Cao Jing, Papadopoulou Nikoletta, Kempuraj Duraisamy, Boucher William S, Sugimoto Koreaki, Cetrulo Curtis L, Theoharides Theoharis C
Department of Biochemistry, Tufts University School of Medicine, Boston, MA 02111, USA.
J Immunol. 2005 Jun 15;174(12):7665-75. doi: 10.4049/jimmunol.174.12.7665.
Mast cells are critical for allergic reactions, but also for innate or acquired immunity and inflammatory conditions that worsen by stress. Corticotropin-releasing hormone (CRH), which activates the hypothalamic-pituitary-adrenal axis under stress, also has proinflammatory peripheral effects possibly through mast cells. We investigated the expression of CRH receptors and the effects of CRH in the human leukemic mast cell (HMC-1) line and human umbilical cord blood-derived mast cells. We detected mRNA for CRH-R1alpha, 1beta, 1c, 1e, 1f isoforms, as well as CRH-R1 protein in both cell types. CRH-R2alpha (but not R2beta or R2gamma) mRNA and protein were present only in human cord blood-derived mast cells. CRH increased cAMP and induced secretion of vascular endothelial growth factor (VEGF) without tryptase, histamine, IL-6, IL-8, or TNF-alpha release. The effects were blocked by the CRH-R1 antagonist antalarmin, but not the CRH-R2 antagonist astressin 2B. CRH-stimulated VEGF production was mediated through activation of adenylate cyclase and increased cAMP, as evidenced by the fact that the effect of CRH was mimicked by the direct adenylate cyclase activator forskolin and the cell-permeable cAMP analog 8-bromo-cAMP, whereas it was abolished by the adenylate cyclase inhibitor SQ22536. This is the first evidence that mast cells express functional CRH receptors and that CRH can induce VEGF secretion selectively. CRH-induced mast cell-derived VEGF could, therefore, be involved in chronic inflammatory conditions associated with increased VEGF, such as arthritis or psoriasis, both of which worsen by stress.
肥大细胞对过敏反应至关重要，对先天或后天免疫以及因压力而恶化的炎症状态也很关键。促肾上腺皮质激素释放激素（CRH）在压力状态下激活下丘脑 - 垂体 - 肾上腺轴，也可能通过肥大细胞产生促炎外周效应。我们研究了CRH受体在人白血病肥大细胞（HMC - 1）系和人脐带血来源的肥大细胞中的表达以及CRH的作用。我们在这两种细胞类型中均检测到CRH - R1α、1β、1c、1e、1f亚型的mRNA以及CRH - R1蛋白。CRH - R2α（而非R2β或R2γ）的mRNA和蛋白仅存在于人脐带血来源的肥大细胞中。CRH增加环磷酸腺苷（cAMP）并诱导血管内皮生长因子（VEGF）分泌，而不释放类胰蛋白酶、组胺、白细胞介素 - 6（IL - 6）、白细胞介素 - 8（IL - 8）或肿瘤坏死因子 - α（TNF - α）。这些效应被CRH - R1拮抗剂安他乐明阻断，但未被CRH - R2拮抗剂阿斯特辛2B阻断。CRH刺激的VEGF产生是通过腺苷酸环化酶的激活和cAMP增加介导的，这一事实证明，CRH的作用被直接腺苷酸环化酶激活剂福斯高林和细胞可渗透的cAMP类似物8 - 溴 - cAMP模拟，而被腺苷酸环化酶抑制剂SQ22536消除。这是肥大细胞表达功能性CRH受体且CRH可选择性诱导VEGF分泌的首个证据。因此，CRH诱导的肥大细胞来源的VEGF可能参与与VEGF增加相关的慢性炎症状态，如关节炎或银屑病，这两种疾病都会因压力而恶化。
