过度训练及补充谷氨酰胺对大鼠腹膜巨噬细胞功能的影响及机制研究
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摘要
研究目的：
（1）研究过度训练对大鼠腹膜巨噬细胞吞噬功能、胞内活性氧（ROS）生成能力及炎性因子应答能力的影响，并对相关机制展开研究，为加深对过度训练的认识提供实验依据。
（2）研究外源性补充谷氨酰胺对过度训练大鼠腹膜巨噬细胞吞噬功能、活性氧生成能力及炎性因子应答能力的影响，探索改善过度训练效应的可行途径。
（3）离体状态下研究胰岛素样生长因子1（IGF-1）和机械生长因子（MGF）对腹膜巨噬细胞吞噬功能、胞内活性氧生成能力及炎性因子应答能力的影响，试图从IGF-1和MGF角度揭示过度训练影响巨噬细胞功能的可能机制。研究方法：
（1）在体实验：8周龄健康雄性wistar大鼠40只，随机分为安静对照组(control，C)、过度训练组（E组）和过度训练补充谷氨酰胺组（EG组）。根据取材时间不同，E组分为训练后36小时取材组（E1）和训练后7天取材组（E2）；EG组分为训练后36小时取材组（EG1）和训练后7天取材组（EG2）；每组8只。除C组外，其他组进行11周递增负荷跑台训练。观察大鼠体重、精神状态及运动能力的变化，并于训练后上述时间点眼眶取血，分析血红蛋白（Hb）和血睾酮（T）含量。分离纯化腹膜巨噬细胞，中性红法测定巨噬细胞吞噬功能；流式细胞术测定巨噬细胞胞内ROS生成；ELISA技术测定巨噬细胞肿瘤坏死因子α（TNF-α）和白介素1β（IL-1β）生成量；比色法测定NADPH氧化酶活性；荧光定量PCR技术测定巨噬细胞如下基因表达：NADPH氧化酶亚基（gp91phox、p22phox、p47phox、p40phox、p67phox）、蛋白激酶C δ（PKC-δ）、葡萄糖6磷酸脱氢酶（G6PD）、诱导型一氧化氮合酶（iNOS）、胰岛素样生长因子1（IGF-1）和机械生长因子（MGF）。
（2）离体实验：离体状态下用不同浓度的IGF-1或MGF（1、10、50、100、200ng/ml）与巨噬细胞孵育，观察IGF-1和MGF对巨噬细胞吞噬功能、胞内活性氧生成能力及炎性因子应答能力的影响。研究结果：
（1）过度训练指标：训练后期，大鼠精神状态及运动能力下降；与安静对照组相比，过度训练组体重，血红蛋白含量及睾酮含量均显著降低（P<0.01），分别下降了约19.3%、13.5%和55.3%。
（2）吞噬功能：与C组相比，E1组大鼠腹膜巨噬细胞吞噬中性红的能力显著降低，下降约27％（P<0.05）；E2组巨噬细胞吞噬功能恢复至安静对照组水平。EG1组巨噬细胞吞噬功能虽低于C组，但无显著差异；EG2组与E2组和C组无显著差异。
（3）ROS生成：与C组相比，E1组大鼠腹膜巨噬细胞ROS生成量显著降低，下降约35%（P<0.01）；E2组巨噬细胞ROS生成量显著高于E1组（P<0.01），恢复至安静对照组水平。EG1组巨噬细胞ROS生成量与E1组相比无显著差异，仍显著低于C组（P<0.01）；EG2组巨噬细胞ROS生成量显著高于EG1组（P<0.01），与E2组和C组无显著差异。
（4）炎性因子应答能力：与C组相比，E1组大鼠腹膜巨噬细胞TNF-α和IL-1β对LPS的应答能力显著降低；E2组显著高于E1组（P<0.05），与C组相比无显著差异。EG1组巨噬细胞TNF-α和IL-1β对LPS的应答能力显著高于E1组，与C组相比无显著差异；EG2组与E2组和C组相比无显著差异。
（5）NADPH氧化酶活性：与C组相比，E1组大鼠腹膜巨噬细胞NADPH氧化酶活性降低，E2组巨噬细胞NADPH氧化酶活性显著高于E1组（P<0.05），与C组相比无显著差异。EG1组和EG2组分别与E1组和E2组相比无显著性差异。相关分析显示（5个组数据），NADPH氧化酶活性与ROS生成量呈线性正相关，相关系数为0.62（P<0.01）。
（6）NADPH氧化酶亚基：与C组相比，E1组大鼠腹膜巨噬细胞NADPH氧化酶亚基gp91phox、p22phox、p40phox、p67phox表达量无显著差异，但胞质亚基p47phox表达量显著升高（P<0.05）；E2组大鼠腹膜巨噬细胞gp91phox、p22phox、p47phox、p40phox、p67phox表达量与E1组和C组相比均无显著差异。EG1组巨噬细胞gp91phox、p22phox、p40phox、p67phox表达量与E1组无显著差异，p47phox表达量显著低于E1组（P<0.05）；EG2组巨噬细胞中各亚基表达量与E2组、C组和EG1组相比均无显著差异。
（7）PKC-δ：与C组相比，E1组大鼠腹膜巨噬细胞PKC-δ基因表达量显著降低（P<0.05）；E2组PKC-δ表达量显著高于E1组（P<0.05），与C组相比无统计学差异。EG1组和EG2组分别与E1组和E2组相比无显著性差异。相关分析显示（5个组数据），PKC-δ表达量与NADPH氧化酶活性呈线性正相关，相关系数为0.51（P<0.01），PKC-δ表达量与ROS生成量相关系数为0.69（P<0.01）。
（8）G6PD：C组、E1组、E2组、EG1组、EG2组五组间比较，腹膜巨噬细胞G6PD基因表达量无显著差异。
（9）iNOS：C组、E1组、E2组、EG1组、EG2组五组间比较，腹膜巨噬细胞iNOS基因表达量无显著差异。
（10）IGF-1和MGF：与C组相比，E1组大鼠腹膜巨噬细胞IGF-1和MGF表达量分别增加了21倍和92倍（P<0.01）；E2组显著低于E1组（P<0.01），与C组相比无统计学差异。EG1组巨噬细胞IGF-1和MGF表达量显著低于E1组（P<0.01），仍显著高于C组（P<0.01）；EG2组显著低于EG1组（P<0.01），与C组和E2组相比无显著差异。
（11）IGF-1对巨噬细胞功能影响：与不加药组相比，不同终浓度的IGF-1（1、10、50、100、200ng/ml）对巨噬细胞吞噬功能和胞内ROS生成均无显著影响（P>0.05）；100ng/ml IGF-1可显著增加巨噬细胞TNF-α对LPS的应答；100、200ng/ml IGF-1可显著增加巨噬细胞IL-1β对LPS的应答。
（12）MGF对巨噬细胞功能影响：与不加药组相比，MGF可呈浓度依赖性的抑制巨噬细胞吞噬功能；1、10、50、100ng/ml MGF可显著抑制巨噬细胞胞内ROS生成；不同浓度的MGF对巨噬细胞炎性因子应答能力无显著影响。研究结论：
（1）过度训练可抑制巨噬细胞吞噬功能，胞内活性氧生成及炎性因子应答能力，这可能是过度训练增加感染风险的原因之一。
（2）补充谷氨酰胺对过度训练诱导的巨噬细胞吞噬功能降低和炎性因子应答能力降低有一定的改善作用，但对过度训练诱导的巨噬细胞胞内ROS生成降低无明显改善效应。
（3）过度训练抑制腹膜巨噬细胞胞内活性氧生成的机制：不通过抑制NADPH氧化酶亚基表达及抑制NADPH氧化酶生成途径发挥作用；PKC-δ介导NADPH氧化酶活性降低在过度训练抑制巨噬细胞ROS生成中发挥重要作用；过度训练诱导产生的MGF可能在过度训练抑制巨噬细胞ROS生成中发挥重要作用。
（4）过度训练抑制腹膜巨噬细胞吞噬功能的机制：过度训练诱导产生的MGF可能通过自分泌或旁分泌形式对巨噬细胞吞噬功能发挥关键调控作用。
（5）过度训练抑制腹膜巨噬细胞炎性因子应答能力的机制：IGF-1和MGF没有参与这一过程，而是有别的机制参与。
Objective
(1) To evaluate the effects of overtraining on phagocytosis, reactive oxygenspecies (ROS) generation and inflammatory cytokines production of peritonealmacrophages (MФs), especially the mechanisms involved. It will provide experimentevidence for strengthen our understanding of overtraining.
(2) To determine the effects of supplement with glutamine on the function ofMФs (i.e., phagocytosis, ROS generation and inflammatory cytokines production)from the overtraining group, and to explore a way to ameliorate the situation inducedby overtraining.
(3) To investigate the effects of IGF-1and MGF peptide on phagocytosis, ROSgeneration and inflammatory cytokines production of MФs in vitro, and attempt todiscover the mechanisms of the inhibiton of MФs induced by overtraining from theview of IGF-1and MGF.
Methods
(1) In vivo.40male wistar rats (8-wk-old) were randomly divided into5groups:sedentary group(C, n=8), overtraining group (E), overtraining supplement with Glngroup (EG). E and EG group were respectively divided into two groups whichsacrificed at36h (E1, EG1, n=8) and7days (E2, EG2, n=8) after the last training. Allgroups except C were training in standard treadmill with an increasing load for11weeks. The criteria to evaluate the condition of the rats and judge whether theprotocol was successful were as follows: locomotory capacity, mental state, weightchange, and concentrations of hemoglobin and testosterone in blood. Peritonealmacrophages were isolated and purified after all rats were sacrificed by decapitation.The phagocytosis and the ROS generation of MФs were measured by the uptake ofneutral red and the flow cytometry respectively; The producitin of TNF-α and IL-1βwere tested by ELISA; The NADPH-oxidase activity was tested by colorimetry;Real-time PCR was used to test the expression of the following genes:NADPH-oxidase subunits (gp91phox, p22phox, p47phox, p40phox, p67phox), PKC-δ,G6PD, iNOS, IGF-1and MGF.
(2) In vitro. MФs were exposed to diffrent concentrations (1,10,50,100,200ng/ml) of IGF-1or MGF peptide for2h. The phagocytosis, the ROS generationand the inflammatory cytokines production of MФs were measured by the uptake ofneutral red, the flow cytometry and ELISA respectively.
Results
(1) Index of overtraining. The rats had to be assisted by hand to complete thejob and their mental state worsened in the later stage of exercise. Overtrainingsignificantly decreased the body weight (19.3%, P<0.01), the hemoglobin (13.5%,P<0.01) and the testosterone (55.3%, P<0.01) in blood.
(2) Phagocytosis. The phagocytosis of MФs from group E1was significantlylower than group C (decreased by27%, P<0.05). There was no significant differencein the phagocytosis of MФs between group E2and group C. Although thephagocytosis of MФs from group EG1was still lower than group C, no differencewas observed between them. There was no significant difference in the phagocytosisof MФs between group EG2, group E2and group C.
(3) ROS. The ROS generation of MФs from group E1was significantly lowerthan group C (decreased by35%, P<0.01). The ROS generation of MФs from groupE2was significantly higher than group E1(P<0.01), and no difference was observedbetween group E2and group C. The ROS generation of MФs from group EG1did notchange as compared with group E1, it still significantly lower than group C (P<0.01).The ROS generation of MФs from group EG2was significantly higher than groupEG1(P<0.01), and there was no difference as compared with group E2or group C.
(4) Response ability of inflammatory cytokines. The production of TNF-α andIL-1β of MФs from group E1was significantly lower than group C as LPSstimulation. The response ability of inflammatory cytokines of MФs from group E2was significantly higher than group E1(P<0.05), and no difference was observedbetween group E2and group C. The response ability of inflammatory cytokines ofMФs from group EG1was significantly higher than group E1, and no difference wasobserved between group EG1and group C. There was no difference between groupEG2, group E2and group C.
(5) NADPH-oxidase activity. The NADPH-oxidase activity of MФs from groupE1was significantly lower than group C. The NADPH-oxidase activity of MФs fromgroup E2was significantly higher than group E1(P<0.05), and no difference wasobserved between group E2and group C. The NADPH-oxidase activity of MФs fromgroup EG1and EG2did not change as compared with group E1and E2, respectively.The correlation analysis showed that NADPH-oxidase activity and ROS generationwere positive correlation and the pearson correlation was0.62(P<0.01)(data from5groups).
(6) NADPH-oxidase subunits. The NADPH-oxidase subunits (gp91phox,p22phox, p40phox, p67phox) mRNA levels of MФs from group E1did not change ascompared with group C, however, the expression of p47phox of MФs from group E1was significantly higher than group C (P<0.05). No difference was observed betweengroup E2, group E1and group C in all subunits of NADPH-oxidase. There was no significant difference in the NADPH-oxidase subunits (gp91phox, p22phox, p40phox,p67phox) mRNA levels of MФs between group EG1and group E1, however, theexpression of p47phox of MФs from group EG1was significantly lower than groupE1(P<0.05). All subunits of NADPH-oxidase of MФs from group EG2did not changeas compared with group E2, group C and group EG1.
(7) PKC-δ. The PKC-δ mRNA level of MФs from group E1was significantlylower than group C (P<0.05). The expression of PKC-δ of MФs from group E2wassignificantly higher than group E1(P<0.05), and no difference was observed betweengroup E2and group C. The PKC-δ mRNA level of MФs from group EG1and EG2did not change as compared with group E1and E2, respectively. The correlationanalysis showed that PKC-δ mRNA and NADPH-oxidase activity were positivecorrelation and the pearson correlation was0.51(P<0.01), PKC-δ mRNA and ROSgeneration were positive correlation and the pearson correlation was0.69(P<0.01)(data from5groups).
(8) There was no difference between group C, group E1, group E2, group EG1and group EG2in the expression of G6PD of MФs.
(9) There was no difference between group C, group E1, group E2, group EG1and group EG2in the expression of iNOS of MФs.
(10) IGF-1anf MGF. IGF-1and MGF mRNA levels in MФs from E1groupincreased significantly compared with the control group (21-fold and92-fold,respectively; p<0.01). IGF-1and MGF mRNA levels in MФs from E2group wassignificantly lower than group E1(p<0.01), and no difference was observed betweengroup E2and group C. IGF-1and MGF mRNA levels in MФs from EG1group wassignificantly lower than group E1(p<0.01), however, they were still higher thangroup C (p<0.01). IGF-1and MGF mRNA levels in MФs from EG2group wassignificantly lower than group EG1(p<0.01), and no difference was observed ascompared with group C and group E2.
(11) In vitro experiments showed that different concentrations of IGF-1(1,10,50,100,200ng/ml) had no significant effect on the phagocytosis and the ROSgeneration of MФs. IGF-1(100ng/ml) significantly increased the secretion of TNF-αof MФs as LPS stimulation. IGF-1(100,200ng/ml) significantly increased theproduction of IL-1β of MФs as LPS stimulation.
(12) In vitro experiments showed that MGF peptide impaired the phagocytosis ofMФs in dose-independent manner. Additonally, MGF peptide of some concentrations(i.e.,1,10,50,100ng/ml) significantly inhibited the ROS generation of MФs.However, different concentrations of MGF (1,10,50,100,200ng/ml) had nosignificant effect on the production of TNF-α and IL-1β of MФs as LPS stimulation.
Conclusion
(1) Overtraining inhibits the phagocytosis, the ROS generation and theinflammatory cytokines production of MФs, it may be a mechanism of whyovertraining cause immunesuppression.
(2) Supplement with glutamine ameliorates the decline of the phagocytosis andthe inflammatory cytokines production of MФs induced by overtraining, however, ithas no significant effect on the ROS generation of MФs.
(3) The mechanisms of overtraining inhibit ROS production of MФs: Thedecline of ROS production in overtraining group did not cause by suppressing theNADPH-oxidase subunits or the pathway of NADPH-oxidase production; The declineof NADPH-oxidase activity mediated by PKC-δ may play important roles in theinhibiton of ROS production; MGF produced by macrophages may play a key role inovertraining inhibit ROS production.
(4) The mechanisms of overtraining inhibit phagocytosis of MФs: MGFproduced by macrophages may play a key role in overtraining inhibit phagocytosis ofMФs.
(5) The mechanisms of overtraining inhibit inflammatory cytokines productionof MФs: IGF-1and MGF produced by macrophages do not involved, there must beother mechanisms involved in this process.
（1）研究过度训练对大鼠腹膜巨噬细胞吞噬功能、胞内活性氧（ROS）生成能力及炎性因子应答能力的影响，并对相关机制展开研究，为加深对过度训练的认识提供实验依据。
（2）研究外源性补充谷氨酰胺对过度训练大鼠腹膜巨噬细胞吞噬功能、活性氧生成能力及炎性因子应答能力的影响，探索改善过度训练效应的可行途径。
（3）离体状态下研究胰岛素样生长因子1（IGF-1）和机械生长因子（MGF）对腹膜巨噬细胞吞噬功能、胞内活性氧生成能力及炎性因子应答能力的影响，试图从IGF-1和MGF角度揭示过度训练影响巨噬细胞功能的可能机制。研究方法：
（1）在体实验：8周龄健康雄性wistar大鼠40只，随机分为安静对照组(control，C)、过度训练组（E组）和过度训练补充谷氨酰胺组（EG组）。根据取材时间不同，E组分为训练后36小时取材组（E1）和训练后7天取材组（E2）；EG组分为训练后36小时取材组（EG1）和训练后7天取材组（EG2）；每组8只。除C组外，其他组进行11周递增负荷跑台训练。观察大鼠体重、精神状态及运动能力的变化，并于训练后上述时间点眼眶取血，分析血红蛋白（Hb）和血睾酮（T）含量。分离纯化腹膜巨噬细胞，中性红法测定巨噬细胞吞噬功能；流式细胞术测定巨噬细胞胞内ROS生成；ELISA技术测定巨噬细胞肿瘤坏死因子α（TNF-α）和白介素1β（IL-1β）生成量；比色法测定NADPH氧化酶活性；荧光定量PCR技术测定巨噬细胞如下基因表达：NADPH氧化酶亚基（gp91phox、p22phox、p47phox、p40phox、p67phox）、蛋白激酶C δ（PKC-δ）、葡萄糖6磷酸脱氢酶（G6PD）、诱导型一氧化氮合酶（iNOS）、胰岛素样生长因子1（IGF-1）和机械生长因子（MGF）。
（2）离体实验：离体状态下用不同浓度的IGF-1或MGF（1、10、50、100、200ng/ml）与巨噬细胞孵育，观察IGF-1和MGF对巨噬细胞吞噬功能、胞内活性氧生成能力及炎性因子应答能力的影响。研究结果：
（1）过度训练指标：训练后期，大鼠精神状态及运动能力下降；与安静对照组相比，过度训练组体重，血红蛋白含量及睾酮含量均显著降低（P<0.01），分别下降了约19.3%、13.5%和55.3%。
（2）吞噬功能：与C组相比，E1组大鼠腹膜巨噬细胞吞噬中性红的能力显著降低，下降约27％（P<0.05）；E2组巨噬细胞吞噬功能恢复至安静对照组水平。EG1组巨噬细胞吞噬功能虽低于C组，但无显著差异；EG2组与E2组和C组无显著差异。
（3）ROS生成：与C组相比，E1组大鼠腹膜巨噬细胞ROS生成量显著降低，下降约35%（P<0.01）；E2组巨噬细胞ROS生成量显著高于E1组（P<0.01），恢复至安静对照组水平。EG1组巨噬细胞ROS生成量与E1组相比无显著差异，仍显著低于C组（P<0.01）；EG2组巨噬细胞ROS生成量显著高于EG1组（P<0.01），与E2组和C组无显著差异。
（4）炎性因子应答能力：与C组相比，E1组大鼠腹膜巨噬细胞TNF-α和IL-1β对LPS的应答能力显著降低；E2组显著高于E1组（P<0.05），与C组相比无显著差异。EG1组巨噬细胞TNF-α和IL-1β对LPS的应答能力显著高于E1组，与C组相比无显著差异；EG2组与E2组和C组相比无显著差异。
（5）NADPH氧化酶活性：与C组相比，E1组大鼠腹膜巨噬细胞NADPH氧化酶活性降低，E2组巨噬细胞NADPH氧化酶活性显著高于E1组（P<0.05），与C组相比无显著差异。EG1组和EG2组分别与E1组和E2组相比无显著性差异。相关分析显示（5个组数据），NADPH氧化酶活性与ROS生成量呈线性正相关，相关系数为0.62（P<0.01）。
（6）NADPH氧化酶亚基：与C组相比，E1组大鼠腹膜巨噬细胞NADPH氧化酶亚基gp91phox、p22phox、p40phox、p67phox表达量无显著差异，但胞质亚基p47phox表达量显著升高（P<0.05）；E2组大鼠腹膜巨噬细胞gp91phox、p22phox、p47phox、p40phox、p67phox表达量与E1组和C组相比均无显著差异。EG1组巨噬细胞gp91phox、p22phox、p40phox、p67phox表达量与E1组无显著差异，p47phox表达量显著低于E1组（P<0.05）；EG2组巨噬细胞中各亚基表达量与E2组、C组和EG1组相比均无显著差异。
（7）PKC-δ：与C组相比，E1组大鼠腹膜巨噬细胞PKC-δ基因表达量显著降低（P<0.05）；E2组PKC-δ表达量显著高于E1组（P<0.05），与C组相比无统计学差异。EG1组和EG2组分别与E1组和E2组相比无显著性差异。相关分析显示（5个组数据），PKC-δ表达量与NADPH氧化酶活性呈线性正相关，相关系数为0.51（P<0.01），PKC-δ表达量与ROS生成量相关系数为0.69（P<0.01）。
（8）G6PD：C组、E1组、E2组、EG1组、EG2组五组间比较，腹膜巨噬细胞G6PD基因表达量无显著差异。
（9）iNOS：C组、E1组、E2组、EG1组、EG2组五组间比较，腹膜巨噬细胞iNOS基因表达量无显著差异。
（10）IGF-1和MGF：与C组相比，E1组大鼠腹膜巨噬细胞IGF-1和MGF表达量分别增加了21倍和92倍（P<0.01）；E2组显著低于E1组（P<0.01），与C组相比无统计学差异。EG1组巨噬细胞IGF-1和MGF表达量显著低于E1组（P<0.01），仍显著高于C组（P<0.01）；EG2组显著低于EG1组（P<0.01），与C组和E2组相比无显著差异。
（11）IGF-1对巨噬细胞功能影响：与不加药组相比，不同终浓度的IGF-1（1、10、50、100、200ng/ml）对巨噬细胞吞噬功能和胞内ROS生成均无显著影响（P>0.05）；100ng/ml IGF-1可显著增加巨噬细胞TNF-α对LPS的应答；100、200ng/ml IGF-1可显著增加巨噬细胞IL-1β对LPS的应答。
（12）MGF对巨噬细胞功能影响：与不加药组相比，MGF可呈浓度依赖性的抑制巨噬细胞吞噬功能；1、10、50、100ng/ml MGF可显著抑制巨噬细胞胞内ROS生成；不同浓度的MGF对巨噬细胞炎性因子应答能力无显著影响。研究结论：
（1）过度训练可抑制巨噬细胞吞噬功能，胞内活性氧生成及炎性因子应答能力，这可能是过度训练增加感染风险的原因之一。
（2）补充谷氨酰胺对过度训练诱导的巨噬细胞吞噬功能降低和炎性因子应答能力降低有一定的改善作用，但对过度训练诱导的巨噬细胞胞内ROS生成降低无明显改善效应。
（3）过度训练抑制腹膜巨噬细胞胞内活性氧生成的机制：不通过抑制NADPH氧化酶亚基表达及抑制NADPH氧化酶生成途径发挥作用；PKC-δ介导NADPH氧化酶活性降低在过度训练抑制巨噬细胞ROS生成中发挥重要作用；过度训练诱导产生的MGF可能在过度训练抑制巨噬细胞ROS生成中发挥重要作用。
（4）过度训练抑制腹膜巨噬细胞吞噬功能的机制：过度训练诱导产生的MGF可能通过自分泌或旁分泌形式对巨噬细胞吞噬功能发挥关键调控作用。
（5）过度训练抑制腹膜巨噬细胞炎性因子应答能力的机制：IGF-1和MGF没有参与这一过程，而是有别的机制参与。
Objective
(1) To evaluate the effects of overtraining on phagocytosis, reactive oxygenspecies (ROS) generation and inflammatory cytokines production of peritonealmacrophages (MФs), especially the mechanisms involved. It will provide experimentevidence for strengthen our understanding of overtraining.
(2) To determine the effects of supplement with glutamine on the function ofMФs (i.e., phagocytosis, ROS generation and inflammatory cytokines production)from the overtraining group, and to explore a way to ameliorate the situation inducedby overtraining.
(3) To investigate the effects of IGF-1and MGF peptide on phagocytosis, ROSgeneration and inflammatory cytokines production of MФs in vitro, and attempt todiscover the mechanisms of the inhibiton of MФs induced by overtraining from theview of IGF-1and MGF.
Methods
(1) In vivo.40male wistar rats (8-wk-old) were randomly divided into5groups:sedentary group(C, n=8), overtraining group (E), overtraining supplement with Glngroup (EG). E and EG group were respectively divided into two groups whichsacrificed at36h (E1, EG1, n=8) and7days (E2, EG2, n=8) after the last training. Allgroups except C were training in standard treadmill with an increasing load for11weeks. The criteria to evaluate the condition of the rats and judge whether theprotocol was successful were as follows: locomotory capacity, mental state, weightchange, and concentrations of hemoglobin and testosterone in blood. Peritonealmacrophages were isolated and purified after all rats were sacrificed by decapitation.The phagocytosis and the ROS generation of MФs were measured by the uptake ofneutral red and the flow cytometry respectively; The producitin of TNF-α and IL-1βwere tested by ELISA; The NADPH-oxidase activity was tested by colorimetry;Real-time PCR was used to test the expression of the following genes:NADPH-oxidase subunits (gp91phox, p22phox, p47phox, p40phox, p67phox), PKC-δ,G6PD, iNOS, IGF-1and MGF.
(2) In vitro. MФs were exposed to diffrent concentrations (1,10,50,100,200ng/ml) of IGF-1or MGF peptide for2h. The phagocytosis, the ROS generationand the inflammatory cytokines production of MФs were measured by the uptake ofneutral red, the flow cytometry and ELISA respectively.
Results
(1) Index of overtraining. The rats had to be assisted by hand to complete thejob and their mental state worsened in the later stage of exercise. Overtrainingsignificantly decreased the body weight (19.3%, P<0.01), the hemoglobin (13.5%,P<0.01) and the testosterone (55.3%, P<0.01) in blood.
(2) Phagocytosis. The phagocytosis of MФs from group E1was significantlylower than group C (decreased by27%, P<0.05). There was no significant differencein the phagocytosis of MФs between group E2and group C. Although thephagocytosis of MФs from group EG1was still lower than group C, no differencewas observed between them. There was no significant difference in the phagocytosisof MФs between group EG2, group E2and group C.
(3) ROS. The ROS generation of MФs from group E1was significantly lowerthan group C (decreased by35%, P<0.01). The ROS generation of MФs from groupE2was significantly higher than group E1(P<0.01), and no difference was observedbetween group E2and group C. The ROS generation of MФs from group EG1did notchange as compared with group E1, it still significantly lower than group C (P<0.01).The ROS generation of MФs from group EG2was significantly higher than groupEG1(P<0.01), and there was no difference as compared with group E2or group C.
(4) Response ability of inflammatory cytokines. The production of TNF-α andIL-1β of MФs from group E1was significantly lower than group C as LPSstimulation. The response ability of inflammatory cytokines of MФs from group E2was significantly higher than group E1(P<0.05), and no difference was observedbetween group E2and group C. The response ability of inflammatory cytokines ofMФs from group EG1was significantly higher than group E1, and no difference wasobserved between group EG1and group C. There was no difference between groupEG2, group E2and group C.
(5) NADPH-oxidase activity. The NADPH-oxidase activity of MФs from groupE1was significantly lower than group C. The NADPH-oxidase activity of MФs fromgroup E2was significantly higher than group E1(P<0.05), and no difference wasobserved between group E2and group C. The NADPH-oxidase activity of MФs fromgroup EG1and EG2did not change as compared with group E1and E2, respectively.The correlation analysis showed that NADPH-oxidase activity and ROS generationwere positive correlation and the pearson correlation was0.62(P<0.01)(data from5groups).
(6) NADPH-oxidase subunits. The NADPH-oxidase subunits (gp91phox,p22phox, p40phox, p67phox) mRNA levels of MФs from group E1did not change ascompared with group C, however, the expression of p47phox of MФs from group E1was significantly higher than group C (P<0.05). No difference was observed betweengroup E2, group E1and group C in all subunits of NADPH-oxidase. There was no significant difference in the NADPH-oxidase subunits (gp91phox, p22phox, p40phox,p67phox) mRNA levels of MФs between group EG1and group E1, however, theexpression of p47phox of MФs from group EG1was significantly lower than groupE1(P<0.05). All subunits of NADPH-oxidase of MФs from group EG2did not changeas compared with group E2, group C and group EG1.
(7) PKC-δ. The PKC-δ mRNA level of MФs from group E1was significantlylower than group C (P<0.05). The expression of PKC-δ of MФs from group E2wassignificantly higher than group E1(P<0.05), and no difference was observed betweengroup E2and group C. The PKC-δ mRNA level of MФs from group EG1and EG2did not change as compared with group E1and E2, respectively. The correlationanalysis showed that PKC-δ mRNA and NADPH-oxidase activity were positivecorrelation and the pearson correlation was0.51(P<0.01), PKC-δ mRNA and ROSgeneration were positive correlation and the pearson correlation was0.69(P<0.01)(data from5groups).
(8) There was no difference between group C, group E1, group E2, group EG1and group EG2in the expression of G6PD of MФs.
(9) There was no difference between group C, group E1, group E2, group EG1and group EG2in the expression of iNOS of MФs.
(10) IGF-1anf MGF. IGF-1and MGF mRNA levels in MФs from E1groupincreased significantly compared with the control group (21-fold and92-fold,respectively; p<0.01). IGF-1and MGF mRNA levels in MФs from E2group wassignificantly lower than group E1(p<0.01), and no difference was observed betweengroup E2and group C. IGF-1and MGF mRNA levels in MФs from EG1group wassignificantly lower than group E1(p<0.01), however, they were still higher thangroup C (p<0.01). IGF-1and MGF mRNA levels in MФs from EG2group wassignificantly lower than group EG1(p<0.01), and no difference was observed ascompared with group C and group E2.
(11) In vitro experiments showed that different concentrations of IGF-1(1,10,50,100,200ng/ml) had no significant effect on the phagocytosis and the ROSgeneration of MФs. IGF-1(100ng/ml) significantly increased the secretion of TNF-αof MФs as LPS stimulation. IGF-1(100,200ng/ml) significantly increased theproduction of IL-1β of MФs as LPS stimulation.
(12) In vitro experiments showed that MGF peptide impaired the phagocytosis ofMФs in dose-independent manner. Additonally, MGF peptide of some concentrations(i.e.,1,10,50,100ng/ml) significantly inhibited the ROS generation of MФs.However, different concentrations of MGF (1,10,50,100,200ng/ml) had nosignificant effect on the production of TNF-α and IL-1β of MФs as LPS stimulation.
Conclusion
(1) Overtraining inhibits the phagocytosis, the ROS generation and theinflammatory cytokines production of MФs, it may be a mechanism of whyovertraining cause immunesuppression.
(2) Supplement with glutamine ameliorates the decline of the phagocytosis andthe inflammatory cytokines production of MФs induced by overtraining, however, ithas no significant effect on the ROS generation of MФs.
(3) The mechanisms of overtraining inhibit ROS production of MФs: Thedecline of ROS production in overtraining group did not cause by suppressing theNADPH-oxidase subunits or the pathway of NADPH-oxidase production; The declineof NADPH-oxidase activity mediated by PKC-δ may play important roles in theinhibiton of ROS production; MGF produced by macrophages may play a key role inovertraining inhibit ROS production.
(4) The mechanisms of overtraining inhibit phagocytosis of MФs: MGFproduced by macrophages may play a key role in overtraining inhibit phagocytosis ofMФs.
(5) The mechanisms of overtraining inhibit inflammatory cytokines productionof MФs: IGF-1and MGF produced by macrophages do not involved, there must beother mechanisms involved in this process.
引文
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