Inhibition of nuclear factor κB by prostaglandin A(1): An effect associated with heat shock transcription factor activation

Prostaglandins (PGs) function as intracellular signal mediators in the regulation of a variety of physiological and pathological processes, including inflammation and immune responses. Cyclopentenone PGs are characterized by antiviral activity against several viruses, including human immunodeficiency virus type 1 (HIV-1), and by the ability to induce heat shock protein expression through activation of the heat shock transcription factor. Here we report that PGA(1) is a potent inhibitor of nuclear factor-κB (NF-κB) activation in human cells and of NF-κB-dependent HIV-1 transcription in long terminal repeat-chloramphenicol acetyltransferase transient transfection experiments. PGA(1) acts by inhibiting phosphorylation and preventing degradation of the NF-κB inhibitor IκB-α. Inhibition does not require protein synthesis, is dependent on the presence of a reactive cyclopentenonic moiety, and is associated with heat shock transcription factor activation. Because NF-κB is critically involved in the activation of immunoregulatory and viral genes, inhibition of its activity could be a major component of the immunosuppressive and antiviral activity of PGs.

前列腺素（Prostaglandins, PGs）作为细胞内信号介质，参与调控包括炎症与免疫应答在内的多种生理及病理过程。环戊烯酮类前列腺素的特征为对包括人类免疫缺陷病毒1型（human immunodeficiency virus type 1, HIV-1）在内的多种病毒具有抗病毒活性，且可通过激活热休克转录因子（heat shock transcription factor）诱导热休克蛋白的表达。本研究报道，PGA(1)可在人类细胞中强效抑制核因子κB（nuclear factor-κB, NF-κB）的激活，并在长末端重复序列-氯霉素乙酰转移酶（long terminal repeat-chloramphenicol acetyltransferase）瞬时转染实验中，抑制依赖NF-κB的HIV-1转录。PGA(1)通过抑制核因子κB的抑制蛋白IκB-α的磷酸化并阻止其降解发挥作用。该抑制作用无需蛋白质合成，依赖于反应性环戊烯酮基团的存在，且与热休克转录因子的激活相关。鉴于NF-κB在免疫调节基因及病毒基因的激活中发挥关键作用，抑制其活性可能是前列腺素发挥免疫抑制与抗病毒活性的核心组成部分。