Local secretion of corticotropin-releasing hormone in the joints of Lewis rats with inflammatory arthritis.
Local secretion of corticotropin-releasing hormone in the joints of Lewis rats with inflammatory arthritis.
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DOI：
10.1172/jci116150
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发表时间：
1992-12
期刊：
影响因子：
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通讯作者：
L. Crofford;H. Sano;K. Karalis;E. Webster;E. Goldmuntz;G. Chrousos;R. Wilder
中科院分区：
文献类型：
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作者：
L. Crofford;H. Sano;K. Karalis;E. Webster;E. Goldmuntz;G. Chrousos;R. Wilder
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，在那里它起到局部促炎因子的作用。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大鼠在同样的刺激下，下丘脑CRH显著增加。与这些下丘脑CRH反应相比，我们现在发现，在患有链球菌细胞壁和佐剂诱导的关节炎的LEW/N大鼠的关节和周围组织中，CRH的表达显著增加，而在类似治疗的F344/N大鼠中，CRH的表达不增加，并且仅在先天性无症状的裸鼠LW.rnu/rnu大鼠中一过性增加。糖皮质激素治疗可抑制LEW/N大鼠关节CRH免疫反应，但不能消除CRH免疫反应。炎症滑膜和脊髓中均有CRH mRNA表达，炎症滑膜中也有CRH结合位点的表达。我们将炎症关节中CRH的表达与另一种具有良好特征的促炎神经肽P物质(SP)进行比较，发现SP的免疫反应与CRH的免疫反应平行。综上所述，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的CRH水平。与SP类似，CRH可通过周围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CRH不仅触发垂体-肾上腺抗炎级联反应，而且在急性和慢性炎症性关节炎中起到相反活性的局部介质的作用。这些数据还说明了神经、内分泌、免疫和炎症系统之间的复杂相互关系。
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.