Unit of Rheumatology, Department of Medicine, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, SE-171 77 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12728-33. doi: 10.1073/pnas.1118748109. Epub 2012 Jul 16.
During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.
在感染或炎症状态引起的外周免疫激活期间，先天免疫反应会向大脑发出信号，并导致中枢神经系统 (CNS) 细胞因子的产生增加。促炎细胞因子，特别是 IL-1β 的中枢作用，对于发热和疲劳的诱导至关重要。在本研究中，研究了类风湿关节炎 (RA) 外周慢性关节炎症对 CNS 炎症的影响。与对照组或多发性硬化症患者相比，RA 患者的鞘内白细胞介素 (IL)-1β 浓度明显升高。相反，RA 脑脊液 (CSF) 中的抗炎性 IL-1 受体拮抗剂和 IL-4 减少。CSF 中肿瘤坏死因子和 IL-6 的水平在患者和对照组之间没有差异。关于 IL-1β，RA 患者的 CSF 浓度高于血清，表明 CNS 中存在局部产生，并且 CSF IL-1β 与疲劳评估呈正相关。接下来，研究了实验性关节炎中的脊髓炎症。在 KBxN 血清转移模型中，观察到脊髓中 IL-1β、IL-18 和肿瘤坏死因子的表达显著增加，而 IL-6 mRNA 的表达没有增加，同时关节炎评分也增加。这些数据表明，外周炎症（如关节炎）与人类和小鼠的 CNS 免疫激活有关，这表明针对慢性炎症性疾病中作为疲劳等中枢影响的条件可能是一种潜在的治疗靶点，目前针对这些疾病还没有特定的治疗方法。
