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含Src同源2结构域的5-肌醇磷酸酶（SHIP）通过提高骨髓中髓样细胞的白细胞介素-6产生来抑制淋巴细胞发育的早期阶段。

Src homology 2-containing 5-inositol phosphatase (SHIP) suppresses an early stage of lymphoid cell development through elevated interleukin-6 production by myeloid cells in bone marrow.

作者信息

Nakamura Koji, Kouro Taku, Kincade Paul W, Malykhin Alexander, Maeda Kazuhiko, Coggeshall K Mark

机构信息

Immunobiology and Cancer Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.

出版信息

J Exp Med. 2004 Jan 19;199(2):243-54. doi: 10.1084/jem.20031193. Epub 2004 Jan 12.

DOI:10.1084/jem.20031193
PMID:14718513
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1797415/
Abstract

The Src homology (SH)2-containing inositol 5-phosphatase (SHIP) negatively regulates a variety of immune responses through inhibitory immune receptors. In SHIP(-/-) animals, we found that the number of early lymphoid progenitors in the bone marrow was significantly reduced and accompanied by expansion of myeloid cells. We exploited an in vitro system using hematopoietic progenitors that reproduced the in vivo phenotype of SHIP(-/-) mice. Lineage-negative marrow (Lin(-)) cells isolated from wild-type mice failed to differentiate into B cells when cocultured with those of SHIP(-/-) mice. Furthermore, culture supernatants of SHIP(-/-) Lin(-) cells suppressed the B lineage expansion of wild-type lineage-negative cells, suggesting the presence of a suppressive cytokine. SHIP(-/-) Lin(-) cells contained more IL-6 transcripts than wild-type Lin(-) cells, and neutralizing anti-IL-6 antibody rescued the B lineage expansion suppressed by the supernatants of SHIP(-/-) Lin(-) cells. Finally, we found that addition of recombinant IL-6 to cultures of wild-type Lin(-) bone marrow cells reproduced the phenotype of SHIP(-/-) bone marrow cultures: suppression of B cell development and expansion of myeloid cells. The results identify IL-6 as an important regulatory cytokine that can suppress B lineage differentiation and drive excessive myeloid development in bone marrow.

摘要

含Src同源区（SH）2的肌醇5-磷酸酶（SHIP）通过抑制性免疫受体对多种免疫反应起负调节作用。在SHIP基因敲除（SHIP(-/-)）的动物中，我们发现骨髓中早期淋巴祖细胞的数量显著减少，并伴有髓样细胞的扩增。我们利用一种体外系统，该系统使用造血祖细胞，重现了SHIP(-/-)小鼠的体内表型。从野生型小鼠分离的谱系阴性骨髓（Lin(-)）细胞与SHIP(-/-)小鼠的细胞共培养时，无法分化为B细胞。此外，SHIP(-/-) Lin(-)细胞的培养上清液抑制了野生型谱系阴性细胞的B谱系扩增，提示存在一种抑制性细胞因子。SHIP(-/-) Lin(-)细胞比野生型Lin(-)细胞含有更多的IL-6转录本，中和抗IL-6抗体挽救了被SHIP(-/-) Lin(-)细胞上清液抑制的B谱系扩增。最后，我们发现向野生型Lin(-)骨髓细胞培养物中添加重组IL-6重现了SHIP(-/-)骨髓培养物的表型：抑制B细胞发育和髓样细胞扩增。这些结果确定IL-6是一种重要的调节性细胞因子，可抑制B谱系分化并驱动骨髓中过度的髓样发育。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/5517a01b4373/20031193f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/5440326edb59/20031193f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/0e54e7065895/20031193f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/ca782ce25ba7/20031193f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/b398c7a25aee/20031193f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/ad3a912b002d/20031193f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/e11b903843b2/20031193f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/5517a01b4373/20031193f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/5440326edb59/20031193f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/0e54e7065895/20031193f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/ca782ce25ba7/20031193f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/b398c7a25aee/20031193f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/ad3a912b002d/20031193f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/e11b903843b2/20031193f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/095a/2211769/5517a01b4373/20031193f7.jpg

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