Humphreys B D, Dubyak G R
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
J Leukoc Biol. 1998 Aug;64(2):265-73. doi: 10.1002/jlb.64.2.265.
Regulation of P2X7 receptor expression is of interest because activation of this receptor by extracellular ATP triggers maturation and release of the pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) in monocytes and macrophages. We report that interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) synergistically induce P2X7R mRNA and functional responses in the human THP-1 monocytic cell line. Induction was dose dependent, with maximal functional activity requiring 1000 units/mL IFN-gamma and 10 ng/mL TNF-alpha and incubations of 36-72 h. The up-regulation of P2X7R function by lipopolysaccharide (LPS)/IFN-gamma and TNF-alpha/IFN-gamma was markedly attenuated by coincubation with prostaglandin E2 or the cell permeant cyclic AMP analog dibutryl cAMP (Bt2cAMP). Bt2cAMP did not significantly alter P2X7 function in HEK-293 cells stably transfected with the human P2X7 cDNA, indicating that Bt2cAMP does not exert a generalized effect on P2X7R synthesis or downstream signal transduction. These studies demonstrate that elevated cAMP negatively modulates P2X7R expression.
P2X7受体表达的调控备受关注，因为细胞外ATP激活该受体可触发单核细胞和巨噬细胞中促炎细胞因子白细胞介素-1β（IL-1β）的成熟和释放。我们报道，干扰素-γ（IFN-γ）和肿瘤坏死因子α（TNF-α）协同诱导人THP-1单核细胞系中的P2X7R mRNA和功能性反应。诱导呈剂量依赖性，最大功能活性需要1000单位/mL IFN-γ和10 ng/mL TNF-α，并孵育36 - 72小时。脂多糖（LPS）/IFN-γ和TNF-α/IFN-γ对P2X7R功能的上调作用在与前列腺素E2或细胞可渗透的环磷酸腺苷类似物二丁酰环磷腺苷（Bt2cAMP）共同孵育时明显减弱。Bt2cAMP对稳定转染人P2X7 cDNA的HEK-293细胞中的P2X7功能没有显著影响，表明Bt2cAMP对P2X7R合成或下游信号转导没有普遍作用。这些研究表明，升高的环磷酸腺苷负向调节P2X7R表达。
