HUMAN INTERFERON-INDUCIBLE PROTEIN-10 - EXPRESSION AND PURIFICATION OF RECOMBINANT PROTEIN DEMONSTRATE INHIBITION OF EARLY HUMAN HEMATOPOIETIC PROGENITORS

被引:91
|
作者
SARRIS, AH
BROXMEYER, HE
WIRTHMUELLER, U
KARASAVVAS, N
COOPER, S
LU, L
KRUEGER, J
RAVETCH, JV
机构
[1] MEM SLOAN KETTERING CANC CTR,LYMPHOMA SERV,NEW YORK,NY 10021
[2] MEM SLOAN KETTERING CANC CTR,BIOCHEM GENET LAB,NEW YORK,NY 10021
[3] INDIANA UNIV,SCH MED,DEPT MED HEMATOL ONCOL & MICROBIOL IMMUNOL,INDIANAPOLIS,IN 46202
[4] INDIANA UNIV,SCH MED,WALTHER ONCOL CTR,INDIANAPOLIS,IN 46202
来源
JOURNAL OF EXPERIMENTAL MEDICINE | 1993年 / 178卷 / 03期
关键词
D O I
10.1084/jem.178.3.1127
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Human interferon-inducible protein 10 (IP-10), a member of the family of the small secreted proteins called intercrine cytokines or chemokines, is secreted by interferon gamma-stimulated T cells,. monocytes, endothelial cells, and keratinocytes. We have begun to explore the biological properties of IP-10 by cloning and overexpression in baculovirus and in bacterial protein expression systems. A 9.9-kD protein was secreted by infected insect cells, which on sodium dodecyl sulfate-polyacrilamide gel electrophoresis comigrated with keratinocyte IP-10 and with f(22-98), a bacterial recombinant fragment lacking the signal sequence but containing all other residues of IP-10. All three reacted with antibodies recognizing residues 10-98 (alphaIP-10) and 77-98 of IP-10 (alpha22), demonstrating that it is secreted by keratinocytes and insect cells after removal of the signal sequence but without proteolysis of the COOH-terminal end. Purified rIP-10 suppresses in vitro colony formation by early human bone marrow progenitor cells which need r-steel factor (rSLF) and rGM-CSF or rSLF and r-erythropoeitin (rEPO). The inhibition is dose dependent, is complete at concentrations greater-than-or-equal-to 50 ng/ml, is prevented by preincubation of rIP-10 with alphaIP-10, but not by alpha22, and is seen with highly purified CD34+ cells, suggesting direct effect of rIP-10 on the progenitors. Combination of rIP-10 and other chemokines at inactive concentrations inhibited colony formation in a synergistic manner. rIP-10 did not affect colony formation in the absence of any growth factors or in the presence of rEPO or rGM-CSF but in absence of rSLF. The effects of IP-10 may be relevant to normal marrow function and might be harnessed to protect human hematopoietic progenitors from the cytotoxic effects of chemotherapy.
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收藏
页码:1127 / 1132
页数:6
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