Tristetraprolin targets Nos2 expression in the colonic epithelium

Abstract

Tristetraprolin (TTP), encoded by the Zfp36 gene, is a zinc-finger protein that regulates RNA stability primarily through association with 3′ untranslated regions (3′ UTRs) of target mRNAs. While TTP is expressed abundantly in the intestines, its function in intestinal epithelial cells (IECs) is unknown. Here we used a cre-lox system to remove Zfp36 in the mouse epithelium to uncover a role for TTP in IECs and to identify target genes in these cells. While TTP was largely dispensable for establishment and maintenance of the colonic epithelium, we found an expansion of the proliferative zone and an increase in goblet cell numbers in the colon crypts of Zfp36ΔIEC mice. Furthermore, through RNA-sequencing of transcripts isolated from the colons of Zfp36fl/fl and Zfp36ΔIEC mice, we found that expression of inducible nitric oxide synthase (iNos or Nos2) was elevated in TTP-knockout IECs. We demonstrate that TTP interacts with AU-rich elements in the Nos2 3′ UTR and suppresses Nos2 expression. In comparison to control Zfp36fl/fl mice, Zfp36ΔIEC mice were less susceptible to dextran sodium sulfate (DSS)-induced acute colitis. Together, these results demonstrate that TTP in IECs targets Nos2 expression and aggravates acute colitis.

Targeting Tristetraprolin Expression or Functional Activity Regulates Inflammatory Response Induced by MSU Crystals

“…In this study, we showed that exposure to MSU crystals accelerated the expression of TTP both in vitro and in vivo, but we did not investigate the underlying molecular mechanism by which MSU crystals promote TTP expression. It has been reported that IL-1b, TNF-a, IL-6, COX-2 and iNOS are targets of TTP-induced mRNA degradation (34,35), and these inflammatory factors are also involved in MSU crystal-induced inflammation. Our data indicated that TTP knockdown led to elevated mRNA and protein levels of these inflammatory factors in macrophages stimulated by MSU crystals.…”

Tristetraprolin Overexpression in Non-hematopoietic Cells Protects Against Acute Lung Injury in Mice

“…For instance, TTP regulation of TNF in keratinocytes, but not in myeloid or dendritic cells, was shown to protect mice from exacerbation of psoriasis-like pathology, development of spontaneous systemic inflammation, and dactylitis ( 30 ). Another study suggested a role of intestinal epithelial cell-specific TTP in exacerbation of acute colitis ( 49 ). Along similar lines, TTP depletion in myeloid cells did not replicate the TTP-deficiency phenotype ( 16 ), and the spontaneous reactive granulopoiesis seen in TTP KO mice was suggested to be caused by a non-cell autonomous mechanism likely contributed by liver cells ( 48 ).…”

Regulation of NOS expression in vascular diseases

“…Translational efficacy and non-sense mediated mRNA decay [78,79] of the human NOS2 mRNA is regulated by a short µORF located in exon 1 of the human NOS2 gene [80]. Several RNA-BP have been shown to bind to the 3'-UTR of the human NOS2 mRNA and regulate mRNA-stability [81][82][83][84][85][86][87][88]. In addition, different miRNAs (miR-26a, miR-146a miR-939) directly bind to the human NOS2 mRNA and regulate its translatability and stability [8,59,89].…”