The activation of the inflammatory cytokines in overweight patients with mild obstructive sleep apnoea

It is widely accepted that obstructive sleep apnoea (OSA) is linked with cardiovascular diseases. The relationship is complex and remains still poorly understood. The presence of chronic systemic inflammation has been connected with pathogenesis of both OSA and cardiovascular diseases. While atherogenesis is believed to be a process of many years, little is known about the potential impact of the largest OSA subgroup, mild OSA, on the development of cardiovascular diseases. The aim of the present study was to assess whether untreated mild OSA is associated with an activation of inflammatory cytokine system. The adult study population consisted of two groups: 84 patients with mild OSA [apnoea–hypopnoea index (AHI) 5–15 h^?1] and 40 controls (AHI <5 h^?1). Serum concentrations of pro‐ and anti‐inflammatory cytokines were measured before any interventions. After adjustments for age, sex, body mass index, fat percentage, most important cardiometabolic and inflammatory diseases, and non‐steroidal anti‐inflammatory medication, the mean level of tumour necrosis factor‐α was significantly elevated (1.54 versus 1.17 pg mL^?1, P = 0.004), whereas the level of interleukin‐1β (IL‐1β) was reduced (0.19 versus 0.23 pg mL^?1, P = 0.004) in patients with mild OSA compared with controls. The concentrations of the protective anti‐inflammatory cytokines, interleukin‐10 (1.28 versus 0.70 pg mL^?1, P < 0.001) and interleukin‐1 receptor antagonist (478 versus 330 pg mL^?1, P = 0.003) were elevated in the OSA group. The concentrations of C‐reactive protein increased, but IL‐1β decreased along with the increase of AHI. Mild OSA was found to be associated not only with the activation of the pro‐inflammatory, but also with the anti‐inflammatory systems.     

下颈椎骨折脱位合并脊髓损伤早期急救治疗对预后的影响

目的探讨下颈椎骨折脱位合并脊髓损伤的早期治疗方法和护理注意事项及其对预后的影响。方法回顾性分析183例伤后3 d内入院的颈椎骨折脱位合并脊髓损伤患者,其中男性120例,女性63例;年龄17~81岁,平均年龄36.5岁。入院时间均在受伤后3d内,平均26h(2~68h),所有患者均发生不同程度四肢瘫痪,按照Frankel分级:A级95例,B级28例,C级20例,D级40例。脊髓损伤水平:C23例,C311例,C429例,C584例,C637例,C719例。受伤类型:高处坠落伤21例,车祸伤162例。结果日本骨科学会(JOA)评分术前(4.2±1.8)分,术后1周(7.9±2.2)分,末次随访(10.0±2.0)分。术后1周、末次随访与术前比较差异均有显著统计学意义(P0.01)。8 h内行甲强龙冲击治疗65例,行早期气管切开38例,行前路手术110例,后路手术42例,前后路联合手术31例。死亡3例,低蛋白血症20例,肺感染6例,深静脉血栓2例。结论早期正确的治疗措施可有效提高颈椎骨折脱位合并脊髓损伤的疗效,降低其并发症的发生。     

Serum and blister fluid levels of cytokines and chemokines in pemphigus and bullous pemphigoid

Bullous pemphigoid and pemphigus constitute two major autoimmune blistering diseases (AIBD) with complicated disease pathomechanisms involving a multitude of cytokines and immunological pathways. The purpose of our literature review of the cytokines and chemokines involved in these AIBDs was to allow for a meta-analysis of studies detailing differential cytokine and chemokine changes in these conditions. Elucidation of inflammatory pathways could lead to more targeted therapies, several of which specific monoclonal antibodies already exist and are used safely for other autoimmune diseases. A systematic review of the Pubmed/Medline database was performed for articles characterizing cytokines/chemokines involved in BP and pemphigus. Further, a meta-analysis was carried out using standardized methods, including assessment for heterogeneity. The results of our analysis demonstrated numerous inflammatory alterations in these AIBDs. Significant alterations included serum levels of IL-5, IL-6, IL-8, IL-17, CCL-17, and CCL-26 in patients with BP, and increased blister fluids levels of IL-5, IL-6, IL-8, CCL11, and TNF-α. Blister fluid levels of IL-1α are decreased in BP. In pemphigus, we identified significantly increased serum levels of IL-10, IL-17, and CCL17. We have additionally summarized all studies excluded from meta-analysis to provide a comprehensive summary of cytokine/chemokine alterations in these two conditions.     

Differences in regulatory pathways identify subgroups of T cell-derived Th2 cytokines

We analysed regulatory mechanisms involved in the production of Th2 cytokines by freshly isolated human T cells. We used an in vitro culture system in which the primary signal was provided by a cross-linking anti-CD3 MoAb presented on the Fc receptors of P815 cells. Both CD80 and CD86, expressed on transfected P815 cells, were able to provide efficient costimulation for the production of IL-4, IL-5 and IL-13. IL-2 was also highly important for induction of all three Th2 cytokines. However, differences between IL-4 on the one hand and IL-5 and IL-13 on the other hand were observed when sensitivity to cyclosporin A (CsA) was studied. CsA (an inhibitor of calcineurin phosphatase activity) strongly inhibited IL-4 production, but it did either not affect or even increased IL-5 and IL-13 production. In accordance with this, CD80 and phorbol myristate acetate (PMA) (without anti-CD3 or calcium ionophore) were sufficient to induce production of IL-5 and IL-13, but not of IL-4. The subgrouping of Th2 cytokines was further confirmed at another level on the basis of differences in cell sources: IL-4 was predominantly produced by CD4+ T cells, while IL-5 and IL-13 were produced by both CD4+ and CD8+ T cells. Thus, differences in cell sources and in the requirement of the calcium/calcineurin-signalling pathway allowed us to identify two subgroups (IL-4 and IL-5/IL-13) among human Th2-type T cell cytokines.     

Expression profiles of cytokines and chemokines in murine MDR1a-/- colitis

Objective: MDR1a-/- mice spontaneously develop colitis as the result of imperfect epithelial barrier derived from MDR1a deficiency in the large intestine; however, the pathogenesis is not well understood. This study investigated the expression profiles of cytokines and chemokines in murine MDR1a-/- colitis. Methods: MDR1a-/- and wild-type FVB mice were monitored from the 6^th to the 16^th week of age. Production of various cytokines and chemokines in the large intestine and mesenteric lymph node (MLN) cells was examined. Results: Inflammatory cell infiltration, IL-1β production, and MPO activity were aberrantly enhanced in the tissue of MDR1a-/- mice. Under various stimuli, MLN cells produced higher levels of Th1-type (IFN-γ, IL-2, and IL-12) and proinflammatory (IL-1β and TNF-α) cytokines. Inflammatory chemokines MIP-2/CXCL2, KC/CXCL1, MIP-1α/CCL3, MCP-1/CCL2, and RANTES/CCL5 were also markedly upregulated in the tissue. Conclusion: Since the expression profiles of cytokines and chemokines correspond well with those in human IBD, MDR1a-/- mouse is a useful model for the analysis of IBD pathophysiology. Received 12 May 2006; returned for revision vision 15 July 2006; accepted by I. Ahnfelt-R?nne 18 January 2007     

缺血性脑卒中患者急性期血清C反应蛋白水平与预后的关系

目的 探讨急性脑梗死患者血清C反应蛋白（CRP）水平与疾病预后的相关性方法。方法 对80例脑梗死患者（脑梗死组）、20例腔隙性脑梗死患者（腔梗组）和40名健康体检者（对照组）血清CRP含量进行测定，计算其异常率并进行比较。按脑卒中患者临床神经功能缺损程度评分（NHISS）标准对患者进行评分。结果 脑梗死组CRP含量高于腔梗组，腔梗组高于对照组（均P〈0.01）；脑梗死组中，CRP异常率高于腔梗组（P〈0．05）；CRP异常的患者NHISS的评分的改善低于CRP正常组，且CRP异常者预后中无变化和死亡明显高于正常对照者（均P〈0．01）。结论 CRP水平是临床评价脑梗死严重程度和预后的一个重要的生物学指标。     

Interleukin-6 as a predictor of subclinical chorioamnionitis in preterm premature rupture of membranes

Citation Gulati S, Bhatnagar S, Raghunandan C, Bhattacharjee J. Interleukin‐6 as a predictor of subclinical chorioamnionitis in preterm premature rupture of membranes. Am J Reprod Immunol 2012; 67: 235–240 Problem One of the major challenges faced by the clinicians in preterm premature rupture of the membranes (PPROM) is to correctly identify when a significant chorioamnionitis is evolving and decide timely delivery of the fetus. Measuring interleukin‐6 levels in maternal serum can be useful for the identification of asymptomatic intrauterine infections in subjects with PPROM. Method of study A total of 75 pregnant women, of which 45 pregnant women presenting with PPROM between 24 and 34 weeks gestation and 30 healthy pregnant women without PPROM, were included in the study. Serum IL‐6 levels were determined by solid‐phase sandwich enzyme‐linked immunosorbent assay (Diaclone Research, Besancon, France). Results The mean serum IL‐6 value at admission in the control group was 2.48 ± 2.7 pg/mL and in the study group was 11.86 ± 14.5 pg/mL (P = 0.001). Mean serum IL‐6 concentrations at admission in subjects without histological chorioamnionitis were 3.98 ± 3.9 pg/mL and in those who had histological chorioamnionitis were 20.09 ± 16.8 pg/ml (P < 0.001). Conclusion Maternal serum IL‐6 levels were significantly elevated in subjects with PPROM with infectious morbidity as compared to those without infectious morbidity in the present study. There was a significant rise in maternal serum IL‐6 levels with increased duration of rupture of membranes and with evidence of histological chorioamnionitis and funisitis in the placenta.     

类风湿关节炎患者血清和关节液细胞因子水平的变化及临床意义

目的探讨幼年类风湿关节炎(JRA)及类风湿关节炎(RA)患者IL-6、IL-8、sIL-2R和TNF-α等细胞因子(CK)水平的变化,及其与风湿活动的传统指标血沉(ESR)和C-反应蛋白(CRP)的相关性。方法采用夹心ELISA法,对30例JRA和34例RA患者的血清中,4例JRA、7例RA、6例骨性关节炎(OA)和9例半月板损伤(MT)患者的关节液中IL-6、IL-8、sIL-2R和TNF-α的水平进行检测。结果①30例JRA、34例RA患者血清IL-6和sIL-2R的水平与对照组相差非常显著(P〈0.01);30例JRA患者血清IL-8水平与对照组比较相差显著(P〈0.05)。②JRA全身型、少关节型患者血清IL-8、sIL-2R的水平和JRA多关节型患者血清IL-6的水平与对照组相差非常显著(P〈0.01)。③4例JRA及7例RA患者关节液sIL-2R的水平和RA患者关节液的IL-6水平与对照组相差显著(P〈0.05)。④JRA患者血清IL-6和sIL-2R的水平与ESR和CRP的变化呈明显的相关关系(r值分别为0.532和0.621)。结论①IL-6、sIL-2R的水平与JRA、RA病的活动性有关,是类风湿活动性的主要指标。②sIL-2R不仅参与JRA和RA的全身病理损伤,而且是引起关节局部损伤的主要CK,IL-6也参与JRA关节局部的病理损伤,在RA关节局部损伤似乎更为重要。③IL-8主要参与JRA的全身病理损伤,对关节局部病理损伤似乎并不重要。     

The role of Th2 cytokines, chemokines and parasite products in eosinophil recruitment to the gastrointestinal mucosa during helminth infection

Trichinella spiralis and Trichuris muris are nematode parasites of the mouse, dwelling in the small and large intestines, respectively: worm expulsion requires development of a Th2 immune response. The chemokine CCL11 is agonist for the chemokine receptor CCR3 and acts in synergy with IL-5 to recruit eosinophils to inflammatory sites. The role of CCL11 in gastrointestinal helminth infection has not been previously studied. We challenged wild-type (WT) BALB/c, CCL11 single knockout (SKO) and CCL11 IL-5 double knockout (DKO) mice with either T. spiralis muscle larvae or T. muris eggs in order to examine eosinophil recruitment to the small and large intestine during helminth infection. A peripheral eosinophilia was seen in WT and SKO mice during T. spiralis infection but not with T. muris. Gastrointestinal eosinophilia was markedly reduced but not ablated in SKO mice -- and negligible in DKO mice -- infected with either nematode. The residual eosinophilia and up-regulation of CCL24 mRNA in the gastrointestinal tract of SKO mice infected with either nematode, together with the presence of an eosinophil-active factor in T. spiralis and T. muris products, suggest that CCL11 is the salient but not the sole eosinophil chemoattractant of biological significance during gastrointestinal helminth infection.     

Modulation of cytokine and chemokine secretions in rhesus monkey trophoblast co-culture with decidual but not peripheral blood monocyte-derived macrophages

Citation
Rozner AE, Dambaeva SV, Drenzek JG, Durning M, Golos TG. Modulation of cytokine and chemokine secretions in rhesus monkey trophoblast co‐culture with decidual but not peripheral blood monocyte–derived macrophages. Am J Reprod Immunol 2011; 66: 115–127 Problem Decidual macrophages are thought to promote pregnancy success, in part through interactions with invading trophoblast cells in hemochorial placentation. However, the factors that constitute this regulatory cross talk are not well understood. Method of study Rhesus monkey decidual and peripheral blood–derived macrophages were co‐cultured with primary Rhesus trophoblasts. Macrophage functions including cell‐surface marker expression, antigen uptake and processing, in vitro migration, and cytokine and chemokine secretions were evaluated. Results While most macrophage functions were unchanged by trophoblast co‐culture, changes in the secretion of selected cytokines and the migration of trophoblasts were noted when decidual (but generally, not peripheral blood monocyte–derived) macrophages were cultured with trophoblasts. In addition, basal secretion differed significantly between peripheral blood–derived and decidual macrophages for a broad spectrum of cytokines. When trophoblasts were pre‐treated with an anti‐Mamu‐AG antibody, 25D3, there was no change in cytokine or chemokine secretion. Conclusion Macrophage cytokine expression can be modulated by trophoblast co‐culture, but it remains unclear how Mamu‐AG is involved.     

Occurrence of C-reactive protein in cryoglobulins

A previous case report described the formation of a complex between a monoclonal IgA with cryolabile properties and C-reactive protein (CRP). Our study provides the first evidence for the frequent occurrence of CRP in cryoglobulins (Cg) of all three types according to Brouet's classification. We performed a systematic immunochemical analysis of cryoglobulins from 18 patients by Western blotting and in 15 of 18 cryoprecipitates a single band (23 KD), immunoreactive with anti-CRP antibody, was demonstrable irrespective of the clonal composition of the cryoglobulins. This band was detectable in 4/5 of type I, in 6/8 of type II, and in 5/5 of type III cryoprecipitates, classified according to Brouet et al. In addition, the complement proteins C1q and C3 were present in nearly all CRP-containing cryoglobulins, presumably reflecting previous activation of the classical complement pathway at least. All three CRP-negative cryoprecipitates were derived from sera with low cryoglobulin content (1-2 g/l). Longitudinal investigation of 23 cryoprecipitates from seven patients confirmed that successful detection of CRP by Western blotting depends on the protein concentration of the cryoglobulins. Since complexed CRP was previously shown to be an effective activator of complement, via C1q binding, CRP may modulate pathophysiologic effects mediated by cryoglobulins in vivo.     

Distribution of interleukin‐10 family cytokines in serum and synovial fluid of patients with inflammatory arthritis reveals different contribution to systemic and joint inflammation

Evidence exists that interleukin (IL)‐10 family cytokines may be involved in the pathogenesis of rheumatoid arthritis (RA). We sought to determine whether or not these cytokines are involved in psoriatic arthritis (PsA). We conducted a prospective study on patients with PsA, RA and osteoarthritis (OA); healthy controls (HC) were also included. We analysed IL‐20, IL‐24 and IL‐19 serum and synovial fluid (SF) levels and change of serum levels following treatment with biological agents. IL‐20 serum levels were increased in PsA and RA compared with OA patients and HC and with matched SF levels. IL‐24 serum levels in PsA, RA and OA patients were higher than those in HC and also with respect to matched SF in PsA. IL‐19 serum levels were higher in HC and OA compared with PsA and RA patients; IL‐19 SF levels were higher in PsA and RA compared with OA patients, and in PsA compared with RA patients. PsA and RA patients showed a reduction of IL‐19 serum levels after biological treatment. Therefore, IL‐19 seems to be involved mainly in the joint inflammation, whereas IL‐20 and IL‐24 appear to participate mainly in the systemic responses. These findings may further the comprehension of the contribution of these cytokines to the inflammatory response involved in chronic arthritis, as well as to the development of novel therapeutic strategies.     

Role of chemokines in metastatic niche: new insights along with a diagnostic and prognostic approach

Chemokines are cytokines that are involved in the movement of leukocytes and the occurrence of immune responses. It has recently been noted that these cytokines play a role in the movement of cancer cells to different parts of the body and create a suitable environment [i.e. (pre) metastatic niche] for their growth and proliferation. We studied the role of chemokines in the metastasis of cancer cells, as well as their involvement in the proliferation and growth of these cells. Relevant literature was identified by a PubMed search (2005–2017) of English language papers using the terms ‘chemokine,’ ‘metastasis niche,’ and ‘organotropism.’ Based on the nature of cancer cells, the expression of chemokine receptors on these cells leads to metastasis to various organs, which ultimately causes changes in different signaling pathways. Finally, the targeting of chemokines on cancer cells could prevent the metastasis of cancer cells toward different organs.     

Induction of cytokines and anti-cytokine autoantibodies in cerebrospinal fluid (CSF) during experimental bacterial meningitis

We have recently described the induction of anti-cytokine autoantibodies (Aabs) in the serum as a novel mechanism for cytokine regulation during bacterial infections. Here we use the infant rat-model of Haemophilus influenzae type b (Hib) meningitis to examine the induction of five potentially important cytokines and their autoantibody responses in the CSF. Protein levels of the cytokines interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), IL-4 and IL-10 were detected at day 3 post-inoculation (p.i.) with maximum induction at day 8. Thereafter, these levels of cytokines had become undetectable. Increased Aab titres to these cytokines, except IL-4, were registered with peak levels between days 7 and 9. Upon re-inoculation with Hib at day 30, regeneration of Aabs was recorded 7 days later (i.e. at day 37). To control the specificity of these Aabs, preincubation of the CSF with a cytokine inhibited the binding effects of that particular cytokine, but not those of any other cytokine. Aabs dose-dependently inhibited IFN-γ-induced MHC expression by peritoneal macrophages and TNF-α-mediated L929 cytotoxicity. Our data demonstrate for the first time the existence of the anti-cytokine antibodies in the CSF of the meningitis Hib model. Furthermore, the data present a role for the Aabs in cytokine regulation, which is consistent with the previously demonstrated effects of the Aabs in the serum.     

Circulating cytokines and chemokines in acute symptomatic parvovirus B19 infection: negative association between levels of pro-inflammatory cytokines and development of B19-associated arthritis

The aim of the study was to characterise the profile and clinical correlates (arthritis, rash, and fatigue) of cytokines, chemokines, and other mediators in symptomatic acute parvovirus B19 infection. Serum was examined from cases of acute B19 infection (as defined by serum anti-B19 IgM positivity) (n = 84), and in normal persons (n = 43) for B19 markers (serum B19 antibodies and DNA), rheumatoid factor (RF), and antinuclear antibody (ANA). A panel of cytokines/chemokines was measured in duplicate using the Bioplex Protein Array system (BioRad Hemel Hempstead, UK). These included interleukin-1 beta (IL-1 beta), IL-4, IL-5, IL-6, IL-8, IL-13, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), macrophage chemoattractant protein-1 (MCP-1), granulocyte-monocyte colony stimulating factor (GM-CSF), transforming growth factor-beta1 (TGF-beta 1), endothelin-1 (ET-1), and neopterin. Acute symptomatic infection was characterised by specific IgG positivity (83%), serum B19 DNA positivity (96%), and raised levels of IL-4, IL-6, IL-8, TNF-alpha, IFN-gamma, MCP-1, GM-CSF, TGF-beta 1, and ET-1. Patients with acute B19-associated arthritis were found to have lower levels of IL-6, TNF-alpha, and GM-CSF than patients without arthritis, while those with rash had lower levels of TGF-beta 1. It is concluded that cytokine levels following acute symptomatic infection with parvovirus B19 indicate a state of immune activation. The profile of circulating mediators may provide insights into the possible pathogenesis of particular clinical manifestations of this infection.     

Influence of mid-trimester amniotic fluid on endogenous and lipopolysaccharide-mediated responses of mononuclear lymphoid cells

PROBLEM We evaluated the influence of amniotic fluid (AF) on immune mediator production by mononuclear leukocytes. METHOD OF STUDY Thirty mid-gestation AFs were incubated with peripheral blood mononuclear cells (PBMCs) in the presence or absence of lipopolysaccharide (LPS). Supernatants were tested for interleukin (IL) - 6, 10, 12, 23, tumor necrosis factor-α (TNF-α) and monocyte chemotactic protein (MCP)-1. RESULTS Endogenous mediator production was minimal or non-detectable. AF stimulated endogenous MCP-1, IL-6 and TNF-α release. In the presence of LPS, production of MCP-1 and IL-10 by PBMCs was enhanced eight- to ninefold by AF. Release of IL-6 and IL-23 was enhanced less than twofold by the addition of AF while TNF-α production was unchanged. AF-stimulated mediator production was similar irrespective of pregnancy outcome. CONCLUSION Selective AF stimulation of LPS-mediated MCP-1 and IL-10 release may be a mechanism to promote antibody production and the influx of phagocytic cells to engulf pathogens while downregulating the production of pro-inflammatory cytokines.     

C‐reactive protein levels in hereditary angioedema

Hereditary angioedema (HAE) patients experience recurrent episodes of angioedema attacks that can be painful, disfiguring and even life‐threatening. The disorder results from a mutation in the gene that controls the synthesis of C1‐inhibitor (C1INH). C1INH is a major regulator of activation of the contact system. It is often assumed that attacks results from uncontrolled local activation of the contact system with subsequent formation of bradykinin. To evaluate the involvement of inflammatory reactions in HAE, we analysed C‐reactive protein (CRP) levels. HAE patients included in a clinical database of recombinant human C1‐inhibitor (rhC1INH) studies were evaluated. For the current study we analysed CRP levels when patients were asymptomatic, during a clinical attack and in a follow‐up period, and correlated these with the clinical manifestations of the attack. Data from 68 HAE patients were analysed and included CRP levels on 273 occasions. While asymptomatic, 20% of the patients analysed had increased CRP. At the onset of the attack (P = 0·049) and during the next 24 h CRP rose significantly (P = 0·002) in patients with an abdominal location, and post‐attack levels were significantly higher in these patients than in patients with attacks at other locations (P = 0·034). In conclusion, CRP levels are elevated in a substantial proportion of asymptomatic HAE patients. Levels of CRP increase significantly during an abdominal attack. These data suggest low‐grade systemic inflammatory reactions in HAE patients as well as a triggering event for attacks that starts prior to symptom onset.