Approximately 15% of patients with coronavirus disease 2019 (COVID-19) experience severe disease, and 5% progress to critical stage that can result in rapid death. No vaccines or antiviral treatments ...have yet proven effective against COVID-19. Patients with severe COVID-19 experience elevated plasma levels of pro-inflammatory cytokines, which can result in cytokine storm, followed by massive immune cell infiltration into the lungs leading to alveolar damage, decreased lung function, and rapid progression to death. As many of the elevated cytokines signal through Janus kinase (JAK)1/JAK2, inhibition of these pathways with ruxolitinib has the potential to mitigate the COVID-19–associated cytokine storm and reduce mortality. This is supported by preclinical and clinical data from other diseases with hyperinflammatory states, where ruxolitinib has been shown to reduce cytokine levels and improve outcomes. The urgent need for treatments for patients with severe disease support expedited investigation of ruxolitinib for patients with COVID-19.
•Severe coronavirus disease 2019 (COVID-19) cases are associated with cytokine storm.•Pro-inflammatory cytokines implicated in the sequelae signal through JAK1/JAK2.•Ruxolitinib, a JAK1/JAK2 inhibitor, could mitigate the cytokine storm in COVID-19.•Ruxolitinib may therefore have potential to reduce mortality in severe COVID-19.
Secretion of type I interferon (IFN) is the first cellular reaction to invading pathogens. Despite the protective function of these cytokines, an excessive response to their action can contribute to ...serious pathologies, such as autoimmune diseases. Transcripts of most cytokines contain adenylate-uridylate (A/U)-rich elements (AREs) that make them highly unstable. RNA-binding proteins (RBPs) are mediators of the regulatory mechanisms that determine the fate of mRNAs containing AREs. Here, we applied an affinity proteomic approach and identified lethal, abnormal vision, drosophila-like 1 (ELAVL1)/Hu antigen R (HuR) as the predominant RBP of the IFN-beta mRNA ARE. Reduced expression or chemical inhibition of HuR severely hampered the type I IFN response in various cell lines and fibroblast-like synoviocytes isolated from joints of rheumatoid arthritis patients. These results define a role for HuR as a potent modulator of the type I IFN response. Taken together, HuR could be used as therapeutic target for diseases where type I IFN production is exaggerated.
Background Schizophrenia is associated with immune system dysfunction, including aberrant cytokine levels. We performed a meta-analysis of these associations, considering effects of clinical status ...and antipsychotic treatment following an acute illness exacerbation. Methods We identified articles by searching PubMed, PsychInfo, and Institute for Scientific Information and the reference lists of identified studies. Results Forty studies met the inclusion criteria. Effect sizes were similar for studies of acutely relapsed inpatients (AR) and first-episode psychosis (FEP). Interleukin (IL)-1β, IL-6, and transforming growth factor-β (TGF-β) appeared to be state markers, as they were increased in AR and FEP ( p < .001 for each) and normalized with antipsychotic treatment ( p < .001, p = .008, and p = .005, respectively). In contrast, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble IL-2 receptor (sIL-2R) appeared to be trait markers, as levels remained elevated in acute exacerbations and following antipsychotic treatment. There was no difference in IL-6 levels between stable medicated outpatients and control subjects ( p = .69). In the cerebrospinal fluid, IL-1β was significantly decreased in schizophrenia versus controls ( p = .01). Conclusions Similar effect sizes in AR and FEP suggest that the association between cytokine abnormalities and acute exacerbations of schizophrenia is independent of antipsychotic medications. While some cytokines (IL-1β, IL-6, and TGF-β) may be state markers for acute exacerbations, others (IL-12, IFN-γ, TNF-α, and sIL-2R) may be trait markers. Although these results could provide the basis for future hypothesis testing, most studies did not control for potential confounding factors such as body mass index and smoking.
Summary Survival after lung transplantation is hampered by chronic lung allograft dysfunction (CLAD). Persistently elevated BAL-neutrophilia is observed in some patients despite treatment with ...azithromycin, which may be induced by IL-1alpha. Our aim is to establish an in vitro model, assess mechanistic pathways and test different therapeutic strategies of IL-1alpha-induced release of IL-8 by human bronchial epithelial cells. Bronchial epithelial cells (16HBE) were stimulated with IL-1alpha with or without azithromycin or dexamethasone. IL-8 protein was analyzed in cell supernatant. Different MAP kinases (p38, JNK,ERK1/2, Ikappabeta) and targets known to be involved in tumor formation (PI3K, Akt) were investigated. Finally, different treatment options were tested for their potential inhibitory effect. IL-1alpha induced IL-8 in bronchial epithelial cells, which was dose-dependently inhibited by dexamethasone but not by azithromycin. IL-1alpha induced p38 and Akt phosphorylation, but activation of these MAPK was not inhibited by dexamethasone. JNK,ERK1/2, Ikappabeta and PI3K were not activated. None of the tested drugs reduced the IL-1alpha induced IL-8 production. We established an in vitro model wherein steroids inhibit the IL-1alpha-induced IL-8 production, while azithromycin was ineffective. Despite using this simple in vitro model, we could not identify a new treatment option for azithromycin-resistant airway neutrophilia.
Methods Primary ASM were transfected with GR-GFP (green fluorescent protein) vector and treated with buffer, Insulin 100 nm, Rosiglitazone 10 uM, or combination Insulin and Rosiglitazone for 2 hours.
To prospectively investigate in patients with severe COVID-19-associated cytokine storm syndrome (CSS) whether an intensive course of glucocorticoids with or without tocilizumab accelerates clinical ...improvement, reduces mortality and prevents invasive mechanical ventilation, in comparison with a historic control group of patients who received supportive care only.
From 1 April 2020, patients with COVID-19-associated CSS, defined as rapid respiratory deterioration plus at least two out of three biomarkers with important elevations (C-reactive protein >100 mg/L; ferritin >900 µg/L; D-dimer >1500 µg/L), received high-dose intravenous methylprednisolone for 5 consecutive days (250 mg on day 1 followed by 80 mg on days 2-5). If the respiratory condition had not improved sufficiently (in 43%), the interleukin-6 receptor blocker tocilizumab (8 mg/kg body weight, single infusion) was added on or after day 2. Control patients with COVID-19-associated CSS (same definition) were retrospectively sampled from the pool of patients (n=350) admitted between 7 March and 31 March, and matched one to one to treated patients on sex and age. The primary outcome was ≥2 stages of improvement on a 7-item WHO-endorsed scale for trials in patients with severe influenza pneumonia, or discharge from the hospital. Secondary outcomes were hospital mortality and mechanical ventilation.
At baseline all patients with COVID-19 in the treatment group (n=86) and control group (n=86) had symptoms of CSS and faced acute respiratory failure. Treated patients had 79% higher likelihood on reaching the primary outcome (HR: 1.8; 95% CI 1.2 to 2.7) (7 days earlier), 65% less mortality (HR: 0.35; 95% CI 0.19 to 0.65) and 71% less invasive mechanical ventilation (HR: 0.29; 95% CI 0.14 to 0.65). Treatment effects remained constant in confounding and sensitivity analyses.
A strategy involving a course of high-dose methylprednisolone, followed by tocilizumab if needed, may accelerate respiratory recovery, lower hospital mortality and reduce the likelihood of invasive mechanical ventilation in COVID-19-associated CSS.
Seronegative spondylorthropathies are a group of disorders with similar etiopathogenesis which are seen in genetically proned individuals with chronic inflamatory symptoms. Prototype of this group of ...disorders is ankylosing spondylitis which involve the axial skeletal system. Clinicaly it does not only effect skeletal sytem but also enthesis areas, joints, eyes, intestines and skin may get involved. Microbial dysbiosis takes an important place in etiopathogenesis. Dysbiosis cause mucosal barier disruption therefore induces releasing of inflamatory cytokines. Th3 type immunity which plays a major role in mucosal integrity, is major factor in inflamatory process and its numbers increase in these patients. Stability of mucosal barier function is also effected by IL-17, IL-22 along with Th3 type of immunity. As a result, activated immune system with different inducers cause chronic inflamatory reaction with inflamatory cytokines with the help of IL-17 and IL-23 thereby lead to spondylitis. Keywords: Spondyloarthritis, type 3 immunity, pro-inflammatry cytokines Seronegatif spondiloartrit; genetik olarak yatkin kisilerde kronik enflamasyonla ortaya cikan benzer patogenezlere sahip bir hastalik grubudur. Bu hastalik grubunun prototipi aksiyel iskelet sistemini tutan ankilozan spondilittir (AS). Klinik olarak sadece iskelet sistemi degil, entezis bolgeleri, eklem, goz, barsak, deri tutulumuda gozlenmektedir. Patogenezde mikrobiyal disbiyozis onemli yer tutmaktadir. Mikrobiyal disbiyozisle beraber mukozal bariyer butunlugu bozulmakta ve enflamatuvar sitokinler salinmaktadir. Bariyer butunlugun saglanmasinda anahtar role sahip olan Tip 3 immunitede bu enflamasyonun olusuma onemli katkida bulunmakta olup bu hasta grubunda periferik kanda sayilarinin arttigi saptanmistir. Bariyer fonksiyonu saglanmasinda tek basina Tip 3 immunite etkili olmayip IL-17 ve IL-22 de katki saglamaktadir. Sonuc olarak; cesitli nedenlerden dolayi aktive olan immun sistemden salinan pro-enflamatuvar sitokinler ozellikle IL-17 ve IL-23'un etkisi ile kronik enflamasyon ile giden spondilit olusumuna neden olmaktadir. Anahtar Kelimeler: Spondiloartrit, tip 3 immunite, pro-enflamatuvar sitokin
The current pandemic caused by SARS-CoV-2 virus infection is known as Covid-19 (coronavirus disease 2019). This disease can be asymptomatic or can affect multiple organ systems. Damage induced by the ...virus is related to dysfunctional activity of the immune system, but the activity of molecules such as C-reactive protein (CRP) as a factor capable of inducing an inflammatory status that may be involved in the severe evolution of the disease, has not been extensively evaluated. A systematic review was performed using the NCBI-PubMed database to find articles related to Covid-19 immunity, inflammatory response, and CRP published from December 2019 to December 2020. High levels of CRP were found in patients with severe evolution of Covid-19 in which several organ systems were affected and in patients who died. CRP activates complement, induces the production of pro-inflammatory cytokines and induces apoptosis which, together with the inflammatory status during the disease, can lead to a severe outcome. Several drugs can decrease the level or block the effect of CRP and might be useful in the treatment of Covid-19. From this review it is reasonable to conclude that CRP is a factor that can contribute to severe evolution of Covid-19 and that the use of drugs able to lower CRP levels or block its activity should be evaluated in randomized controlled clinical trials.
Summary
The significantly higher mortality rates seen in the elderly compared with young children during the coronavirus disease 2019 (Covid‐19) pandemic is likely to be driven in part by an impaired ...immune response in older individuals. Cytomegalovirus (CMV) seroprevalence approaches 80% in the elderly. CMV has been shown to accelerate immune ageing by affecting peripheral blood T cell phenotypes and increasing inflammatory mediated cytokines such as IL‐6. The elderly with pre‐existing but clinically silent CMV infection may therefore be particularly susceptible to severe Covid‐19 disease and succumb to a cytokine storm which may have been promoted by CMV. Here, we evaluate the potential role of CMV in those with severe Covid‐19 disease and consider how this relationship can be investigated in current research studies.
PDF
![Interleukin-1[alpha] induce...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0934-0874/small "Interleukin-1[alpha] induced release of interleukin-8 by human bronchial epithelial cells in vitro: assessing mechanisms and possible treatment options")
