多发性骨髓瘤、非霍奇金淋巴瘤及Castleman病例hepcidin mRNA的表达
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摘要
研究背景：
慢性病贫血(ACD),也叫炎性贫血(AOI)是临床上最常见的贫血类型,铁利用障碍是其发病机制之一,hepcidin为调节铁代谢的激素,在其中起着重要作用。国内外研究均提示多发性骨髓瘤贫血的原因之一是ACD,病人血清中IL-6水平往往升高,白介素6(IL-6)在体外和动物实验中证实能促进hepcidin表达。但多发性骨髓瘤患者体内hepcidin的表达不详。贫血也是非霍奇金淋巴瘤及Castleman病常见的临床表现,文献报道其血清IL-6升高,hepcidin是否在这两种疾病贫血中也有作用,目前尚不清楚。
研究目的：
1,多发性骨髓瘤血清对肝腺瘤细胞系Hep-3b细胞hepcidin表达的影响。如有变化,是否能被IL-6单抗或重组人促红细胞生成素(rhEPO)抑制。
2,其它疾病如非霍奇金淋巴瘤及Castleman病hepcidin的表达。
研究方法：
1,样本收集：多发性骨髓瘤、非霍奇金淋巴瘤患者的临床资料及血清；一例Castleman病例的临床资料、血清、肝活检及受累淋巴结组织；
2,肝腺瘤细胞系Hep-3b细胞的培养；
3, Hep-3b细胞培养液中按10%浓度加入多发性骨髓瘤及非霍奇金淋巴瘤患者血清；提取Hep-3b细胞的mRNA及Castleman病例肝组织、受累淋巴结组织的mRNA,进行RT-PCR,产物电泳后荧光分析,以hepcidin与内参β-actin PCR产物的比值进行半定量分析。
研究结果：
1,未治疗的多发性骨髓瘤患者血清与Hep-3b细胞共同培养的hepcidin mRNA表达量高于正常对照组,这种升高作用能被IL-6单抗或rhEPO抑制。
2,治疗后的多发性骨髓瘤患者血清与Hep-3b细胞共同培养的hepcidin mRNA表达量显著低于未治疗者。
3,多发性骨髓瘤患者短期随访中,规律治疗能稳定血红蛋白,降低患者血清对Hep-3b细胞hepcidin mRNA的影响。
4,非霍奇金淋巴瘤患者(未治疗及治疗后)血清与Hep-3b细胞共同培养的hepcidin mRNA表达量较正常对照组降低。
5, Castleman病例肝脏hepcidin mRNA表达量升高,受累淋巴结检测到hepcidin mRNA表达。
结论：
1,未治疗的多发性骨髓瘤患者血清能促进肝腺瘤细胞系Hep-3b细胞hepcidin表达,这种促进作用可被IL-6单抗拮抗,提示IL-6可能导致Hep-3b细胞hepcidin表达量升高,从而造成ACD。这种促进作用也能被rhEPO抑制,rhEPO可能对ACD有治疗作用。治疗后的多发性骨髓瘤患者不能促进Hep-3b细胞hepcidin表达,多发性骨髓瘤患者短期随访中,血红蛋白稳定,患者血清对Hep-3b细胞hepcidin mRNA的影响减小,可能治疗使病情稳定,改善了ACD。
2,非霍奇金淋巴瘤患者血清不能促进hepcidin表达,提示ACD可能不是该组非霍奇金淋巴瘤患者贫血的原因之一
3,研究的Casleman病例的肝脏hepcidin表达量升高,淋巴结肿物也检测到hepcidin的表达,可能大量表达的hepcidin导致了该病例严重的ACD。
Background:
Anemia of chronic disease (ACD), also called anemia of inflammation (AOI) is the most common cause of anemia in clinic. A specific feature of ACD is iron disorder, which probably is caused by hepcidin, an iron-regulation hormone. Hepcidin can be elevated by interleukin6(IL-6) both in vivo and in vitro, the cytokine proved to elevate in multiple myeloma, non-Hodgkin's lymphoma and Castleman disease. It's unclear whether hepcidin is also elevated in these diseases.
Purpose:
1. The effect of multiple myeloma patients'serum on hepcidin expression of Hep-3b hepatoma cell line. If hepcidin expression is elevated, try to decrease it by adding IL-6antibody or recombinant human erythropoietin (rhEPO).
2. Hepcidin expression in non-Hodgkin's lymphoma patients and a Castleman disease patient.
Methods:
1. Sample collection:Collect the clinic information and serum of multiple myeloma and non-Hodgkin's lymphoma. Collect the clinic information, serum, liver biopsy tissue and lymphnode mass tissue of a Castleman disease patient.
2. Culture Hep-3b hepatoma cell line.
3. Add multiple myeloma and non-Hodgkin's lymphoma patients'serum the medium. Extract mRNA from Hep-3b cell and tissue, and detect hepcidin mRNA using RT-PCR.
Results:
1. The serum of untreated multiple myeloma patients elevated hepcidin expression of Hep-3b cell, compared to health control. This effect was neutralized by human IL-6antibody or rhEPO.
2. The serum of treated multiple myeloma patients did not elevate hepcidin expression of Hep-3b cell.
3. The hemoglobin was stable during the follow up period of regularly treated multiple myeloma patients and the serum effect on Hep-3b cell hepcidin expression was reduced.
4. The serum of non-Hodgkin's lymphoma patients did not elevate hepcidin expression of Hep-3b cell.
5. The Castleman disease patient's Liver hepcidin expression was elevated, and there was hepcidin expression in the lymph node.
Conclusion:
Hepcidin could be increased by treated multiple myeloma patients' serum and decreased by rhEPO, which indicates rhEPO is a potent treatment for ACD. IL-6/hepcidin pathway in Castleman disease patient's liver and lymph node probably led to her severe anemia.
慢性病贫血(ACD),也叫炎性贫血(AOI)是临床上最常见的贫血类型,铁利用障碍是其发病机制之一,hepcidin为调节铁代谢的激素,在其中起着重要作用。国内外研究均提示多发性骨髓瘤贫血的原因之一是ACD,病人血清中IL-6水平往往升高,白介素6(IL-6)在体外和动物实验中证实能促进hepcidin表达。但多发性骨髓瘤患者体内hepcidin的表达不详。贫血也是非霍奇金淋巴瘤及Castleman病常见的临床表现,文献报道其血清IL-6升高,hepcidin是否在这两种疾病贫血中也有作用,目前尚不清楚。
研究目的：
1,多发性骨髓瘤血清对肝腺瘤细胞系Hep-3b细胞hepcidin表达的影响。如有变化,是否能被IL-6单抗或重组人促红细胞生成素(rhEPO)抑制。
2,其它疾病如非霍奇金淋巴瘤及Castleman病hepcidin的表达。
研究方法：
1,样本收集：多发性骨髓瘤、非霍奇金淋巴瘤患者的临床资料及血清；一例Castleman病例的临床资料、血清、肝活检及受累淋巴结组织；
2,肝腺瘤细胞系Hep-3b细胞的培养；
3, Hep-3b细胞培养液中按10%浓度加入多发性骨髓瘤及非霍奇金淋巴瘤患者血清；提取Hep-3b细胞的mRNA及Castleman病例肝组织、受累淋巴结组织的mRNA,进行RT-PCR,产物电泳后荧光分析,以hepcidin与内参β-actin PCR产物的比值进行半定量分析。
研究结果：
1,未治疗的多发性骨髓瘤患者血清与Hep-3b细胞共同培养的hepcidin mRNA表达量高于正常对照组,这种升高作用能被IL-6单抗或rhEPO抑制。
2,治疗后的多发性骨髓瘤患者血清与Hep-3b细胞共同培养的hepcidin mRNA表达量显著低于未治疗者。
3,多发性骨髓瘤患者短期随访中,规律治疗能稳定血红蛋白,降低患者血清对Hep-3b细胞hepcidin mRNA的影响。
4,非霍奇金淋巴瘤患者(未治疗及治疗后)血清与Hep-3b细胞共同培养的hepcidin mRNA表达量较正常对照组降低。
5, Castleman病例肝脏hepcidin mRNA表达量升高,受累淋巴结检测到hepcidin mRNA表达。
结论：
1,未治疗的多发性骨髓瘤患者血清能促进肝腺瘤细胞系Hep-3b细胞hepcidin表达,这种促进作用可被IL-6单抗拮抗,提示IL-6可能导致Hep-3b细胞hepcidin表达量升高,从而造成ACD。这种促进作用也能被rhEPO抑制,rhEPO可能对ACD有治疗作用。治疗后的多发性骨髓瘤患者不能促进Hep-3b细胞hepcidin表达,多发性骨髓瘤患者短期随访中,血红蛋白稳定,患者血清对Hep-3b细胞hepcidin mRNA的影响减小,可能治疗使病情稳定,改善了ACD。
2,非霍奇金淋巴瘤患者血清不能促进hepcidin表达,提示ACD可能不是该组非霍奇金淋巴瘤患者贫血的原因之一
3,研究的Casleman病例的肝脏hepcidin表达量升高,淋巴结肿物也检测到hepcidin的表达,可能大量表达的hepcidin导致了该病例严重的ACD。
Background:
Anemia of chronic disease (ACD), also called anemia of inflammation (AOI) is the most common cause of anemia in clinic. A specific feature of ACD is iron disorder, which probably is caused by hepcidin, an iron-regulation hormone. Hepcidin can be elevated by interleukin6(IL-6) both in vivo and in vitro, the cytokine proved to elevate in multiple myeloma, non-Hodgkin's lymphoma and Castleman disease. It's unclear whether hepcidin is also elevated in these diseases.
Purpose:
1. The effect of multiple myeloma patients'serum on hepcidin expression of Hep-3b hepatoma cell line. If hepcidin expression is elevated, try to decrease it by adding IL-6antibody or recombinant human erythropoietin (rhEPO).
2. Hepcidin expression in non-Hodgkin's lymphoma patients and a Castleman disease patient.
Methods:
1. Sample collection:Collect the clinic information and serum of multiple myeloma and non-Hodgkin's lymphoma. Collect the clinic information, serum, liver biopsy tissue and lymphnode mass tissue of a Castleman disease patient.
2. Culture Hep-3b hepatoma cell line.
3. Add multiple myeloma and non-Hodgkin's lymphoma patients'serum the medium. Extract mRNA from Hep-3b cell and tissue, and detect hepcidin mRNA using RT-PCR.
Results:
1. The serum of untreated multiple myeloma patients elevated hepcidin expression of Hep-3b cell, compared to health control. This effect was neutralized by human IL-6antibody or rhEPO.
2. The serum of treated multiple myeloma patients did not elevate hepcidin expression of Hep-3b cell.
3. The hemoglobin was stable during the follow up period of regularly treated multiple myeloma patients and the serum effect on Hep-3b cell hepcidin expression was reduced.
4. The serum of non-Hodgkin's lymphoma patients did not elevate hepcidin expression of Hep-3b cell.
5. The Castleman disease patient's Liver hepcidin expression was elevated, and there was hepcidin expression in the lymph node.
Conclusion:
Hepcidin could be increased by treated multiple myeloma patients' serum and decreased by rhEPO, which indicates rhEPO is a potent treatment for ACD. IL-6/hepcidin pathway in Castleman disease patient's liver and lymph node probably led to her severe anemia.
引文
1. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005:352:1011-23.
2. John A. The anemia of inflammation/malignancy:mechanisms and management. Hematolgoy 2008:159-64.
3. Fleming MD. The regulation of hepcidin and its effects on systemic and cellular iron metabolism. Hematology Am Soc Hematol Educ Program 2008:2008:151-8.
4. Krause A, Neitz S, Magert HJ, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000:480:147-50.
5. Kemna EH, Tjalsma H, Willems HL, et al. Hepcidin:from discovery to differential diagnosis. Haematologica 2008:93:90-7.
6. Nicolas G, Vlatte L, Bennoun M, et al. Hepcidin, a new iron regulatory pepetide. Blood Cells Mol Dis 2002:29:327-35.
7.孟婵,周道斌,赵永强.重组人EPO对IL-6诱导人原代肝细胞和HepG2细胞Hepcidin mRNA表达的抑制作用.中国实验血液学杂志2008;16：1413-7.
8.孙雪峰,周道斌,赵永强.EPO对铁调节蛋白hepcidin表达影响的研究.中国实验血液学杂志2006;14：778-82.
9. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004:113:1271-6.
10. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001:276:7806-10.
11. Inamura J, Ikuta K, Jimbo J, et al. Upregulation of hepcidin by interleukin-lbeta in human hepatoma cell lines. Hepatol Res 2005:33:198-205.
12. Goldman L, Ausiello D, eds. Cecil.23 ed:Saunders; 2007.
13. Sharma S, Nemeth E, Chen YH, et al. Involvement of hepcidin in the anemia of multiple myeloma. Clin Cancer Res 2008:14:3262-7.
14.朱宏丽,汪月增,韩小萍,等.恶性淋巴瘤患者血清中IL-2、Sil-2R、IL-6、IL-8和TNF-a的测定.中华血液学杂志1998;19：85-8.
15.郭晓强,王利青,黄凯Hepcidin检测研究进展.临床检验杂志2007：25：474-5.
16.段明辉.人体内血清pro-hepcidin水平检测及其在临床诊断中应用的初步研究.北京：中国医学科学院北京协和医学院;2008.
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1, Guenter W and Lawrence G. Anemia of chronic disease. New England Journal of Medicine,10 March 2005; 352(10):1011-1023.
2, Parviz K, Amir A, Lotta H, et al. Expression of erythropoietin receptor and in vitro functional effects of epoetins in B-cell malignancies. Clinic Cancer Research,2007; 13(12):3536-3543.
3, John A. The anemia of inflammation/malignancy:mechanisms and management. Hematology 2008; 159-164.
4, Alexander K, Susanne N, Hans M, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Letters,31 July 2000; 480(2000):147-150.
5, Christina P, Erika V, Alan W, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver, the Journal of Biologic Chemistry,16 March 2001:276(11):7806-7810.
6, Pigeon C, Ilyin G, Courselaud B, et al. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is over expressed during iron overload. Journal of Biological Chemistry,2001; 276:7811-7819.
7, Erwin K, Harold T, Hans W, et al. Hepcidin:from discovery to differential diagnosis. Haemotologica, Jan 2008; 93(1):90-97.
8, Sanjai S, Elizabeta N, Yi-Hsiang C, et al. Involvement of hepcidin in the anemia of multiple myeloma. Human Cancer Biology,1 June 2008; 14(11):3262-3267.
9, Tomas G, Gordana 0, Domenico G, et al. Immunoassay for human serum hepcidin. Blood, prepublised online 8 August 2008; Dol 10.1182.
10,孙雪峰,周道斌,赵永强.EPO对铁调节蛋白hepcidin表达影响的研究.中国实验血液学杂志,2006：14(4)：778-782.
11,孟婵,周道斌,赵永强等.重组人EPO对IL-6诱导人原代肝细胞和HepG2细胞Hepcidin mRNA表达的抑制作用.中国实验血液学杂志,2008;16(6)：1413-1417.
12, Mark F. The regulation of hepcidin and its effects on systemic and cellular iron metabolism. Hematology 2008; 151-156.
2. John A. The anemia of inflammation/malignancy:mechanisms and management. Hematolgoy 2008:159-64.
3. Fleming MD. The regulation of hepcidin and its effects on systemic and cellular iron metabolism. Hematology Am Soc Hematol Educ Program 2008:2008:151-8.
4. Krause A, Neitz S, Magert HJ, et al. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000:480:147-50.
5. Kemna EH, Tjalsma H, Willems HL, et al. Hepcidin:from discovery to differential diagnosis. Haematologica 2008:93:90-7.
6. Nicolas G, Vlatte L, Bennoun M, et al. Hepcidin, a new iron regulatory pepetide. Blood Cells Mol Dis 2002:29:327-35.
7.孟婵,周道斌,赵永强.重组人EPO对IL-6诱导人原代肝细胞和HepG2细胞Hepcidin mRNA表达的抑制作用.中国实验血液学杂志2008;16：1413-7.
8.孙雪峰,周道斌,赵永强.EPO对铁调节蛋白hepcidin表达影响的研究.中国实验血液学杂志2006;14：778-82.
9. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004:113:1271-6.
10. Park CH, Valore EV, Waring AJ, et al. Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001:276:7806-10.
11. Inamura J, Ikuta K, Jimbo J, et al. Upregulation of hepcidin by interleukin-lbeta in human hepatoma cell lines. Hepatol Res 2005:33:198-205.
12. Goldman L, Ausiello D, eds. Cecil.23 ed:Saunders; 2007.
13. Sharma S, Nemeth E, Chen YH, et al. Involvement of hepcidin in the anemia of multiple myeloma. Clin Cancer Res 2008:14:3262-7.
14.朱宏丽,汪月增,韩小萍,等.恶性淋巴瘤患者血清中IL-2、Sil-2R、IL-6、IL-8和TNF-a的测定.中华血液学杂志1998;19：85-8.
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