immune regulation.MethodsThe presence of the p40-EBI3 heterodimer was confirmed by ELISA, immunoprecipitation, and western blotting. A p40-EBI3 vector and p40-EBI3-Fc protein were synthesized to confirm the immunological role of this protein in mice with collagen-induced arthritis (CIA). The anti-inflammatory effects of p40-EBI3 were analyzed with regard to clinical, histological, and immune cell-regulating features in mice with CIA.ResultsClinical arthritis scores and the expression levels of proinflammatory cytokines (e.g., IL-17, IL-1β, IL-6, and TNF-α) were significantly attenuated in p40-EBI3-overexpressing and p40-EBI3-Fc-treated mice with CIA compared to vehicle-treated mice with CIA. Structural joint damage and vessel formation-related gene expression were also reduced by p40-EBI3 heterodimer treatment. In vitro, the p40-EBI3-Fc protein significantly suppressed the differentiation of Th17 cells and reciprocally induced CD4+CD25+Foxp3+ (regulatory T) cells. p40-EBI3 also inhibited osteoclast formation in a concentration-dependent manner.ConclusionIn this study, p40-EBI3 ameliorated proinflammatory conditions both in vivo and in vitro. We propose that p40-EBI3 is a novel anti-inflammatory cytokine involved in suppressing the immune response through the expansion of Treg cells and suppression of Th17 cells and osteoclastogenesis.

Interleukin 38 serum level is increased in patients with vitiligo, correlated with disease severity, and associated with signs of disease activity.

Vitiligo is an acquired cutaneous depigmenting disease caused by a T helper (Th) 1-cytotoxic T cells driven autoimmune attack against melanocytes, in which Th17 is also involved. Interleukin (IL)-38 belongs to the IL-1 family of cytokines and suppresses Th1 and Th17 activation. IL-38 protein and mRNA levels have been found to be elevated in various autoimmune disorders and correlated with disease severity and activity, including psoriasis, systemic sclerosis, rheumatoid arthritis, and atopic dermatitis. No previous studies have been performed to investigate the expression of IL-38 in patients with vitiligo. To evaluate IL-38serum level in patients with vitiligo compared to healthy controls (Hcs) and examine the association between IL-38level and severity and activity of vitiligo. The study comprised 21 patients with vitiligo and 21 Hcs. Vitiligo severity and activity were evaluated via Vitiligo Extent Score (VES) and Vitiligo Disease Activity (VIDA) Score, respectively. IL-38serum level was evaluated by enzyme-linked immunosorbent assay. Vitiligo patients had significantly higher serum level of IL-38 than Hcs (p<0.001). This level was significantly higher among patients with signs of vitiligo activity (p=0.048), correlated positively with VES (p<0.001), and correlated negatively with the age of patients (p=0.001) and the age of disease onset (p=0.022). IL-38serum level was higher in patients with vitiligo than in Hcs and was related to vitiligo severity and signs of activity.

A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics.

The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and pathological conditions, resulting in therapeutic applications in cancer and age-related macular degeneration, blocking ligands have been developed. These have mostly been large biomolecules like antibodies. Ligands with high affinities, at least in the nanomolar range, and accurate structural data from X-ray crystallography and NMR spectroscopy have been described. They constitute the main focus of this overview, which evidences similarities and differences in their binding modes. For VEGF-A ligands, and to a limited extent also for PlGF, a transition is now observed towards developing smaller ligands like nanobodies and peptides. These include unnatural amino acids and chemical modifications for designed and improved properties, such as serum stability and greater affinity. However, this review also highlights the scarcity of such small molecular entities and the striking lack of small organic molecule ligands. It also shows the gap between the rather large array of ligands targeting VEGF-A and the general absence of ligands binding other VEGF members, besides some antibodies. Future developments in these directions are expected in the upcoming years, and the study of these growth factors and their promising therapeutic applications will be welcomed.

Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis.

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.

Fibroblast-like Synoviocytes – Actors in Osteoimmunology

AbstractRheumatoid arthritis (RA) is an immune mediated inflammatory disease (IMID), characterized by chronic inflammation and irreversible bone loss. Studies have shown that fibroblast-like synoviocytes (FLS), a key cell population in the pathogenesis of RA, have an impact on balancing bone-forming osteoblasts and bone-destroying osteoclasts towards joint damage. Once activated, RA-FLS are able to destroy cartilage and subchondral bone through the release of RANKL, members of the metalloproteinase family and many more cytokines, chemokines and growth factors. Additionally, RA-FLS are responsible for the perpetuation and chronicity of the disease due the interaction with immune cells supporting the influx of T and B lymphocytes, monocytes, macrophages neutrophils and dendritic cells from the blood stream into the inflamed synovial tissue. In this review we highlight the direct and indirect impact of synovial fibroblasts in RA on joint damage and disease progression. Moreover, we describe mechanisms of synovitis and regulators of bone homeostasis in further inflammatory joint diseases such as ankylosing spondylitis (AS) and psoriatic arthritis (PsA) and compare them to RA.