Cytokine Patterns In Patients Research Articles

Cytokine pattern in patients with ST-elevation myocardial infarction treated with the interleukin-6 receptor antagonist tocilizumab

BackgroundTocilizumab improves myocardial salvage index (MSI) in patients with ST-elevation myocardial infarction (STEMI), but its mechanisms of action are unclear. Here, we explored how cytokines were affected by tocilizumab and...

Association of cytokine profile with prior treatment failure and revision surgery in chronic rhinosinusitis.

Inflammatory patterns in chronic rhinosinusitis (CRS) may predict disease severity, need for multiple sinus surgeries, and treatment response. This study analyzes nasal mucus inflammatory cytokine patterns in patients with (CRSwNP) and without (CRSsNP) nasal polyposis and their association with revision sinus surgery. A total of 319 CRS patients who underwent sinus surgery were included. Cytokines were quantified in intraoperative mucus specimens using a multiplex flow cytometric bead assay. Cytokine expression patterns in patients with 0, 1, and ≥2 previous surgeries were analyzed using Kruskal-Wallis and principal component (PC) regression analyses. There were 122 (38%) patients with CRSsNP and 197 (62%) with CRSwNP. On univariate analysis, interleukin (IL)-1β, IL-6, IL-8, and IL-21 were associated with increasing number of sinus surgeries in CRSsNP, as were IL-2, IL-4, IL-5, IL-6, IL-9, IL-17A, and tumor necrosis factor (TNF)-α in CRSwNP. PC analysis with continuous Poisson regression in CRSwNP demonstrated that high IL-5 and IL-13 and low IL-1β, IL-12, and IL-21 were associated with more prior surgeries. In CRSsNP low IL-13 and high IL-5 and regulated-on-activation, normal T-cell-expressed and secreted (RANTES) were associated with more prior surgeries. Age remained a significant covariate in the full regression model for CRSsNP, but was nonsignificant in CRSwNP. In CRSwNP, elevated IL-5 and IL-13 levels were higher at time of surgery in patients with more prior surgeries. Type 2 cytokines in CRSsNP demonstrated mixed associations with revision surgery. For both phenotypes, IL-10, IL-12, and IL-21 were consistently lower as number of prior surgeries increased, suggesting that treatment-resistant disease may be modulated by impairment in these signaling pathways.

Identification of serological biomarkers for diagnosis of rheumatoid arthritis using a protein array-based approach

To study the cytokine patterns in patients with rheumatoid arthritis (RA) and healthy individuals and identify candidate serum biomarkers for clinical diagnosis of RA. This study was conducted among 59 patients diagnosed with RA in our hospital from 2015 to 2019 with 46 age- and gender-matched healthy subjects who received regular physical examinations in our hospital as the control group. Serological autoimmune profiles of 5 RA patients and 5 healthy control subjects were obtained from human cytokine microarrays. We selected 4 differentially expressed cytokines (LIMPII, ROBO3, Periostin and IGFBP-4) and 2 soluble cytokine receptors of interest (2B4 and Tie-2) and examined their serum levels using enzyme-linked immunosorbent assay in 54 RA patients and 41 healthy control subjects. Spearman correlation test was performed to assess the correlation of serum cytokine and soluble receptor expression levels with the clinical features including rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), disease activity score (DAS28) and health assessment questionnaire (HAQ). Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic capability of these cytokines. We identified 6 dysregulated cytokines and soluble receptors (2B4, LIMPII, Tie-2, ROBO3, periostin and IGFBP-4) in RA patients (P < 0.01). The serum levels of LIMPII, ROBO3 and periostin were significantly correlated with the disease activity indicators including RF (P < 0.001), CRP (P < 0.001), DAS28 (P < 0.001) and HAQ (P < 0.001) in RA patients. Among the 6 candidate cytokines, 2B4 showed the largest area under the curve (AUC) of 0.861 for RA diagnosis (P < 0.001), followed then by LIMPII, ROBO3, periostin, Tie-2 and IGFBP-4. Serum levels of LIMPII, ROBO3 and periostin can be indicative of the disease activity of RA, and serum 2B4, LIMPII, periostin, ROBO3, IGFBP-4 and Tie-2 levels may serve as biomarkers for the diagnosis of RA.

Multiple Roles for Cytokines in Atopic Dermatitis: From Pathogenic Mediators to Endotype-Specific Biomarkers to Therapeutic Targets.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, which generally presents with intense itching and recurrent eczematous lesions. AD affects up to 20% of children and 10% of adults in high-income countries. The prevalence and incidence of AD have increased in recent years. The onset of AD mostly occurs in childhood, although in some cases AD may persist in adult life or even manifest in middle age (adult-onset AD). AD pathophysiology is made of a complex net, in which genetic background, skin barrier dysfunction, innate and adaptive immune responses, as well as itch contribute to disease development, progression, and chronicization. One of the most important features of AD is skin dehydration, which is mainly caused by filaggrin mutations that determine trans-epidermal water loss, pH alterations, and antigen penetration. In accordance with the “outside-inside” theory of AD pathogenesis, in a context of an altered epidermal barrier, antigens encounter epidermal antigen presentation cells (APCs), such as epidermal Langerhans cells and inflammatory epidermal dendritic cells, leading to their maturation and Th-2 cell-mediated inflammation. APCs also bear trimeric high-affinity receptors for immunoglobulin E (IgE), which induce IgE-mediated sensitizations as part of pathogenic mechanisms leading to AD. In this review, we discuss the role of cytokines in the pathogenesis of AD, considering patients with various clinical AD phenotypes. Moreover, we describe the cytokine patterns in patients with AD at different phases of the disease evolution, as well as in relation to different phenotypes/endotypes, including age, race, and intrinsic/extrinsic subtypes. We also discuss the outcomes of current biologics for AD, which corroborate the presence of multiple cytokine axes involved in the background of AD. A deep insight into the correlation between cytokine patterns and the related clinical forms of AD is a crucial step towards increasingly personalized, and therefore more efficient therapy.

Identification and Characterization of the miRNAs and Cytokines in Response to Leishmania infantum Infection with Different Response to Treatment.

Due to the complexity of cytokine and microRNA function in progression and/or suppression of an infection, in this study, we examined miR-3473f, miR-2128, miR-6994-5p, miR-7093-3p, miR-5128, miR-574-5p, miR-7235, IL-2, IL-4, IL-5, IL-10 and IL-13 in patients with VL caused by Leishmania infantum in an in vivo study. Sampling was carried out from patient with leishmaniasis and with different responses to treatment during March 2016-January 2020. DNA was extracted and purified using QIAamp Kit. The L. infantum were cultured in DMEM medium and protein content was determined by the Micro BCA Protein Assay Kit. Cytokines were evaluated using a MILLIPLEX MAP Mouse Cytokine/Chemokine Panel I kit. The relative expression of miRNAs was measured in duplicate using automatic thermocycler ABI Prism 7500 sequence detection system (Applied Bio-systems) using the TaqMan MicroRNA Assay kit. The real-time PCR assay revealed that miR-2128, miR-6994-5p, miR-7093-3p, miR-5128, miR-574-5p and miR-7235 were down-regulated and miR-3473 were up-regulated in patients with semi-resistance and resistance parasite strain (P < 0.05). In the current work, cytokine patterns in patients who were slow-to-clear or unable-to-clear L. infantum infection during drug treatment were seen to have decreased protective Th1 cytokines (IL-2, IL-12, TNF-α, and IFN-ɤ, P < 0.001) and increased Th2 cytokines (IL-5, IL-10, and IL-13, P < 0.001). No association was seen with IL-4 in patients with different treatment outcomes. Overall, the results of a recent study have shown that cytokines and microRNAs can play a key role in response to treatment, and more comprehensive studies are needed to support this hypothesis.

Cytokine changes during immune-related adverse events and corticosteroid treatment in melanoma patients receiving immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) often cause immune-related adverse events (irAEs), most of which are treated with corticosteroids despite evidence suggesting that corticosteroids may blunt antitumor efficacy. We sought to identify cytokine changes that correlate with irAEs and study the impact of corticosteroid treatment on cytokine levels. We analyzed expression of 34 cytokines in 52 melanoma patients who developed irAEs during therapy with ICIs. Luminex serum assay was performed at baseline, 1, 2, and 3months after starting ICI. Baseline cytokine levels and longitudinal log2 fold-change was compared with incidence and grade of irAEs. Cytokine patterns were compared between patients based on development of irAEs and steroid treatment. There were no differences in baseline cytokine levels between patients who developed grade 1-2 irAEs (N = 28) vs. grade 3-4 irAEs (N = 24). Dermatitis patients (N = 8) had significantly higher baseline Ang-1 (p = 0.006) and CD40L (p = 0.005). Pneumonitis patients (N = 4) had significantly higher baseline IL-17 (p = 0.009). Colitis patients (N = 8) had a trend toward decreased GCSF (p = 0.08). Through Spearman's correlation analysis, patients who developed irAEs without receiving corticosteroids (N = 23) exhibited harmonization of cytokine fold-change, with 0/276 pairwise comparisons demonstrating significant divergence. In contrast, corticosteroid treatment in patients with irAEs (N = 15) altered fold-change to a discordant pattern (42/276 diverged, 15.2%). This discordant cytokine pattern in patients receiving corticosteroids is similar to the cytokine pattern in patients who did not develop irAEs (N = 8) during the longitudinal profiling period (41/276, 14.9%). Baseline levels of certain cytokines correlate with specific irAEs in melanoma patients receiving ICIs. irAEs drive a concordant pattern of cytokine fold-change, which is disrupted by corticosteroid treatment.

Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison

A central paradigm of immunity is that interferon (IFN)-mediated antiviral responses precede pro-inflammatory ones, optimizing host protection and minimizing collateral damage1,2. Here, we report that for coronavirus disease 2019 (COVID-19) this paradigm does not apply. By investigating temporal IFN and inflammatory cytokine patterns in 32 moderate-to-severe patients with COVID-19 hospitalized for pneumonia and longitudinally followed for the development of respiratory failure and death, we reveal that IFN-λ and type I IFN production were both diminished and delayed, induced only in a fraction of patients as they became critically ill. On the contrary, pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-6 and IL-8 were produced before IFNs in all patients and persisted for a prolonged time. This condition was reflected in blood transcriptomes wherein prominent IFN signatures were only seen in critically ill patients who also exhibited augmented inflammation. By comparison, in 16 patients with influenza (flu) hospitalized for pneumonia with similar clinicopathological characteristics to those of COVID-19 and 24 nonhospitalized patients with flu with milder symptoms, IFN-λ and type I IFN were robustly induced earlier, at higher levels and independently of disease severity, whereas pro-inflammatory cytokines were only acutely produced. Notably, higher IFN-λ concentrations in patients with COVID-19 correlated with lower viral load in bronchial aspirates and faster viral clearance and a higher IFN-λ to type I IFN ratio correlated with improved outcome for critically ill patients. Moreover, altered cytokine patterns in patients with COVID-19 correlated with longer hospitalization and higher incidence of critical disease and mortality compared to flu. These data point to an untuned antiviral response in COVID-19, contributing to persistent viral presence, hyperinflammation and respiratory failure.

Plasma cytokine profile on admission related to aetiology in community-acquired pneumonia.

Potentially unnecessary antibiotic use for community-acquired pneumonia (CAP) contributes to selection of antibiotic-resistant pathogens. Cytokine expression at the time that treatment is started may assist in identifying patients not requiring antibiotics. We determined plasma cytokine patterns in patients retrospectively categorized as strict viral, pneumococcal or combined viral-bacterial CAP. To investigate whether cytokine-based prediction models can be used to differentiate strict viral CAP from other aetiologies at admission. From 344 hospitalized CAP patients, 104 patients were categorized as viral CAP (n=17), pneumococcal CAP (n=48) and combined bacterial-viral CAP (n=39). IL-6, IL-10, IL-27, IFN-γ and C-reactive protein (CRP) were determined on admission in plasma. Prediction of strict viral aetiology was explored with two multivariate regression models and ROC curves. Viral pneumonia was predicted by logistic regression using multiple cytokine levels (IL-6, IL-27 and CRP) with an AUC of 0.911 (95% CI: 0.852-0.971, P<.001). For the same patients the AUC of CRP was 0.813 (95% CI: 0.728-0.898, P<.001). This study demonstrated differences in cytokine expression in selected CAP patients between viral and bacterial aetiology. Prospective validation studies are warranted.

B-cell depletion induces a shift in self antigen specific B-cell repertoire and cytokine pattern in patients with bullous pemphigoid

Bullous Pemphigoid is the most common auto-immune bullous skin disease. It is characterized by the production of auto-antibodies directed against 2 proteins of the hemi-desmosome (BP180 and BP230). We assessed the efficacy and mechanisms of action of rituximab, an anti-CD20 monoclonal antibody, in 17 patients with severe and relapsing type of bullous pemphigoid. The phenotype, cytokine gene expression, and rearrangement of BP180-specific B-cell receptor genes were performed over 2 years following treatment. At the end of the study, 5 patients had died, 3 had withdrawn from the study, and 9 patients were in complete remission. The one- and two-year relapse rates were 44.1% (95% Confidence Interval (CI): 21.0–76.0%) and 66.5%, (95% CI: 38.4–91.4%), respectively. Phenotypic analyses confirmed dramatic B-cell depletion, which lasted for 9 to 12 months. The ELISA values of serum anti-BP180 antibodies and the frequency of BP180-specific circulating B cells decreased dramatically following treatment, which paralleled the improvement of skin lesions. During B-cell reconstitution, a polyclonal IgM repertoire appeared and a shift in the rearrangement of the B-cell receptor genes of BP180-specific circulating B cells was observed. Concurrently, we observed a decrease of IL-15, IL-6 and TNFα expressing BP180-specific B cells, and the emergence of IL-10 and IL-1RA-expressing BP180-specific IgM+ B cells in patients in complete remission off therapy, suggesting the functional plasticity of BP180-specific auto-immune B cells after rituximab treatment.

Nasal lavage VEGF and TNF-α levels during a natural cold predict asthma exacerbations.

Asthma exacerbations contribute to significant morbidity, mortality and healthcare utilization. Furthermore, viral infections are associated with asthma exacerbations by mechanisms that are not fully understood. The aim of this analysis was to determine whether cytokine patterns in patients with colds could identify risks for subsequent asthma exacerbations. We analysed cytokine levels in nasal lavage fluid (NLF) in 59 subjects (46 with asthma) with acute upper respiratory symptoms and after symptomatic resolution. Analyte choice was based on potential relevance to asthma exacerbations: antiviral (IFN-α, IFN-β, IFN-γ, IFN-λ1, IP-10, TRAIL), cell recruiting (G-CSF, IL-1β, IL-8, MCP-1, MCP-3, TNF-α), polarizing (CXCL13, IL-10, IL-13, IL-17, TSLP), and injury remodelling (fibronectin, IL-33, MMP-9, VEGF). The overall cytokine response induced during viral infections was not different between asthmatic and non-asthmatic individuals for a wide array of cytokines. However, mean levels of VEGF, TNF-α and IL-1β were 1.7-, 5.1- and 4.7-fold higher in samples from asthma subjects who exacerbated in the first 3 weeks of the cold compared with those who did not exacerbate (P = 0.006, 0.01, 0.048, respectively). Using receiver operating characteristic curve-defined thresholds, high VEGF and TNF-α levels predicted a shorter time-to-exacerbation after NLF sampling (25% exacerbation rate: 3 vs. 45 days, and 3 vs. 26 days; P = 0.03, 0.04, respectively). Although they produce similar cytokine responses to viral infection as non-asthmatics, asthmatics with higher levels of VEGF and TNF-α in NLF obtained during acute cold phases predicted subsequent asthma exacerbations in this cohort of patients with mild-to-moderate disease. In the future, stratifying the risk of an asthma exacerbation by cytokine profile may aid the targeting of personalized treatment and intervention strategies.

Local and systemic pro-inflammatory and anti-inflammatory cytokine patterns in patients with chronic subdural hematoma: a prospective study

Innate immune pro- and anti-inflammatory responses in patients with chronic subdural hematoma (CSDH) were investigated by measuring and comparing the systemic and subdural fluid levels of cytokines. Cytokine values were analyzed in samples obtained during surgery of 56 adult patients who were operated on for unilateral CSDHs using a Multiplex antibody bead kit. There were significantly higher levels of the pro-inflammatory IL-2R (p = 0.004), IL-5 (p < 0.001), IL-6 (p < 0.001), and IL-7 (p < 0.001), and anti-inflammatory mediators IL-10 (p < 0.001) and IL-13 (p = 0.002) in CSDH fluid compared with systemic levels. The pro-inflammatory TNF-alpha (p < 0.001), IL-1beta (p < 0.001), IL-2 (p = 0.007) and IL-4 (p < 0.001) were significantly lower in hematoma fluid compared with systemic levels. The ratios between pro- versus anti-inflammatory cytokines were statistically significant higher in CSDH (7.8) compared with systemic levels (1.3). The innate immune responses occur both locally at the site of CSDH, as well as systematically in patients with CSDH. The local hyper-inflammatory and low anti-inflammatory responses exist simultaneously. The findings suggest poorly coordinated innate immune responses at the site of CSDH that may lead to propagating of local inflammatory process and basically contribute to formation and progression of CSDH.

Arterial and venous thrombosis is associated with different angiogenic cytokine patterns in patients with antiphospholipid syndrome

Antiphospholipid syndrome (APS) is defined as a combination of antiphospholipid antibodies, arterial and/or venous thrombosis, and, in women, recurrent fetal loss. The mechanisms underlying this prothrombotic tendency are unclear. Here we determined plasma levels of the angiogenic growth factors vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and stromal cell-derived factor-1 (SDF-1) in 34 patients with APS (median age 40 years) compared with 180 healthy controls and with 80 age-matched deep-venous thrombosis patients in whom the diagnosis of APS had been excluded. All of the patients met updated APS criteria and two-thirds of them were triply positive for antiphospholipid antibodies (lupus anticoagulant, anti-beta2-glycoprotein I and anti-cardiolipin antibodies). Angiogenic cytokines were quantified at least 6 months after an acute thrombotic event. VEGF levels were similar in the patients and controls, but were significantly higher in the patients with arterial thrombosis than in the patients with venous thrombosis. Plasma levels of SDF-1 and PlGF were significantly elevated in the patients, regardless of the arterial/venous nature of the thrombosis. Together, these results suggest that APS is associated with an angiogenic process, but that the angiogenic signal differs between patients with arterial and venous thrombosis. Lupus (2010) 19, 837-843.

Distinct Cytokine Patterns in Different States of Kidney Allograft Function

Cytokines are crucial inflammatory mediators involved in the development of immune response leading to allograft rejection. We investigated the cytokine patterns in patients sera from cases of acute rejection episodes (ARE), chronic rejection (CR), and long-term stable courses (STABLE). The project included 20 patients with ARE, 20 with CR, and 15 with at least a 5-year stable course. Serum samples collected at the time of rejection diagnosis were cytometrically tested for concentrations of interleukin (IL) 2, IL-4, IL-6, IL-10, interferon (IFN) γ, and tumor necrosis factor α. No significant differences between investigated groups were observed before transplantation ( P > .05). Significant differences were observed among the groups in serum levels of IFN-γ, IL-4, IL-6, and IL-10. Our data suggested that distinct serum cytokine patterns were present among various states of kidney allograft function. ARE was characterized by a mixed cytokine pattern with elevated IL-10 and IFN-γ compared with the STABLE patients. The cytokine pattern in CR patients, in turn, was characterized by elevated levels of IL-4, IL-6, and IL-10 and decreased levels of IFN- γ compared with both STABLE and ARE subjects. Our results suggested that the T H2 response may contribute to the initiation and/or maintenance of CR, because IL-4, IL-6, and IL-10 serve as growth and differentiation factors for B cells to increase antibody production. We also observed up-regulated production of IFN-γ and down-regulation of T H2 cytokines among patients with stable long- term graft function.

Quality of life, depression, and cytokine patterns in patients with chronic hepatitis C treated with antiviral therapy

To evaluate the effect of chronic hepatitis C and antiviral therapy on health-related quality of life (HRQoL), depression symptoms and cytokine patterns. Twenty HCV+ patients treated with peginterferon plus ribavirin were enrolled in this cohort study and invited to complete SF-12 and BDI questionnaires prior to (T0) and at the end of the treatment (T1). HCV-RNA, serum levels of ALT, AST, haemoglobin, ferritin and IFN-gamma, TNF-alpha, IL-2, IL-4, IL-6 and IL-10 were evaluated at T0 and T1. The questionnaire results were correlated to biochemical and cytokine parameters. Two patients (1%) dropped out and 18 HCV patients composed the final sample (11 males (61.1%); mean age 42.5+/-11.9 yr; mean disease duration 9.7+/-6.9 yr). Between T0 and T1 ALT (p=0.02), AST (p=0.052) HCV-RNA (P=0.0002) and haemoglobin levels decreased (p=0.0003), whereas ferritin level increased (P=0.003). Also, at T1 all cytokine levels were augmented. Regarding depression status, at T0 10 patients (55.5%) scored above to the BDI questionnaire (suggesting clinically significant depression), whereas at T1 14 patients scored 10 or above (77.7%). At T1 the mean BDI score increased, but this difference was not significant. Regarding HRQoL, the majority of patients had T0 summary scores < or = 50. At T1 HRQoL changed and scores decreased in 66.7% of the patients. A correlation was observed between the T0 level of ferritin and the amount of change in BDI and SF-12 mental score between T0 and T1 (Spearman rho = -0.56 and +0.61, respectively) and IL-4 level at T0 and the change in BDI and SF-12 mental scores (Spearman rho = -0.49 and +0.45, respectively). BDI, SF-12, IL-4 and ferritin are good tools to predict the appearance of depressive symptoms and worsening of the quality of life in the HCV+ population.

LIPID PEROXIDATION AND SERUM CYTOKINES IN ACUTE ALCOHOLIC HEPATITIS

Increased exposure of Kupffer cells to intestinal-borne Gram-negative bacteria enhances the metabolism and leads to cytokine production by these cells. Activation of Kupffer cells increases free radical release, which may, in turn, enhance cytokine secretion, creating a positive feedback loop, which contributes to liver inflammation. Cytokines act on T cells, inducing their proliferation and secretion of additional interleukins. Lipid peroxidation products (malondialdehyde; MDA) form adducts with proteins and acetaldehyde, triggering a T cell immune response. Controversy exists about the predominance of either Th-1 or Th-2 cellular responses. We performed the present study in order to analyse the cytokine pattern in patients with acute alcoholic hepatitis, its relation to MDA and the relation between all these parameters and liver function and prognosis. The study included 53 male alcoholics, 47 followed up for a median time of 32 months, during which 17 of them died. We measured serum MDA, tumour necrosis factor-alpha, interferon gamma (IFNG) and interleukins (IL) 4, 6, 8, and 10. MDA levels were raised in cirrhotics and non-cirrhotics with alcoholic hepatitis, maintaining a relationship with bilirubin and Maddrey index, and with mortality in the univariate analysis. Both IFNG and IL-4 were raised in our patients compared with controls, as well as IL-8, and IL-6, but IL-10 were below the detection limit in the majority of cases, especially in cirrhotics. Using a Cox regression model, Maddrey index displaced MDA in the survival analysis. Our data lend support to the hypothesis that activation of both Th-1 and Th-2 cell subsets take place. MDA levels are raised in alcoholics with alcoholic hepatitis and are closely related to liver function derangement and to survival, although this is displaced by Maddrey index using Cox regression model.

Inflammatory cell and cytokine patterns in patients with chronic polyarthritis and temporomandibular joint involvement

Objective. To investigate the occurrence of selected markers for inflammatory cells and cytokines in patients with chronic polyarthritis (CPA) and temporomandibular joint (TMJ) involvement. Material and Methods. Eleven patients (11 joints) with CPA and TMJ disorder were included in the study. Synovial specimens were obtained during TMJ open surgery and these were subjected to immunohistochemistry on frozen sections post-fixed with paraformaldehyde and with the cell membranes permeabilized by saponin. In all patients, the cytokines IL-1α, IL-1β, IL-1ra, TNFα, IFNγ, IL2, and TGFβ were investigated using specific antibodies. The occurrence of macrophages and T-lymphocytes was investigated using immunohistochemistry with monoclonal antibodies against antigens CD68 and CD45RO, respectively. In addition, PCNA was used as a marker for cell proliferation. Results. Staining of IL-1α, IL-1, and TGF was seen in all 11 specimens, IFN? in 1, TNFα in 4, and IL-2 in none. CD45RO-positive T cells were detected in 7 specimens, CD68-positive macrophages in 6, and cell proliferation seen with PCNA was noted in 8. Conclusions. The predominant cytokines of TMJ CPA were IL-1α, IL-1β, and TGFβ, and there appeared to be no differences between the subgroups (rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis) involved. Moreover, the cytokine pattern of TMJ CPA patients seemed to differ from patients with osteoarthritis, as shown in our previous study. The main difference was the absence of IFNγ and TNFα in TMJ CPA patients and a stronger TGFβ and IL-1α expression.

Activated nuclear factor-kappa B and cytokine profiles in the esophagus parallel tumor regression following neoadjuvant chemoradiotherapy

Esophageal adenocarcinoma is increasing in incidence; it relates to chronic gastroesophageal reflux, it is difficult to cure, and treatment modalities increasingly use chemotherapy and radiation therapy prior to resectional surgery. Nuclear factor-kappa B (NF-kappaB) is a pleiotropic transcription factor that regulates several genes for cytokines and enzymes involved in inflammation and immunity, and we have previously described sequential expression of NF-kappaB from the normal esophagus through Barrett's metaplasia to adenocarcinoma. The aim of this exploratory study was to assess the NF-kappaB status and cytokine profiles pre- and post-chemoradiotherapy for esophageal adenocarcinoma. Fresh biopsy specimens obtained from 20 patients with esophageal adenocarcinoma and normal adjacent squamous epithelium were obtained pre-, during and post-chemoradiotherapy, and NF-kappaB expression was analyzed by electrophoretic mobility shift assay. The cytokine protein content of interleukin-1 beta (IL-1beta) and interleukin-8 (IL-8) of tissue homogenates was measured using the ELISA technique. NF-kappaB was constitutively activated in tumor tissues from esophageal adenocarcinoma but was not detected in adjacent normal esophageal mucosa. Elevated levels of IL-1beta and IL-8 were significantly (P < 0.05) higher in tumor tissues compared to control tissues. Patients with a major or complete pathological response (responders) were associated with absence of activated NF-kappaB from nuclear extracts after treatment. Moreover, IL-1beta and IL-8 levels were significantly (P < 0.05) down-regulated in tumor tissues from patients who demonstrated a complete pathological response. No differences in NF-kappaB, IL-1beta and IL-8 levels were detected pre- and post-treatment in patients who did not have a major or complete pathological response (non-responders). The study suggests that monitoring of molecular and cytokine patterns in patients undergoing this neoadjuvant regimen may help subselect the cohort that derives most benefit from the multimodal approach.

Interleukin (IL)‐4, IL‐10, IL‐18 and IFN‐γ Cytokines Pattern in Patients with Combined Hepatitis C Virus and Schistosoma mansoni Infections‡

Schistosoma mansoni infection is characterized by a strong T-helper type 2 (Th2) cell-associated immune response, but in the case of viral infection, it is associated with interferon-gamma (IFN-gamma) increase and induction of Th1 immune response. Few data are available about the immune response of cases infected with combined hepatitis C virus (HCV) and schistosomiasis. Thus, the investigation of the cytokine pattern in patients coinfected with both HCV and Schistosoma mansoni was our rationale. This study included four patient groups: Group 1 included 20 patients infected with chronic HCV, Group 2 included 15 patients infected with schistosomiasis alone, Group 3 included 20 patients with chronic HCV and schistosomiasis and Group 4 included 15 healthy control individuals with matched age and sex. Serum levels of IFN-gamma, interleukin (IL)-4, IL-10 and IL-18 were measured in all groups by enzyme-linked immunosorbent assay. The results showed that the patients infected with HCV had significantly higher serum levels of IFN-gamma and IL-18 compared with the controls and with the patients with schistosomiasis and coinfection (P < 0.001). On the other hand, serum levels of IL-4 and IL-10 were significantly higher in patients with schistosomiasis and coinfection compared with the control group (P < 0.001 and 0.0001, respectively) and with the HCV patients (P < 0.05 and P < 0.001, respectively). A significant increase in serum levels of IL-4 and IL-10 was also found in HCV patients compared with the control (P < 0.05). Schistosomiasis appears to induce a Th2 cytokine profile, with increase in serum levels of IL-4 and IL-10, even in the presence of HCV coinfection. In conclusion, schistosomiasis may downregulate the stimulatory effect of HCV on Th1 cytokines and this may lead to the chronicity of HCV infection in coinfected patients.

The effect of budesonide on the cytokine pattern in patients with perennial allergic rhinitis

A T(H)2-polarized cytokine pattern has been demonstrated in allergic rhinitis. Budesonide represents an effective topical corticosteroid in the management of allergic rhinitis. To evaluate cytokine pattern and symptoms in patients with perennial allergic rhinitis before and after treatment with intranasal budesonide. All patients received budesonide aqueous nasal spray or placebo for 2 weeks. The study was double-blind, parallel group, placebo controlled, and randomized. Nasal lavage was performed in all patients before and after treatment. A panel of cytokines, including interleukin 4 (IL-4), IL-5, and IL-6, was measured by immunoassay on fluids recovered from nasal lavage. Total symptom score (including rhinorrhea, nasal itching, sneezing, and nasal obstruction) was evaluated before and after treatment. Twenty patients with perennial allergic rhinitis were evaluated (13 men and 7 women; mean age, 24.7 years). Budesonide aqueous nasal spray treatment showed a significant decrease of IL-4 (P = .007), IL-5 (P = .04), and IL-6 levels (P = .009). Budesonide aqueous nasal spray treatment also induced significant symptom relief (P = .006). Placebo treatment did not significantly affect the evaluated parameters. This study shows that budesonide aqueous nasal spray is effective in exerting immunomodulatory activity by reducing cytokine pattern and relieving symptoms. These findings are evidence of the effects of intranasal budesonide in treating perennial allergic rhinitis.

Inflammatory cell and cytokine patterns in patients with painful clicking and osteoarthritis in the temporomandibular joint

Abstract.The occurrence of a subset of cytokines and leukocytes in the posterior disc attachment area of the temporomandibular joint (TMJ) was investigated in two patient groups, i.e, one group with painful clicking and one with osteoarthritis. Synovial biopsies were taken during discectomy in 19 patients with painful clicking and 20 with osteoarthritis. One set of specimens was examined with immunohistochemistry, using frozen sections postfixed by para-formaldehyde and with the cell membranes permeablized in saponin. These sections were incubated with antibodies against cytokines IL-1α, IL-1β, IL-1ra, TNFα, IFNγ, IL2 in all patients and TGFβ1,2,3 in 16. The other set of specimens was used to characterize cell infiltrates using immunohistochemistry with monoclonal antibodies against antigens CD68 and CD45RO, respectively. Moreover, PCNA was included as a marker for cell proliferation.The cytokine staining was most frequently positive for IL-1α and IL-1β in both patient groups. However, joints with OA showed a more complex cytokine pattern, also involving IFN-γ (P=0.019), IL-ra (P=0.047), and apparently but without reaching the chosen level of significance, IL-2, TNF-α and TGF-β1,2,3.Positive staining for CD45RO was frequent in both groups. OA patients showed more frequently positive staining for CD68 (P=0.025) and apparently for PCNA.