The role of IL-6 and IL-1β in painful perineural inflammatory neuritis

Inflammation along a nerve trunk (perineural inflammation), without detectable axonal damage, has been shown to induce transient pain in the organ supplied by the nerve. The aims of the present study were to study the role IL-6 and IL-1β, in pain induced by perineural inflammation.MethodsIL-6 and IL-1β secretion from rat’s sciatic nerves, L-5 Dorsal Root Ganglia (DRG), and the hind paw skin, 3 and 8 days following exposure of the nerve to Complete Freund’s Adjuvant (CFA), were measured using ELISA method. Hind paw tactile-allodynia, mechano-hyperalgesia, heat-allodynia and electrical detection thresholds were tested up to 8 days following the application of CFA, IL-6 or IL-1β adjacent to the sciatic nerve trunk. Employing electrophysiological recording, saphenous nerve spontaneous activity, nerve trunk mechano-sensitivity and paw tactile detection threshold (determined by recording action potential induced by the lowest mechanical stimulus) were assessed 3 and 8 days following exposure of the nerve trunk to CFA, IL-6, or IL-1β.ResultsIL-6 and IL-1β secretion from the nerve was significantly elevated on the 3rd day post-operation (DPO). On the 8th DPO, IL-6 levels returned to baseline while IL-1β levels remained significantly elevated. The DRG cytokine’s level was increased on the 3rd and 8th DPOs, contralateral cytokine’s level was increased on the 3rd DPO. The skin IL-6 level was increased bilaterally on the 3rd DPO and returned to baseline on the 8th DPO. IL-1β levels increased in the affected side on the 3rd and bilaterally on the 8th DPO. Direct application of IL-6 or CFA on the sciatic nerve induced significant hind paw tactile-allodynia from the 1st to 5th DPOs, reduced electrical detection threshold from the 1st to 3rd DPOs, mechano-hyperalgesia from 3rd to 5th DPOs and heat-allodynia on the 3rd DPO. Direct application of IL-1β induced paw tactile and heat-allodynia on the 7–8th DPOs and mechano-hyperalgesia on the 5–8th DPOs.Perineural inflammation significantly increased spontaneous activity myelinated fibres 3 and 8 days following the application. Direct application of IL-6 induced elevation of spontaneous activity on the 3rd while IL-1β on the 8th DPO.Nerve mechano-sensitivity was significantly increased on the 3rd day following exposure to CFA and IL-6 and on the 8th following CFA application. The rat’s paw lowest mechanical force necessary for induction of action potential, was significantly reduced 3 days following CFA application.ConclusionIL-6 and IL-1β play an important role in pain induced by perineural inflammation. IL-6 activity is more prominent immediately following application (2–5th DPOs), while IL-1β, activity is more significant in a later stage (5–8th DPOs).     

Cerebrospinal Fluid TNF-α, IL-6, and IL-8 in Children With Bacterial Meningitis

ObjectiveWe evaluated the levels of cerebrospinal fluid concentrations of tumor necrosis factor-α, interleukin-6, and interleukin-8 in bacterial meningitis in children.MethodsThe study included children up to 14 years of age admitted to a pediatric ward with fever, headache, vomiting, and seizures. The diagnosis of bacterial meningitis was based on clinical features: physical examination, blood and cerebrospinal fluid cytochemical findings, Gram stain, and bacterial culture. The cerebrospinal fluid levels of tumor necrosis factor-α, interleukin-6, and interleukin-8 were measured in 57 children with bacterial meningitis, 15 with viral meningitis, and 15 controls by enzyme-linked immunosorbent assay methods.ResultsThe mean concentrations of cerebrospinal fluid, tumor necrosis factor-α, interleukin-6, and interleukin-8 were 1108 ± 183, 652 ± 287, and 442 ± 120 pg/mL, respectively, in children with bacterial meningitis and were significantly increased in those in the viral meningitis group (tumor necrosis factor-α : 711 ± 105, IL-6 : 272 ± 161, IL-8 : 175 ± 62 pg/mL; P < 0.001) or control (390 ± 37, 59 ± 17, 19 ± 13 pg/mL, respectively, P < 0.001). At optimum cutoff level based on the receiver operating characteristic curve, cerebrospinal fluid cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-8) showed sensitivity and specificity of 100% for the diagnosis of bacterial meningitis. For differentiation of bacterial from viral meningitis, cerebrospinal fluid level of tumor necrosis factor-α, IL-6, and IL-8 showed sensitivity and specificity of 94.7% and 86.7%, 80.7% and 53.3%, and 89.5% and 86.7%, respectively.ConclusionThe increased concentration of cerebrospinal fluid tumor necrosis factor-α, interleukin-6, and interleukin-8 in children with meningitis suggests a role in the pathogenesis of bacterial meningitis and these levels might prove to be useful in children whose diagnosis is in question.     

The role of genetic variation across IL-1β, IL-2, IL-6, and BDNF in antipsychotic-induced weight gain

Objectives. Antipsychotics with high weight gain-inducing propensities influence the expression of immune and neurotrophin genes, which have been independently related to obesity indices. Thus, we investigated whether variants in the genes encoding interleukin (IL)-1β, IL-2, and IL-6 and brain-derived neurotrophic factor (BDNF) Val66Met are associated with antipsychotic-induced weight gain (AIWG). Methods. Nineteen polymorphisms were genotyped using Taqman^® assays in 188 schizophrenia patients on antipsychotic treatment for up to 14 weeks. Mean weight change (%) from baseline was compared across genotypic groups using analysis of covariance (ANCOVA). Epistatic effects between cytokine polymorphisms and BDNF Val66Met were tested using Model-Based Multifactor Dimensionality Reduction. Results. In European patients, IL-1β rs16944*GA (P = 0.013, P_corrected = 0.182), IL-1β rs1143634*G (P = 0.001, P_corrected = 0.014), and BDNF Val66Met (Val/Val, P = 0.004, P_corrected = 0.056) were associated with greater AIWG, as were IL-1β rs4849127*A (P = 0.049, P_corrected = 0.784), and IL-1β rs16944*GA (P = 0.012, P_corrected = 0.192) in African Americans. BDNF Val66Met interacted with both IL-1β rs13032029 (Val/Met+ TT, P_Perm = 0.029), and IL-6 rs2069837 (Val/Val+ AA, P_Perm = 0.021) in Europeans, in addition to IL-1β rs16944 (Val/Val+ GA, P_Perm = 0.006) in African Americans. Conclusions. SNPs across IL-1β and BDNF Val66Met may influence AIWG. Replication of these findings in larger, independent samples is warranted.     

Decreased IFN-γ and IL-12 levels in panic disorder

ObjectiveThe aim of this study is to assess the measures of proinflammatory cytokines in patients with panic disorder in comparison with the healthy subjects.MethodsTwenty three patients with panic disorder with or without agoraphobia and twenty three controls were recruited for the study. Plasma samples of all subjects were analyzed for TNF-α, IFN-γ, IL-1β, IL-2, IL-6, and IL-12 concentrations and NK-cell activity is measured in the peripheral blood samples of the subjects.ResultsWe found significant differences on the mean values of IL-12 (p = 0.01) and IFN-γ (p = 0.02) between the panic disorder and control groups. In a logistic regression analysis, IFN-γ values were significant statistical predictors of the presence of panic disorder (B = ? 0.07, SE = 0.03, p = 0.04).ConclusionThe most important implication of our results is to suggest a relation between panic disorder and low levels of IFN-γ, compatible with the results of the animal studies showing that IFN-γ plays a role by acting to regulate the development of anxiety-like behaviors.     

Association between plasma levels of transforming growth factor-β1, IL-23 and IL-17 and the severity of autism in Egyptian children

It has been recently shown that dysregulation of transforming growth factor-β1 (TGF-β1), IL-23 and IL-17 has been identified as a major factor involved in autoimmune disorders. Based on the increasing evidence of immune dysfunction in autism the aim of this study was to measure serum levels of TGF-β 1, IL-23 and IL-17 in relation to the degree of the severity of autism. Serum TGF-β1, IL-23 and IL-17 were measured by Enzyme-linked Immunosorbent Assay technique in 50 autistic children aged 6–12 years, in comparison to 50 developmental disabilities and 50 typically developing-matched children. The severity of autism was assessed by using the Childhood Autism Rating Scale. We found that TGF-β1 and IL-23 levels were significantly decreased in the plasma of children with ASD in comparison to control groups (P < 0.0001 for both) with no significant difference in IL-17 levels. There was no correlation between IL-23 and TGF-β1 with IL-17 in children with ASD. There was a negative correlation between TGF-β1, IL-23 and IL-17 with the severity of autism (P < 0.0001, 0.0001, 0.005 respectively). Our results support the findings that immune dysfunction may occur in some children with autism.     

Lack of association between IL-1β, TNF-α, and IL-10 gene polymorphisms and sporadic Parkinson's disease in an Italian cohort

Pascale E, Passarelli E, Purcaro C, Vestri AR, Fakeri A, Guglielmi R, Passarelli F, Meco G. Lack of association between IL‐1β, TNF‐α, and IL‐10 gene polymorphisms and sporadic Parkinson’s disease in an Italian cohort.
Acta Neurol Scand: 2011: 124: 176–181.
© 2010 John Wiley & Sons A/S. Objective – There is increasing evidence suggesting that neuroinflammation and microglia activation may play important roles in the pathway leading to neuronal cell death in Parkinson’s disease (PD). Chronic activation of microglia may cause neuronal damage through the release of potentially cytotoxic molecules, such as pro‐inflammatory cytokines. Different functional promoter polymorphisms within genes coding pro‐ or anti‐inflammatory cytokines involved in the immune reactions in the brain might influence the risk of developing PD or the age of disease onset. Aim – To investigate the interleukin (IL)‐1β‐511, tumor necrosis factor alpha (TNF‐α)‐308, and interleukin (IL)‐10‐1082 gene polymorphisms as susceptibility factors for PD. Methods;– We analyzed genotype and allele distributions of these polymorphisms in146 Italian patients with PD and 156 healthy controls. Results – None of the polymorphisms we investigated was found to be associated with PD or with age of disease onset. No significant differences between patients with PD and controls were found as regards the concomitant presence of variant alleles in the three polymorphisms studied. We found that only the combined genotype TNF‐α‐308GG/IL‐1β‐511T(+) is associated with a decreased risk of PD. Conclusion – Our results indicate that the cytokine gene polymorphisms we investigated are not related to the development of PD in the Italian population; further studies are warranted to clarify the role of the TNF‐α‐308GG/IL‐1β‐511T(+) combined genotype.     

Microglial IL-10 and β-endorphin expression mediates gabapentinoids antineuropathic pain

Gabapentinoids are recommended first-line treatments for neuropathic pain. They are neuronal voltage-dependent calcium channel α2δ-1 subunit ligands and have been suggested to attenuate neuropathic pain via interaction with neuronal α2δ-1 subunit. However, the current study revealed their microglial mechanisms underlying antineuropathic pain. Intrathecal injection of gabapentin, pregabalin and mirogabalin rapidly inhibited mechanical allodynia and thermal hyperalgesia, with projected ED₅₀ values of 30.3, 6.2 and 1.5 µg (or 176.9, 38.9 and 7.2 nmol) and E_max values of 66%, 61% and 65% MPE respectively for mechanical allodynia. Intrathecal gabapentinoids stimulated spinal mRNA and protein expression of IL-10 and β-endorphin (but not dynorphin A) in neuropathic rats with the time point parallel to their inhibition of allodynia, which was observed in microglia but not astrocytes or neurons in spinal dorsal horns by using double immunofluorescence staining. Intrathecal gabapentin alleviated pain hypersensitivity in male/female neuropathic but not male sham rats, whereas it increased expression of spinal IL-10 and β-endorphin in male/female neuropathic and male sham rats. Treatment with gabapentin, pregabalin and mirogabalin specifically upregulated IL-10 and β-endorphin mRNA and protein expression in primary spinal microglial but not astrocytic or neuronal cells, with EC₅₀ values of 41.3, 11.5 and 2.5 µM and 34.7, 13.3 and 2.8 µM respectively. Pretreatment with intrathecal microglial metabolic inhibitor minocycline, IL-10 antibody, β-endorphin antiserum or μ-opioid receptor antagonist CTAP (but not κ- or δ-opioid receptor antagonists) suppressed spinal gabapentinoids-inhibited mechanical allodynia. Immunofluorescence staining exhibited specific α2δ-1 expression in neurons but not microglia or astrocytes in the spinal dorsal horns or cultured primary spinal cells. Thus the results illustrate that gabapentinoids alleviate neuropathic pain through stimulating expression of spinal microglial IL-10 and consequent β-endorphin.     

IL-18: a key player in neuroinflammation and neurodegeneration?

Interleukin (IL)-18 is a potent inflammatory cytokine of the IL-1 family. It is synthesized as an inactive precursor (pro-IL-18), which is cleaved into its functionally active form by caspase-1. Resident cells of the CNS express IL-18 and caspase-1 constitutively, thus providing a local IL-18-dependent immune response. Recent studies have highlighted a crucial role for IL-18 in mediating neuroinflammation and neurodegeneration in the CNS under pathological conditions, such as bacterial and viral infection, autoimmune demyelinating disease, and hypoxic-ischemic, hyperoxic and traumatic brain injuries. This review provides a synopsis of the current knowledge of IL-18-dependent mechanisms of action during acute neurodegeneration in immature and adult brains.     

Serum BDNF, TNF-α and IL-1β levels in dementia patients

Neurotrophins such as the brain-derived neurotrophic factor (BDNF) are reportedly related to the pathogenesis of Alzheimer's disease (AD). Several studies have revealed an alteration in BDNF expression in the postmortem brains of AD patients. BDNF has great potential as a therapeutic agent because of its ability to cross the blood-brain barrier and due to its wide in vivo distribution. However, little is known about in vivo BDNF in dementia patients. Moreover, the immunological function of neurotrophins such as BDNF has received great interest. Therefore, we investigated the serum levels of BDNF and cytokines such as TNF-alpha and IL-1beta in dementia patients by the enzyme-linked immunosorbent assay (ELISA). The following subjects were included in this study: 60 AD patients, 60 vascular dementia (VaD) patients and 33 healthy controls. AD and VaD patients were matched for age, gender and severity of dementia. Serum BDNF levels in AD patients were significantly lower than those in VaD patients and controls. TNF-alpha and IL-1beta levels showed no significant difference among the three groups. In the dementia groups, neither the TNF-alpha nor the IL-1beta levels correlated with the BDNF levels. Our results suggest that BDNF may play a pathological role in some cases of AD.     

IL-23/IL-17与多发性硬化

多发性硬化(multiple sclerosis, MS)是一种病因未明的中枢神经系统(central nervous system, CNS)炎性脱髓鞘性自身免疫性疾病, 以髓鞘脱失、神经胶质细胞增生、轴索病变、进行性神经功能障碍以及缓解与复发病程等为主要特点.近年来,对于MS病因及发病机制方面进行了大量研究,但观点不一,确切机制仍不明确.目前认为可能是一些携带有先天遗传易感基因的个体有易于发生免疫调节功能紊乱的趋势,在后天环境因素(如病毒感染等)的作用下,诱发异常自身免疫应答,从而导致的中枢神经系统脱髓鞘疾病.     

帕金森病患者IL-2、IL-6、IL-10的检测及临床意义

目的：检测帕金森病（PD）患者血清及脑脊液（CSF）中IL-2、IL-6和IL-10含量,为深入研究细胞免疫与PD的关系及从炎症角度干预提供实验依据.方法：采用双抗体夹心ELISA法测定PD组血清及CSF中IL-2、IL-6和IL-10的含量,并与对照组（同期体检健康者）比较.结果：PD组血清IL-2、IL-6和IL-10含量均高于对照组（ P〈0.01,P〈0.05）;PD组CSF中IL-6含量高于对照组（ P〈0.05）.新发PD患者、服左旋多巴制剂及服非左旋多巴制剂组PD患者血清及CSF中 IL-2、IL-6、IL-10含量与对照组比较,差异均无统计学意义（ P〉0.05）.PD组血清及CSF中IL-2、IL-6、IL-10含量与年龄、病程、Webster评分、Hoehn-Yahr分级分期、UPDRS-Ⅱ和UPDRS-Ⅲ评分间均无相关性.结论：①PD患者存在血清及CSF中IL-2、IL-6和IL-10水平的改变,PD发病与细胞免疫功能失调有关; ②PD细胞免疫状态的改变不能归因于外源性多巴胺的摄入.     

缺血性脑卒中急性期IL-6、IL-8、IL-10变化的观察

目的观察IL-6、8、10在缺血性脑卒中急性期的变化及意义。方法采取双抗体夹心ELISA法对20例缺血性脑卒中患者分别在发病后第1、3、7d和15例健康体检者第1d的血清IL-6、IL-8、IL-10进行检测。结果急性缺血性脑卒中患者与正常健康体检者相比,IL-6、IL-8均在发病后第1、3d明显增高(P<0.05);第7d结果相差不大(P>0.05);IL-10在第1、3、7d逐渐增高(P<0.05)。结论白细胞介素的监测可以为早期临床治疗及康复干预提供试验指标,以便控制脑卒中的进展及复发。     

焦虑症患者血清IL-1β、IL-6、IL-10水平分析

目的研究白细胞介素1β(IL-1β)、白细胞介素6(IL-6)、白细胞介素10(IL-10)在焦虑症患者血清变化及意义。方法选取2017年11月～2018年11月我院收治的42例慢性焦虑症患者和42例抑郁症患者分别作为焦虑组和抑郁组,选择同期42例健康体检者作为健康组。患者均采用选择性5-羟色胺再摄取抑制剂连续治疗8周。比较治疗前后两组患者和对照组的血清IL-1β、IL-6、IL-10水平。结果焦虑组患者IL-6水平显著低于健康组和抑郁组(P0.05);抑郁组患者IL-6水平与健康组比较差异无统计学意义(P0.05)。焦虑组和抑郁组患者IL-10水平均显著高于健康组(P0.05);焦虑组患者IL-10水平与抑郁组比较差异无统计学意义(P0.05)。治疗后两组患者的IL-1β、IL-6、IL-10水平均有显著改善(P0.05),两组患者IL-1β、IL-6、IL-10水平无明显差异(P0.05)。结论焦虑症和抑郁症与健康者可能具有不同免疫机制,可通过血清IL-10和IL-6来鉴别。     

缺血性脑卒中急性期IL-6、IL-8、IL-10变化的观察

目的观察IL-6、8、10在缺血性脑卒中急性期的变化及意义。方法采取双抗体夹心ELISA法对20例缺血性脑卒中患者分别在发病后第1、3、7d和15例健康体检者第1d的血清IL-6、IL-8、IL-10进行检测。结果急性缺血性脑卒中患者与正常健康体检者相比，IL-6、IL-8均在发病后第1、3d明显增高（P〈0．05）；第7d结果相差不大（P〉0．05）；IL-10在第1、3、7d逐渐增高（P〈0．05）。结论白细胞介素的监测可以为早期临床治疗及康复干预提供试验指标，以便控制脑卒中的进展及复发。     

急性脑梗死患者血清IL-8、IL-17、IL-18水平变化

目的探讨急性脑梗死患者血清白介素(IL)-8、IL-17、IL-18的水平变化及意义。方法采用ELISA法检测89例急性脑梗死患者和45例健康对照者血清中IL-8、IL-17、IL-18的水平,比较2组差异。结果急性脑梗死患者血清中IL-8、IL-17、IL-18的水平均高于健康对照者,差异有统计学意义(P<0.05)。结论炎症反应参与了急性脑梗死的病理生理过程,IL-8、IL-17、IL-18水平的变化可用于监测急性脑梗死的病情严重程度。     

IL-1β Induction and IL-6 Suppression Are Associated with Aggravated Neuronal Damage in a Lipopolysaccharide-Pretreated Kainic Acid-Induced Rat Pup Seizure Model

Objectives: Reportedly, hippocampal neuronal degeneration by kainic acid (KA)-induced seizures in rats <14 days old was enhanced by lipopolysaccharide (LPS). This study was to test the hypothesis that cytokines such as interleukin (IL)-1β, IL-6 and tumor necrosis factor-α are associated with aggravated neuronal damage. Materials and Methods: Sixty male Sprague-Dawley, 14-day-old rats were used. Experiments were conducted in saline, LPS + saline, saline + KA and LPS + KA groups. Intraperitoneal LPS injections (0.04 mg/kg) were administered 3 h prior to KA injection (3 mg/kg). Results: The LPS + KA group showed a tendency toward shorter latency to seizure onset (p = 0.086) and significantly longer seizure duration (p < 0.05) compared with the KA group. Induction of the proconvulsant cytokine IL-1β in rat pup brains was significantly greater in the LPS + KA group compared to the KA group (38.8 ± 5.5 vs. 9.2 ± 1.0 pg/μg; p < 0.05); however, IL-6 levels were higher in the KA group than in the LPS + KA group (108.7 ± 6.8 vs. 60.9 ± 4.7 pg/μg; p < 0.05). The difference in tumor necrosis factor-α between the LPS + KA group and the KA group was insignificant (12.1 ± 0.6 vs. 10.9 ± 2.3 pg/μg; p = 0.64). Conclusions: Our results showed an increase in the proconvulsant cytokine IL-1β and a decrease in a potentially neuroprotective cytokine, IL-6, in rat pups treated with LPS + KA. These results warrant further investigation into the possible role of IL-1β induction and IL-6 suppression in LPS-promoted neuronal damage.     

IL-3、IL-6和IL-8在人脑膜瘤中的表达和作用

目的：探讨白细胞介素（IL）－3、IL－6和IL－8在脑膜瘤细胞中的表达和作用，以及体外针对这种生长调节环路抑制脑膜瘤细胞增殖的可行性。方法：原代培养起21例脑膜瘤细胞。采用ABC免疫细胞化学法明确IL－3、IL－6和IL－8在脑膜瘤细胞中的表达，并选用四唑盐（MTT）比色法观察上述细胞因子及IL－3单抗对脑膜瘤细胞增殖的调控作用。结果：脑膜瘤细胞可分泌IL－3、IL－6和IL－8。IL－3和IL－8皆以剂量依赖关系刺激培养脑膜瘤细胞增殖，而IL－8仅在10ng/ml时对脑膜瘤细胞增殖的刺激效应有统计学差异。IL－3单抗以剂量依赖关系分别抑制正常脑膜瘤细胞及50％V／V脑膜瘤培养是取液刺激的脑膜瘤细胞增殖。结论：IL－3、IL－6和IL－8为脑膜瘤自泌细胞因子；IL－3和IL－6刺激体外培养脑膜瘤细胞增殖；IL－3单抗抑制体外培养脑膜瘤细胞增殖，为脑膜瘤的生物治疗提供新 的理论基础。