The scope of functional heterogeneity in macrophages has been defined by two polarized end states known as M1 and M2, which exhibit the proinflammatory activities necessary for host defense and the tissue repair activities required for restoration of homeostasis, respectively. Macrophage populations in different tissue locations exist in distinct phenotypic states across this M1/M2 spectrum and the development and abundance of individual subsets result from the local and systemic action of myeloid colony-stimulating factors (CSFs) including M-CSF and GM-CSF. These factors have relatively non-overlapping roles in the differentiation and maintenance of specific macrophage subsets. Furthermore, there is now evidence that CSFs may also regulate macrophage phenotype during challenge. Cell culture studies from multiple laboratories demonstrate that macrophages developed in the presence of GM-CSF exhibit amplified response to M1 polarizing stimuli while M-CSF potentiates responses to M2 stimuli. As a consequence, these factors can be important determinants of the magnitude and duration of both acute and chronic inflammatory pathology and may, therefore, be potential targets for therapeutic manipulation in specific human disease settings.

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IL-17 contributes to inflammatory response in part by promoting enhanced expression of chemokines, such as CXCL1, by prolonging the t1/2 of this constitutively unstable mRNA. Although IL-17 is a weak stimulus for transcription of the CXCL1 gene, it strongly potentiates message accumulation via stabilization when the mRNA is transcribed in cells stimulated with TNF. In myeloid cells, LPS-induced CXCL1 mRNA stabilization is dependent on AUUUA-containing sequence motifs that are recognized by the RNA binding protein tristetraprolin (TTP). Using deletion and site-specific mutagenesis, we report that IL-17–mediated stabilization of CXCL1 mRNA in nonmyeloid cells depends on a sequence that does not contain the AUUUA motif. Furthermore, a specific two-nucleotide mutation within this region markedly abrogates sensitivity for IL-17–mediated stabilization. Consistent with this finding, the IL-17–sensitive sequence does not exhibit increased instability in the presence of TTP, and CXCL1 mRNA remains unstable and can be stabilized in response to treatment with IL-17 in embryo fibroblasts from mice in which the TTP gene has been deleted. Whereas the RNA binding protein KSRP has been shown to participate in regulating the instability of human CXCL8 mRNA, inhibitory RNA-based reduction in KSRP does not effect the instability mediated by the IL-17–sensitive sequence motif. These findings suggest that IL-17–mediated chemokine mRNA stabilization in nonmyeloid cells uses a mechanism that is distinct from that operating to control AU-rich mRNA stability in myeloid cells.

Non-alcohol-associated fatty liver/steatohepatitis (NAFL/NASH) has become the leading cause of liver disease worldwide. NASH, an advanced form of NAFL, can be progressive and more susceptible to developing cirrhosis and hepatocellular carcinoma. Currently, lifestyle interventions are the most essential and effective strategies for preventing and controlling NAFL without the development of fibrosis. While there are still limited appropriate drugs specifically to treat NAFL/NASH, growing progress is being seen in elucidating the pathogenesis and identifying therapeutic targets. In this review, we discussed recent developments in etiology and prospective therapeutic targets, as well as pharmacological candidates in pre/clinical trials and patents, with a focus on diabetes, hepatic lipid metabolism, inflammation, and fibrosis. Importantly, growing evidence elucidates that the disruption of the gut–liver axis and microbe-derived metabolites drive the pathogenesis of NAFL/NASH. Extracellular vesicles (EVs) act as a signaling mediator, resulting in lipid accumulation, macrophage and hepatic stellate cell activation, further promoting inflammation and liver fibrosis progression during the development of NAFL/NASH. Targeting gut microbiota or EVs may serve as new strategies for the treatment of NAFL/NASH. Finally, other mechanisms, such as cell therapy and genetic approaches, also have enormous therapeutic potential. Incorporating drugs with different mechanisms and personalized medicine may improve the efficacy to better benefit patients with NAFL/NASH.

The expression of neutrophil-specific chemokines is known to be regulated via adenine-uridine-rich sequence elements in the 3-untranslated regions of their mRNAs that confer a high degree of mRNA instability. Although the presence of intron sequences in eukaryotic genes is known to enhance expression, the effect of intron content on the rate of mature, translatable mRNA degradation has not been demonstrated. In this study, we have determined the effects of intron content on the rate of decay of the chemokine CXCL1 (KC) mRNA. The half-life of KC mRNA was markedly prolonged when the primary transcript was obtained from a genomic clone containing three introns as compared with the half-life observed with sequence-identical KC mRNA derived from an intron-free cDNA construct. The effect of intron content was achieved with a single intron, and neither the intron sequences nor the intron positions were critical determinants of the outcome. The intron content produced the same effect when expressed in multiple cell types and when the sequences were stably integrated into the genome. The differential decay rates were not a consequence of differential nuclear to cytoplasmic transport. The intron content of the primary transcript did not influence the rate of KC mRNA translation and did not modulate the ability of interleukin-1 stimulation to stabilize the otherwise unstable mRNA. The intron effect on mRNA decay was seen with mRNAs containing two distinct instability determinants. These findings document that intron content marks the mRNA sequence leading to enhanced stability that is particularly evident in short lived ARE-containing mRNAs.Inflammation, a process essential in protection against the consequences of injury and infection, has the potential to produce unnecessary tissue damage and hence must be stringently controlled (1). This regulation occurs in part through the modulation of gene expression and is achieved mechanistically at multiple levels that include transcription, mRNA stability, and mRNA translation (2-5). The induction of inflammatory gene expression frequently necessitates a rapid burst of transcription, and the features controlling this process have been well studied. It is becoming increasingly recognized, however, that post-transcriptional regulation at the level of mRNA stability is also a vitally important mechanism to control gene expression during inflammation (6 -10).Adenylate-uridylate-rich elements (AREs), 2 located in the 3Ј-untranslated region (3ЈUTR) of many short lived mRNAs are the most widely recognized cis-acting elements involved in regulating mRNA decay (11, 12). These sequences have been associated not only with mRNA instability but also with stimulusinduced stabilization of mRNAs and control of translational efficiency (12-17). The pathophysiologic impact of this kind of regulation is perhaps best illustrated by the systemic inflammatory disease seen in mice bearing mutations affecting the halflife of tumor necrosis factor-␣ mRNA (18,19).Genes in most higher eukaryotes contain i...

This tutorial review highlights the mechanism of a novel non-enzymatic fast repair of DNA damage, which refers exclusively to repair DNA radicals including DNA-OH* adducts, DNA radical cations and anions by various endogenous, natural and synthetic compounds. The repair rate constants are as high as 10(9) M(-1) s(-1). In cells, when the enzymatic repair system was inhibited or before the enzymatic repair mechanism was initiated, DNA oxidative damage was significantly reduced by natural polyphenols. This decrease of DNA damage is assigned to the fast repair. Fast repair takes place through an electron transfer process, and docking of polyphenol into the DNA minor groove could be the essential step.

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mRNAs encoding inflammatory chemokines that recruit neutrophils frequently exhibit short half-lives that serve to limit their expression under inappropriate conditions but are often prolonged to ensure adequate levels during inflammatory response. Extracellular stimuli that modulate the stability of such mRNAs may be the same as the transcriptional activator, as is the case with TLR ligands, or may cooperate with independent transcriptional stimuli, as with IL-17, which extends the half-life of TNF-induced transcripts. These different stimuli engage independent signaling pathways that target different instability mechanisms distinguished by dependence on different regulatory nucleotide sequence motifs within the 3'UTRs, which involve that action of different mRNA-binding proteins. The selective use of these pathways by different stimuli and in distinct cell populations provides the potential for tailoring of chemokine expression patterns to meet specific needs in different pathophysiologic circumstances.