哮喘气道炎症对PBMC中HSP90和GR表达的影响及HSP90和GR失衡在T细胞凋亡中的作用
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摘要
目的 探讨GR和HSP90在糖皮质激素敏感型(SS)、依赖型(SD)和抵抗型(SR)哮喘中的表达及其在SR哮喘发病中的作用。
方法 采用反转录-聚合酶链反应(RT-PCR)和蛋白印迹(Western blot)的方法，分别测定正常人(10例)、SS哮喘(10例)、SD哮喘(5例)和SR哮喘(10例)的外周血单个核细胞(PBMC)中，GR、HSP90mRNA表达和GR、HSP90蛋白水平，并在体外用IL-2、IL-4分别和联合刺激上述细胞，观察其受刺激后GR、HSP90mRNA表达和GR、HSP90蛋白水平的改变情况。
结果 SR哮喘的GR和HSP90mRNA表达水平最高(分别为0.730±0.171、1.122±0.165)，SS哮喘次之(分别为0.359±0.350、0.885_+0.250)，SD哮喘最低(分别为0.017_+0.008、0.078_+0.039)。正常人有一定表达(分别为0.052±0.013、0.362±0.101)。GR和HSP90mRNA的表达各组间相比P<0.05。正常人、SS、SD和SR哮喘HSP90／GR的比值分别为7.15±1.84、8.39±7.95、5.51±3.30、1.574±0.18，SR哮喘HSP90／GR比值明显低于前三组(P<0.05)。IL-2和IL-4单独刺激对SS、SD和SR哮喘的GR、HSP90mRNA表达无明显影响，二者联合刺激可使SS、SD和SR哮喘GRmRNA表达增强和SS、SD哮喘HSP90mRNA表达增强，却不能使SR哮喘HSP90mRNA表达增强。GR和HSP90的蛋白水平与其mRNA的表达相同。
结论 SR哮喘中HSP90表达相对不足造成HSP90／GR比值降低可能是SR哮喘形成的原因之一，IL-2+IL-4对GR和HSP90表达的不同调节作用可能是形成SR哮喘HSP90／GR比值降低的原因。
Objective To investigate the expression of GR,HSP90mRNA in peripheral blood mononuclear cells(PBMC) from steroid-sensitive asthma(SS),steroid-dependant asthma(SD) and steroid-resistant asthma(SR) and the role of GR and HSP90 on the pathogenesis of SR. Method With reverse transcription-polymerase chain reaction(RT-PCR) and Western blot ,the expression of GR and HSP90 were detected in PBMC from 10 normal volunteers, 10SS,5SD and 6SR as and as in vitro cultured in the absence and presence of IL-2 and IL-4. Results The expression of GR,HSP90mRNA in PBMC from SR patients(0.730± 0.171,1.122 ± 0.165 respectively) was the highest.The seconds from SS patients(0.359±0.350,0.885 ± 0.250 respectively).The lowest was from SD patients(0.017±0.008, 0.078±0.039 respectively).The expression of GR and HSP90mRNA in PBMC from normal volunteers was 0.052 ± 0.013 and 0.362±0.101 respectively.The difference of the expression of GR or HSP90 between each other of them was significant(P<0.05).The ratio of hsp90/GR in normal volunteers,SS,SD and SR patients was 7.15 ± 1.84,8.39 ± 7.95,5.51 ± 3.30 and 1.57 ± 0.18 respectively.HSP90/GR in SR was significant lower than that of the others and it suggested that the expression of HSP90mRNA was not sufficient in this patients.When PBMC from SS,SD and SR were incubated with IL-2 or IL-4 alone,no change of GR and HSP90 mRNA expression were observed. When incubated with combination of IL-2 and IL-4,a significant higher expression of GRmRNA expression was observed in all asthmatics and a significant higher expression of HSP90mRNA was observed only in SS and SD patients but not in SR patients.The level of proteins of GR and HSP90 was similar with that of their mRNA experssion.
Conclusion The low of the ratio of HSP90/GR may be one of the cause of SR.IL-2 and IL-4 may play a important role in the imbalance of HSP90/GR.
方法 采用反转录-聚合酶链反应(RT-PCR)和蛋白印迹(Western blot)的方法，分别测定正常人(10例)、SS哮喘(10例)、SD哮喘(5例)和SR哮喘(10例)的外周血单个核细胞(PBMC)中，GR、HSP90mRNA表达和GR、HSP90蛋白水平，并在体外用IL-2、IL-4分别和联合刺激上述细胞，观察其受刺激后GR、HSP90mRNA表达和GR、HSP90蛋白水平的改变情况。
结果 SR哮喘的GR和HSP90mRNA表达水平最高(分别为0.730±0.171、1.122±0.165)，SS哮喘次之(分别为0.359±0.350、0.885_+0.250)，SD哮喘最低(分别为0.017_+0.008、0.078_+0.039)。正常人有一定表达(分别为0.052±0.013、0.362±0.101)。GR和HSP90mRNA的表达各组间相比P<0.05。正常人、SS、SD和SR哮喘HSP90／GR的比值分别为7.15±1.84、8.39±7.95、5.51±3.30、1.574±0.18，SR哮喘HSP90／GR比值明显低于前三组(P<0.05)。IL-2和IL-4单独刺激对SS、SD和SR哮喘的GR、HSP90mRNA表达无明显影响，二者联合刺激可使SS、SD和SR哮喘GRmRNA表达增强和SS、SD哮喘HSP90mRNA表达增强，却不能使SR哮喘HSP90mRNA表达增强。GR和HSP90的蛋白水平与其mRNA的表达相同。
结论 SR哮喘中HSP90表达相对不足造成HSP90／GR比值降低可能是SR哮喘形成的原因之一，IL-2+IL-4对GR和HSP90表达的不同调节作用可能是形成SR哮喘HSP90／GR比值降低的原因。
Objective To investigate the expression of GR,HSP90mRNA in peripheral blood mononuclear cells(PBMC) from steroid-sensitive asthma(SS),steroid-dependant asthma(SD) and steroid-resistant asthma(SR) and the role of GR and HSP90 on the pathogenesis of SR. Method With reverse transcription-polymerase chain reaction(RT-PCR) and Western blot ,the expression of GR and HSP90 were detected in PBMC from 10 normal volunteers, 10SS,5SD and 6SR as and as in vitro cultured in the absence and presence of IL-2 and IL-4. Results The expression of GR,HSP90mRNA in PBMC from SR patients(0.730± 0.171,1.122 ± 0.165 respectively) was the highest.The seconds from SS patients(0.359±0.350,0.885 ± 0.250 respectively).The lowest was from SD patients(0.017±0.008, 0.078±0.039 respectively).The expression of GR and HSP90mRNA in PBMC from normal volunteers was 0.052 ± 0.013 and 0.362±0.101 respectively.The difference of the expression of GR or HSP90 between each other of them was significant(P<0.05).The ratio of hsp90/GR in normal volunteers,SS,SD and SR patients was 7.15 ± 1.84,8.39 ± 7.95,5.51 ± 3.30 and 1.57 ± 0.18 respectively.HSP90/GR in SR was significant lower than that of the others and it suggested that the expression of HSP90mRNA was not sufficient in this patients.When PBMC from SS,SD and SR were incubated with IL-2 or IL-4 alone,no change of GR and HSP90 mRNA expression were observed. When incubated with combination of IL-2 and IL-4,a significant higher expression of GRmRNA expression was observed in all asthmatics and a significant higher expression of HSP90mRNA was observed only in SS and SD patients but not in SR patients.The level of proteins of GR and HSP90 was similar with that of their mRNA experssion.
Conclusion The low of the ratio of HSP90/GR may be one of the cause of SR.IL-2 and IL-4 may play a important role in the imbalance of HSP90/GR.
引文
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11 Sousa AR,Lane SJ, Soh C, et al. In vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosyphorylation of JUN N-terminal kinase and failure of prednisolone to inhibit JUN N-terminal kinase phosphorylation. J Allergy Clin Immunol,1999,104( 3pt 1):565-574.
12 Kang KI, Meng X, Leelerc JD, et al. The molecular chaperone HSP90 can negatively regulate the activity of glucocorticosteroid-dependent promoter. Proc Natl Acad Sci USA, 1999, 96: 1439-1444.
13 Bronnegard M, Boos J, Marcus C, et al. Expression of HSP90 beta messenger ribonucleic acid in patients with familial glucocorticoid resistant-correlation to receptor status. J Steroid Biochem Mol Biol, 1995, 52: 345-349.
14 姚彬，佟万成，朱元珏等，热休克蛋白70、90基因在糖皮质激素抵抗型哮喘患者单个核细胞中的表达．中华结核和呼吸杂志，1998，5：289-291．
15 Sher ER, Surs W, Kam JC, et al. Characterization of T lymphocytes and glucocorticoid receptor in steroid resistant asthma. J Allergy Clin Immunol, 1992, 89: 285-287.
16 Jeffrey CK, Stanley JS, Surs W, et al. Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol, 1993, 151: 3460-3466.
17 Spahn JD, Szefler SJ, Surs W, et al. A Novel Action of IL-13: Induction of diminished monocyte glucocord receptor-binding affinity. J Immunol, 1996, 157: 2654-2659.
18 Adock IM, Sterens DA, Barnes PJ, et al. Interactions of glucocorticoids and β2-agonist. Eur Respir J, 1996, 9: 160-168.
19 Barnes PJ. Anti-inflammatary actions of glucocorticoids: molecular mechanisms. Clinical Science, 1998, 94: 557-572.
20 Corrigan CJ, Bungre JK, Assoufi B, et al. Glucocorticoid resistant asthma:T-lymphocyte steroid metabolism and sensitivity to glucocorticoids and immunosuppewssive agents. Eur Respir J, 1996, 9: 2077-86.
21 Khatri SB, Erzurum SC. Alternative therapies for corticosteroid-dependent asthma. Clinical Pulmonary Medicine, 1999, 6: 271-277.
22 Rabinovitch N, Gelfand EW, Leung DY. The role of immunoglobulin therapy in allergic diseases. Allergy, 1999, 54: 662-8.
23 Spahn JD, Leung DY, Chan MT, et al. Mechanisms of glucocorticoid reduction in asthmatic subjects treated with intravenous immunglulin. J allergy Clin??Immunol, 1999, 103 (3 pt 1): 421-6.
24 Ihaku D, Cameron L, Suzuki M, et al. Montelukast, a leukotriene receptor antagonist, inhibits the late airway response to antigen, airway eosinophilia, and IL-5 expressing cells in brown norway rats. J Allergy Clin Immunol, 1999, 104: 1147-54.
25 Pizzichini E, Leff JA, Reiss TF, et al .Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J, 1999, 14: 12-8.
26 Spahn JD, handwehr LD, Nimmagadda S, et al. Effects of glucocorticords on lymphocyte activation in patients with steroid-sensitiveand steroid-resistant asthma. J Allergy clin Immunol, 1996, 98: 1073-79.
2 Spahn JD, Leung DY, Szefler SJ New insights into the pathogenesis and management of steroid-resistant asthma Journal of asthma. 1997, 34: 177-194
3 BarnesPJ. Ant-iinflammatory action of glucocorticoids: molecular mechanism. Clinical Science 1998, 94: 557-572
4 Picard D, Khursheed B, Carbedian MJ, et al Reduced levels of hsp90 compromise steroid receptor action in vivo Nature 1990, 348: 166-168
5 Vamvakopoulos NO Tissue-specific exxpression of heat shock protein 90 and 90: potential implication for differential sensitivity of tissues to glucocorticoids Molecular and cellular endocrinology 1993, 98: 49-54
6 Kang Kl, Meng X, Leclerc JD etal The molecular chaperone hsp90 can negatively regulate the activity of a glucocorticosteroid dependent promoter Proc Natl Acad Sci USA 1999, 96: 1439-1444
7 姚彬，佟万成，朱元珏等 热休克蛋白70、90基因在糖皮质激素抵抗型哮喘患者血单个核细胞中的表达中华结核和呼吸杂志，1998，21：289-292
8 Sher ER, Surs W, KamJC et al Characterization of T lymphocytes and glucocorticoid receptor in steroid resistant asthma J Allergy Clin Immunol 1992, 89: 285-287
9 Kam JC, Azefler SJ, surs Wet al Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids The Journal of Immunology 1993, 151: 3460-3466
10 Sher ER, Leung DYM, Surs Wet al Steroid-resistant asthma: Cellular mechanisms contributing to inadequate response to glucocorticoid therapy J Clin Invest 1994, 93: 33-39
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17 Demoly P, Chung KF Pharmacology of cortisteroids Respiratory Medicine 1998,92:385-394
18 Barnes PJ Anti-inflammatory action of glucocorticoids:molecular mechnisms Clinical Science 1998,94:557-572
19 Lane SJ, Vaja S, Swaminathan R Effects of prednisolone on bone turnover in patients with corticosterpid resistant asthma Clin Exp Allergy 1996,26:1197-1201
20 Rose JO, Nickelson JA,Yurchak AM et al Prednisolone disposition in steroid dependent asthmatics J Allergy Clin Immunol 1980,66:366-373
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23 Lane SJ, Arkinson BA,Swaminathan R et al Hypothalamic-pituitary-adrenal axis in corticosteroid-resisitant bronchial asthma Am J Respir Care Med 1996,153:557-560
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1 Demoly P, Chung KF. Pharmaclogy of corticosteroids. Respiratoey Medicine 1998,92:385-394.
2 Barnes PJ, Woolcock AJ. Difficult asthma. Eur Respir J , 1998,12:1209-1218.
3 Spahn JD, Leung DYM, Szeffer SJ. New insights into pathogenesis and management of steroid-resistant asthma. Journal of asthma, 1997, 34:177-194.
4 Sher ER, Leung DYM, Surs W, et al. Steroid-resistant asthma:cellular mechanisms contributing to inadequate response to glucocorticoid therapy, J Clin Invest 1994, 93:33-39.
5 Demoly P, Jaffuel D, Mathieu M, et al. Glucocorticoid insensitive asthma:A one year clinical follow up pilot study. Thoax, 1998, 53 :1063-1065.
6 Bamberger CM, Bamberge AM, Castro MD, et al. Glucocorticoid receptor B, a potential endogenous inhabtor of glucocorticoid action in humans. J Clin Invest,1995,95:2435-2441.
7 Barnes PJ, Adcock IM. Transcription factors and asthma. Eur Respir J, 1998,12:221-234.
8 Adcock IM, Lane SJ, Brown CR, et al . Differences in binding of glucocorticoid receptor to DNA in steroid-resistant asthma. J Immunol, 1995 154: 3500-3505.
9 Adcock IM, Lane SJ, Brown CR, et al. Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid resistant asthma. J Exp Med, 1995,182:1951-1958.
10 Lane SJ, Adcock IM, Richards SD, et al. Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes. J Clin Invest,1998,102:2156-2164.
11 Sousa AR,Lane SJ, Soh C, et al. In vivo resistance to corticosteroids in bronchial asthma is associated with enhanced phosyphorylation of JUN N-terminal kinase and failure of prednisolone to inhibit JUN N-terminal kinase phosphorylation. J Allergy Clin Immunol,1999,104( 3pt 1):565-574.
12 Kang KI, Meng X, Leelerc JD, et al. The molecular chaperone HSP90 can negatively regulate the activity of glucocorticosteroid-dependent promoter. Proc Natl Acad Sci USA, 1999, 96: 1439-1444.
13 Bronnegard M, Boos J, Marcus C, et al. Expression of HSP90 beta messenger ribonucleic acid in patients with familial glucocorticoid resistant-correlation to receptor status. J Steroid Biochem Mol Biol, 1995, 52: 345-349.
14 姚彬，佟万成，朱元珏等，热休克蛋白70、90基因在糖皮质激素抵抗型哮喘患者单个核细胞中的表达．中华结核和呼吸杂志，1998，5：289-291．
15 Sher ER, Surs W, Kam JC, et al. Characterization of T lymphocytes and glucocorticoid receptor in steroid resistant asthma. J Allergy Clin Immunol, 1992, 89: 285-287.
16 Jeffrey CK, Stanley JS, Surs W, et al. Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol, 1993, 151: 3460-3466.
17 Spahn JD, Szefler SJ, Surs W, et al. A Novel Action of IL-13: Induction of diminished monocyte glucocord receptor-binding affinity. J Immunol, 1996, 157: 2654-2659.
18 Adock IM, Sterens DA, Barnes PJ, et al. Interactions of glucocorticoids and β2-agonist. Eur Respir J, 1996, 9: 160-168.
19 Barnes PJ. Anti-inflammatary actions of glucocorticoids: molecular mechanisms. Clinical Science, 1998, 94: 557-572.
20 Corrigan CJ, Bungre JK, Assoufi B, et al. Glucocorticoid resistant asthma:T-lymphocyte steroid metabolism and sensitivity to glucocorticoids and immunosuppewssive agents. Eur Respir J, 1996, 9: 2077-86.
21 Khatri SB, Erzurum SC. Alternative therapies for corticosteroid-dependent asthma. Clinical Pulmonary Medicine, 1999, 6: 271-277.
22 Rabinovitch N, Gelfand EW, Leung DY. The role of immunoglobulin therapy in allergic diseases. Allergy, 1999, 54: 662-8.
23 Spahn JD, Leung DY, Chan MT, et al. Mechanisms of glucocorticoid reduction in asthmatic subjects treated with intravenous immunglulin. J allergy Clin??Immunol, 1999, 103 (3 pt 1): 421-6.
24 Ihaku D, Cameron L, Suzuki M, et al. Montelukast, a leukotriene receptor antagonist, inhibits the late airway response to antigen, airway eosinophilia, and IL-5 expressing cells in brown norway rats. J Allergy Clin Immunol, 1999, 104: 1147-54.
25 Pizzichini E, Leff JA, Reiss TF, et al .Montelukast reduces airway eosinophilic inflammation in asthma: a randomized, controlled trial. Eur Respir J, 1999, 14: 12-8.
26 Spahn JD, handwehr LD, Nimmagadda S, et al. Effects of glucocorticords on lymphocyte activation in patients with steroid-sensitiveand steroid-resistant asthma. J Allergy clin Immunol, 1996, 98: 1073-79.