NDLI: Deletion of Tristetraprolin (TTP) caused spontaneous reactive granulopoiesis by a non-cell autonomous mechanism without disturbing LT-HSC quiescence1

Content Provider	PubMed Central
Author	Kaplan, Ian M. Morisot, Sebastien Heiser, Diane Cheng, Wen-chih Kim, Min Jung Civin, Curt I.
Abstract	Tristetraprolin (TTP, Zfp36, Nup475, Tis11) dramatically reduces the stability of target mRNAs by binding to AU-rich elements (AREs) in their 3′UTRs. Through this mechanism, TTP functions as a rheostatic, temporal regulator of gene expression. TTP KO mice exhibit completely penetrant granulocytic hyperplasia. We have shown that the hematopoietic stem-progenitor cell (HSPC) compartment in TTP KO mice is also altered. Although no change was detected in long-term HSC (LT-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 (ST-HSCs), multipotent progenitors (MPPs) and granulocyte-monocyte progenitors (GMPs). 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 WT bone marrow (BM) into TTP KO mice and found the ‘reactive granulopoiesis’ phenocopied, indicating a non-HSPC-autonomous mechanism. Correspondingly, we found elevated levels of the granulopoietic TTP targets IL-1β, TNFα 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, TNFα and IL-6 transcripts in the livers of TTP KO mice and no detectable difference in the BMs. 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.
Related Links	http://dx.doi.org/10.4049/jimmunol.1002806
Ending Page	2834
Page Count	9
Starting Page	2826
File Format	PDF
ISSN	00221767
e-ISSN	15506606
Journal	Journal of immunology (Baltimore, Md. : 1950)
Issue Number	5
Volume Number	186
Language	English
Publisher Date	2011-03-01
Access Restriction	Open
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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