Chedeville A, Mirossay L, Chastre E, Hurbain-Kosmath I, Lopez M, Gespach C
INSERM U.55, Hôpital Saint-Antoine, Paris, France.
FEBS Lett. 1993 Mar 15;319(1-2):171-6. doi: 10.1016/0014-5793(93)80061-x.
The activation of the cAMP signaling pathway by vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating peptide (PACAP) and related peptides was studied (i) in normal peripheral human monocytes and THP-1 leukemic human monocytes, (ii) in their derived macrophage counterparts respectively obtained after spontaneous differentiation or retinoic acid (RA) treatment, and (iii) in human bronchoalveolar macrophages. In THP-1 monocytes, PACAP increased basal adenylate cyclase activity 5.3-fold, with an affinity 50-times greater than that of VIP or helodermin (Ka = 3.2 x 10(-11) M VIP), whereas in normal peripheral monocytes, PACAP and VIP exhibited similar affinities and only increased cAMP generation 2-fold (EC50 = 10(-9) M). Spontaneous and RA-induced differentiation into normal and leukemic macrophages induced a progressive loss of cAMP production and regulation of superoxide anion production by VIP and related peptides. The neoplastic transformation in THP-1 monocytes and the deficiencies in the cAMP cascade observed during the terminal differentiation of normal and leukemic human macrophages may relate to a differential genetic expression of the VIP/PACAP receptor subtypes, and alterations in the functional activity of the stimulatory and inhibitory Gs/Gi subunits of adenylate cyclase.
研究了血管活性肠肽（VIP）、垂体腺苷酸环化酶激活肽（PACAP）及相关肽对环磷酸腺苷（cAMP）信号通路的激活作用：（i）在正常外周血人单核细胞和THP-1人白血病单核细胞中；（ii）在分别经自发分化或视黄酸（RA）处理后获得的相应巨噬细胞中；（iii）在人支气管肺泡巨噬细胞中。在THP-1单核细胞中，PACAP使基础腺苷酸环化酶活性增加5.3倍，其亲和力比VIP或蛙皮素高50倍（VIP的Ka = 3.2×10⁻¹¹ M），而在正常外周血单核细胞中，PACAP和VIP表现出相似的亲和力，仅使cAMP生成增加2倍（EC50 = 10⁻⁹ M）。自发和RA诱导分化为正常和白血病巨噬细胞导致cAMP生成逐渐减少，以及VIP和相关肽对超氧阴离子生成的调节作用减弱。THP-1单核细胞中的肿瘤转化以及正常和白血病人类巨噬细胞终末分化过程中观察到的cAMP级联反应缺陷可能与VIP/PACAP受体亚型的差异基因表达以及腺苷酸环化酶刺激和抑制性Gs/Gi亚基功能活性的改变有关。
