Delgado Mercedes, Fuentes José A, Fernandez-Alfonso María S
Departamento de Farmacolog a, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain.
Med Sci Monit. 2003 Jun;9(6):BR212-9.
An increase of phosphodiesterase 4 (PDE4) has been described in blood mononuclear white cells of patients with atopic dermatitis (AD). This study was intended to search for the putative relationship between histamine and PDE4 in inflammatory cells.
MATERIAL/METHODS: The human monocyte cell line U-937 was used as a model of blood mononuclear leucocytes. PDE4 activity was determined as the increase of cAMP degradation, which is specifically inhibited by rolipram. Intracellular cAMP content was measured and correlated to PDE4 activity.
1 microM histamine produced a 2- to 3-fold selective increase in PDE4 activity in U-937 cells after 4 hours of incubation. Enzyme activation was reversible, concentration- and time dependent. Cycloheximide (10 microM) prevented histamine-induced stimulation of PDE4. The H2-receptor antagonist, ranitidine, but not the H1-receptor antagonist, diphenhydramine, prevented histamine-induced activation of PDE4 in a concentration-dependent manner. Inhibition of cAMP degradation in the presence of histamine plus rolipram after 4 h of incubation further increased cAMP levels and PDE4 activity.
These results suggest that histamine-induced stimulation of PDE4 is mediated by the H2 receptor and related to intracellular levels of cAMP. AMPc enhancement of the cyclic nucleotide levels may trigger expression and synthesis of this enzyme.
已有研究报道特应性皮炎（AD）患者血液单核白细胞中磷酸二酯酶4（PDE4）增加。本研究旨在探寻炎症细胞中组胺与PDE4之间的潜在关系。
材料/方法：将人单核细胞系U - 937用作血液单核白细胞模型。PDE4活性通过环磷酸腺苷（cAMP）降解的增加来测定，罗匹尼罗可特异性抑制该降解过程。测量细胞内cAMP含量并将其与PDE4活性相关联。
孵育4小时后，1微摩尔组胺使U - 937细胞中PDE4活性选择性增加2至3倍。酶激活是可逆的，具有浓度和时间依赖性。放线菌酮（10微摩尔）可阻止组胺诱导的PDE4刺激。H2受体拮抗剂雷尼替丁可浓度依赖性地阻止组胺诱导的PDE4激活，而H1受体拮抗剂苯海拉明则无此作用。孵育4小时后，在组胺加罗匹尼罗存在的情况下抑制cAMP降解可进一步提高cAMP水平和PDE4活性。
这些结果表明，组胺诱导的PDE4刺激是由H2受体介导的，并且与细胞内cAMP水平相关。环核苷酸水平的cAMP增强可能触发该酶的表达和合成。
