Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration.

Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (>40%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of >1000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver pro-regenerative therapies.

Human decidual NK cells from gravid uteri and NK cells from cycling endometrium are distinct NK cell subsets.

Human NK cells from the decidua basalis of gravid uteri and from the cycling endometrium of women undergoing hysterectomy were isolated and compared by gene expression profiling using Affymetrix microarrays with probes representing approximately 47,400 transcripts. Substantial differences indicate that these two types of NK cells represent distinct subsets.

Two AraC/XylS family members can independently counteract the effect of repressing sequences upstream of the hilA promoter.

During infection of its hosts, Salmonella enterica serovar Typhimurium (S. typhimurium) enters the epithelial cells of the small intestine. This process requires a number of invasion genes encoded on Salmonella pathogenicity island 1 (SPI1), a 40 kb stretch of DNA located near minute 63 of the S. typhimurium chromosome. Expression of S. typhimurium SPI1 invasion genes is activated by the transcription factor HilA. hilA is tightly regulated in response to many environmental conditions, including oxygen, osmolarity and pH. Regulation of hilA expression may serve to limit invasion gene expression to the appropriate times during Salmonella infection. We have mapped the transcription start site of hilA and identified regions of the promoter that are required for the repression of hilA expression by conditions unfavourable for Salmonella invasion. We have also identified two SPI1-encoded genes, hilC and hilD, that can independently derepress hilA expression. HilC and HilD are both members of the AraC/XylS family of transcriptional regulators. A mutation in hilD significantly reduces the ability of S. typhimurium to enter tissue culture cells, whereas a mutation in hilC only modestly affects Salmonella invasion. Based on these results, we have updated our model of Salmonella SPI1 invasion gene regulation. We also speculate on the possible significance of this model for Salmonella pathogenesis.