Document Detail


Deletion of tristetraprolin caused spontaneous reactive granulopoiesis by a non-cell-autonomous mechanism without disturbing long-term hematopoietic stem cell quiescence.
MedLine Citation:
PMID:  21270394     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Tristetraprolin (TTP, Zfp36, Nup475, Tis11) dramatically reduces the stability of target mRNAs by binding to AU-rich elements in their 3' untranslated regions. Through this mechanism, TTP functions as a rheostatic, temporal regulator of gene expression. TTP knockout (KO) mice exhibit completely penetrant granulocytic hyperplasia. We have shown that the hematopoietic stem-progenitor cell compartment in TTP KO mice is also altered. Although no change was detected in long-term hematopoietic stem cell (HSC) frequency or function, as assayed by immunophenotypic markers or limiting dilution transplants, we observed increases in the frequencies and numbers of short-term HSCs, multipotent progenitors, and granulocyte-monocyte progenitors. This pattern is consistent with "reactive granulopoiesis," in which committed myeloid progenitors and more primitive progenitors cycle more actively to increase production of mature granulocytes in response to infection or adjuvant. We created reverse chimeras by transplanting wild-type bone marrow into TTP KO mice and found the "reactive granulopoiesis" phenocopied, indicating a non-hematopoietic stem-progenitor cell-autonomous mechanism. Correspondingly, we found elevated levels of the granulopoietic TTP targets IL-1β, TNF-α, and IL-6 in the plasma of TTP KO mice. Consistent with the non-cell-autonomous nature of the phenotype, we found elevated levels of IL-1β, TNF-α, and IL-6 transcripts in the livers of TTP KO mice and no detectable difference in the bone marrows. These findings demonstrate the importance of TTP in inflammatory homeostasis and highlight the ability of the hematopoietic system to respond to stress without significant numbers of quiescent HSCs entering the cell cycle.
Authors:
Ian M Kaplan; Sebastien Morisot; Diane Heiser; Wen-Chih Cheng; Min Jung Kim; Curt I Civin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-01-26
Journal Detail:
Title:  Journal of immunology (Baltimore, Md. : 1950)     Volume:  186     ISSN:  1550-6606     ISO Abbreviation:  J. Immunol.     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-02-17     Completed Date:  2011-05-16     Revised Date:  2014-09-08    
Medline Journal Info:
Nlm Unique ID:  2985117R     Medline TA:  J Immunol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2826-34     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Bone Marrow Cells / cytology,  immunology,  metabolism
Cell Cycle / immunology
Cells, Cultured
Cytokines / biosynthesis,  metabolism
Female
G0 Phase / genetics,  immunology*
Granulocytes / immunology*,  metabolism,  pathology
Hematopoietic Stem Cells / cytology,  immunology*,  metabolism
Homeostasis / genetics,  immunology
Immunophenotyping
Leukopoiesis / genetics,  immunology*
Liver / immunology,  metabolism,  pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Tristetraprolin / deficiency*,  genetics*,  physiology
Up-Regulation / immunology
Grant Support
ID/Acronym/Agency:
P01 CA070970/CA/NCI NIH HHS; P01 CA070970-02/CA/NCI NIH HHS; P01CA070970/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Cytokines; 0/Tristetraprolin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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