D'Isanto Marina, Vitiello Mariateresa, Raieta Katia, Galdiero Massimiliano, Galdiero Marilena
Dipartimento di Patologia Generale, Facoltà di Medicina e Chirurgia, Seconda Università di Napoli, Via De Crecchio 7, 80138 Naples, Italy.
Immunobiology. 2004;209(7):523-33. doi: 10.1016/j.imbio.2004.06.001.
Prolactin (PRL) induces cell proliferation and cell differentiation through the well-known mitogen-activated protein kinases (MAPKs) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathways, depending on the cell line. MAPKs play a central role in signaling transduction mechanisms that transmit mitogenic or differentiation signals from an activated receptor to the intracellular machinery. All of the cytokine receptors that activate the JAK/STAT pathway also activate the MAPK pathway. The aim of the present study was to delineate the signal pathways implicated in IL-8 release by THP-1 cells, pretreated with PRL, after stimulation with either lipopolysaccharide (LPS) or porins from Salmonella enterica serovar Typhimurium. PRL activates the JAK2/STAT1-3 signaling pathway, while LPS or porins from S. enterica serovar Typhimurium does not induce any phosphorylation of this pathway. However, in THP-1 cells, the combination of PRL followed by either S. enterica serovar Typhimurium LPS or porins produced a greater MEK1-MEK2/MAPKs activation response than treatment with PRL alone. Similarly, PRL pretreatment of THP-1 cells resulted in an increase in IL-8 release in response to stimulation with either LPS or porins. This additive effect on IL-8 release was reduced when the cells were also treated with PD-098059, a selective inhibitor of the MEK1 activator and the MAPK cascade, or SB203580, a specific inhibitor of the p38 pathway, or AG490, a specific JAK/STAT pathway inhibitor, providing evidence that there are different signal pathways activated which have a cumulative effect.
催乳素（PRL）根据细胞系的不同，通过著名的丝裂原活化蛋白激酶（MAPK）和Janus激酶（JAK）/信号转导子和转录激活子（STAT）途径诱导细胞增殖和细胞分化。MAPK在信号转导机制中起核心作用，该机制将有丝分裂原或分化信号从活化受体传递至细胞内机制。所有激活JAK/STAT途径的细胞因子受体也会激活MAPK途径。本研究的目的是阐明经PRL预处理的THP-1细胞在受到脂多糖（LPS）或鼠伤寒沙门氏菌血清型鼠伤寒的孔蛋白刺激后，与白细胞介素-8释放相关的信号通路。PRL激活JAK2/STAT1-3信号通路，而鼠伤寒沙门氏菌血清型鼠伤寒的LPS或孔蛋白不会诱导该途径的任何磷酸化。然而，在THP-1细胞中，PRL与鼠伤寒沙门氏菌血清型鼠伤寒的LPS或孔蛋白联合使用所产生的MEK1-MEK2/MAPK激活反应比单独使用PRL治疗更强。同样，PRL对THP-细胞的预处理导致在受到LPS或孔蛋白刺激时白细胞介素-8释放增加。当细胞同时用MEK1激活剂和MAPK级联的选择性抑制剂PD-098059、p38途径的特异性抑制剂SB203580或JAK/STAT途径特异性抑制剂AG490处理时，这种对白细胞介素-8释放的累加效应会降低，这表明存在不同的激活信号通路并具有累加效应。
