哺乳动物速激肽hemokinin-1对痛觉的调节作用及其对白血病细胞增殖与分化作用的研究
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摘要
人HK-1是由近来在人类中鉴定的TAC4基因所编码的哺乳动物速激肽,这个肽的生物学功能还没有被完全研究清楚。本研究打算通过温浴甩尾实验来研究人HK-1对小鼠脊髓上水平痛觉的调节作用及其作用机理。侧脑室注射(0.3,1,3,6 nmol/mouse)人HK-1产生了剂量和时间依赖性的镇痛作用。此作用能够被速激肽NK_1受体拮抗剂SR140333显著拮抗,但是速激肽NK_2受体拮抗剂SR48968对此没有显著影响,表明侧脑室注射人HK-1引起的镇痛作用是通过激活速激肽NK_1受体所介导的。有趣的是,纳洛酮、β-funaltrexamine和naloxonazine,而非naltrindole和nor-binaltorphimine也能够显著阻断人HK-1引起的镇痛作用,表明这种作用与下行μ阿片能神经元有关(主要是μ_1亚型)。这些结果表明:人HK-1在小鼠脊髓上水平的痛觉调节中可能起着重要作用,且这些作用由激活NK_1受体所介导,也与下行μ阿片能神经元有关。
本文的第二部分初步探讨了人HK-1对白血病细胞增殖与分化的作用。许多文献已报道速激肽在人体内具有免疫调节功能。本研究中我们检测了人HK-1对人类急性髓系白血病细胞HL-60增殖与分化的影响。结果显示人HK-1(1-300μM)能够剂量依赖的抑制HL-60细胞的增殖。细胞周期分析发现,不同浓度的人HK-1对HL-60细胞增殖的抑制,伴随着细胞进程阻滞于S期;人HK-1能显著增强HL-60细胞的NBT还原能力,即具有诱导HL-60细胞分化的作用。然而这个作用不能被速激肽NK_1受体拮抗剂SR140333和速激肽NK_2受体拮抗剂SR48968所拮抗,表明这种作用可能不是通过典型的速激肽受体来介导的。此外,我们的研究也表明人HK-1可以作为癌症治疗的一种免疫调节因子。
Human hemokinin-1(h HK-1) is a mammalian tachykinin peptide encoded by the recently identified TAC4 gene in human,and the biological functions of this peptide have not been well investigated.In the present study,an attempt has been made to investigate the effect and mechanism of action of h HK-1 on pain modulation at the supraspinal level in mice using the tail immersion test.Intracerebroventricular(i.c.v.) administration of h HK-1(0.3,1,3 and 6 nmol/mouse) produced a dose- and time-related antinociceptive effect.This effect was significantly antagonized by the NK_1 receptor antagonist SR140333,but not by the NK_2 receptor antagonist SR48968,indicating that the analgesic effect induced by i.c.v,h HK-1 is mediated through the activation of NK_1 receptors.Interestingly,naloxone,b-funaltrexamine and naloxonazine,but not naltrindole and nor-binaltorphimine,could also block the analgesic effect markedly,suggesting that this effect is related to descendingμopioidergic neurons (primaryμ_1 subtype).These findings suggested that h HK-1 might play an important role in pain modulation at supraspinal level in mice and the effect was elicited through the activation of NK_1 receptor,and related to descendingμopioidergic neurons.
In the second section we studied the effects of human hemokinin-1(h HK-1) on the proliferation and differentiation of human leukemia cells in vitro.The tachykinins have shown immuno-regulatory activities in humans.In the present study,we investigated the effects of h HK-1 on the proliferation and differentiation of a human promyelocyte leukemia cell line,HL-60.It is noteworthy that h HK-1(1-300μM) displayed inhibitory effects on the proliferation of HL-60 cells in a dose- and time-dependent manner.The effect of suppressing proliferation induced by thise peptide was accompanied by an accumulation of cell cycle in the S phase.Moreover,this peptide induced differentiation of HL-60 cells by significantly increasing the NBT-reduction activity.However the effect induced by h HK-1 was not antagonized by the NK_1 receptor antagonist SR140333 or the NK_2 receptor antagonist SR48968.All the results indicated that h HK-1 was able to significantly inhibit proliferation and induce differentiation and S phase arrest of a human promyelocyte leukemia cell line HL-60,which may not be mediated through the activation of classical tachykinin NK_1 receptors and tachykinin NK_2 receptors.Our observations also implied that h HK-1 could act as an immunomodulatory factor in cancer chemotherapy.
本文的第二部分初步探讨了人HK-1对白血病细胞增殖与分化的作用。许多文献已报道速激肽在人体内具有免疫调节功能。本研究中我们检测了人HK-1对人类急性髓系白血病细胞HL-60增殖与分化的影响。结果显示人HK-1(1-300μM)能够剂量依赖的抑制HL-60细胞的增殖。细胞周期分析发现,不同浓度的人HK-1对HL-60细胞增殖的抑制,伴随着细胞进程阻滞于S期;人HK-1能显著增强HL-60细胞的NBT还原能力,即具有诱导HL-60细胞分化的作用。然而这个作用不能被速激肽NK_1受体拮抗剂SR140333和速激肽NK_2受体拮抗剂SR48968所拮抗,表明这种作用可能不是通过典型的速激肽受体来介导的。此外,我们的研究也表明人HK-1可以作为癌症治疗的一种免疫调节因子。
Human hemokinin-1(h HK-1) is a mammalian tachykinin peptide encoded by the recently identified TAC4 gene in human,and the biological functions of this peptide have not been well investigated.In the present study,an attempt has been made to investigate the effect and mechanism of action of h HK-1 on pain modulation at the supraspinal level in mice using the tail immersion test.Intracerebroventricular(i.c.v.) administration of h HK-1(0.3,1,3 and 6 nmol/mouse) produced a dose- and time-related antinociceptive effect.This effect was significantly antagonized by the NK_1 receptor antagonist SR140333,but not by the NK_2 receptor antagonist SR48968,indicating that the analgesic effect induced by i.c.v,h HK-1 is mediated through the activation of NK_1 receptors.Interestingly,naloxone,b-funaltrexamine and naloxonazine,but not naltrindole and nor-binaltorphimine,could also block the analgesic effect markedly,suggesting that this effect is related to descendingμopioidergic neurons (primaryμ_1 subtype).These findings suggested that h HK-1 might play an important role in pain modulation at supraspinal level in mice and the effect was elicited through the activation of NK_1 receptor,and related to descendingμopioidergic neurons.
In the second section we studied the effects of human hemokinin-1(h HK-1) on the proliferation and differentiation of human leukemia cells in vitro.The tachykinins have shown immuno-regulatory activities in humans.In the present study,we investigated the effects of h HK-1 on the proliferation and differentiation of a human promyelocyte leukemia cell line,HL-60.It is noteworthy that h HK-1(1-300μM) displayed inhibitory effects on the proliferation of HL-60 cells in a dose- and time-dependent manner.The effect of suppressing proliferation induced by thise peptide was accompanied by an accumulation of cell cycle in the S phase.Moreover,this peptide induced differentiation of HL-60 cells by significantly increasing the NBT-reduction activity.However the effect induced by h HK-1 was not antagonized by the NK_1 receptor antagonist SR140333 or the NK_2 receptor antagonist SR48968.All the results indicated that h HK-1 was able to significantly inhibit proliferation and induce differentiation and S phase arrest of a human promyelocyte leukemia cell line HL-60,which may not be mediated through the activation of classical tachykinin NK_1 receptors and tachykinin NK_2 receptors.Our observations also implied that h HK-1 could act as an immunomodulatory factor in cancer chemotherapy.
引文
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