Crofford L J, Sano H, Karalis K, Webster E L, Goldmuntz E A, Chrousos G P, Wilder R L
Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892.
J Clin Invest. 1992 Dec;90(6):2555-64. doi: 10.1172/JCI116150.
Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamic-pituitary-adrenal axis, is also secreted in peripheral inflammatory sites, where it acts as a local proinflammatory agent. Arthritis-susceptible LEW/N rats have profoundly deficient hypothalamic CRH responses to inflammatory stimuli and other stressors. Arthritis-resistant F344/N rats, on the other hand, have a robust increase in hypothalamic CRH in response to the same stimuli. Contrasting with these hypothalamic CRH responses, we now show that CRH expression is markedly increased in the joints and surrounding tissues of LEW/N rats with streptococcal cell wall- and adjuvant-induced arthritis, whereas it is not increased in similarly treated F344/N rats and is only transiently increased in congenitally athymic nude LEW.rnu/rnu rats. Glucocorticoid treatment suppressed, but did not eliminate, CRH immunoreactivity in the joints of LEW/N rats. CRH mRNA was present in inflamed synovia, as well as in spinal cord, and inflamed synovia also expressed specific CRH-binding sites. We compared CRH expression in inflamed joints with another well-characterized proinflammatory neuropeptide, substance P (SP), and found that SP immunoreactivity paralleled that of CRH. In summary, although LEW/N rats have deficient hypothalamic CRH responses to inflammatory stimuli compared with F344/N rats, they express relatively high levels of CRH at the site of inflammation. Analogous to SP, CRH may be delivered to the inflammatory site by peripheral nerves and/or synthesized at the inflammatory site. These data provide further support for the concept that CRH not only triggers the pituitary-adrenal antiinflammatory cascade, but also functions as an antithetically active local mediator of acute and chronic inflammatory arthritis. These data also illustrate the complex interrelationships of the nervous, endocrine, immune, and inflammatory systems.
促肾上腺皮质激素释放激素（CRH）是下丘脑 - 垂体 - 肾上腺轴的主要调节因子，也在外周炎症部位分泌，在那里它作为一种局部促炎因子发挥作用。易患关节炎的LEW/N大鼠对炎症刺激和其他应激源的下丘脑CRH反应严重不足。另一方面，抗关节炎的F344/N大鼠在受到相同刺激时，下丘脑CRH会显著增加。与这些下丘脑CRH反应形成对比的是，我们现在发现，在患有链球菌细胞壁和佐剂诱导性关节炎的LEW/N大鼠的关节和周围组织中，CRH表达明显增加，而在同样处理的F344/N大鼠中CRH表达并未增加，并且在先天性无胸腺裸LEW.rnu/rnu大鼠中仅短暂增加。糖皮质激素治疗可抑制LEW/N大鼠关节中的CRH免疫反应性，但不能消除。CRH mRNA存在于炎症滑膜以及脊髓中，炎症滑膜也表达特异性CRH结合位点。我们将炎症关节中的CRH表达与另一种特征明确的促炎神经肽P物质（SP）进行了比较，发现SP免疫反应性与CRH的相似。总之，尽管与F344/N大鼠相比，LEW/N大鼠对炎症刺激的下丘脑CRH反应不足，但它们在炎症部位表达相对较高水平的CRH。与SP类似，CRH可能通过外周神经传递到炎症部位和/或在炎症部位合成。这些数据进一步支持了这样的概念，即CRH不仅触发垂体 - 肾上腺抗炎级联反应，而且还作为急性和慢性炎症性关节炎的一种具有相反活性的局部介质发挥作用。这些数据还说明了神经、内分泌、免疫和炎症系统之间复杂的相互关系。
