Downregulation of the AU-Rich RNA-Binding Protein ZFP36 in Chronic HBV Patients: Implications for Anti-Inflammatory Therapy

Inflammation caused by chronic hepatitis B virus (HBV) infection is associated with the development of cirrhosis and hepatocellular carcinoma; however, the mechanisms by which HBV infection induces inflammation and inflammatory cytokine production remain largely unknown. We analyzed the gene expression patterns of lymphocytes from chronic HBV-infected patients and found that the expression of ZFP36, an AU-rich element (ARE)-binding protein, was dramatically reduced in CD4+ and CD8+ T lymphocytes from chronic HBV patients. ZFP36 expression was also reduced in CD14+ monocytes and in total PBMCs from chronic HBV patients. To investigate the functional consequences of reduced ZFP36 expression, we knocked down ZFP36 in PBMCs from healthy donors using siRNA. siRNA-mediated silencing of ZFP36 resulted in dramatically increased expression of multiple inflammatory cytokines, most of which were also increased in the plasma of chronic HBV patients. Furthermore, we found that IL-8 and RANTES induced ZFP36 downregulation, and this effect was mediated through protein kinase C. Importantly, we found that HBsAg stimulated PBMCs to express IL-8 and RANTES, resulting in decreased ZFP36 expression. Our results suggest that an inflammatory feedback loop involving HBsAg, ZFP36, and inflammatory cytokines may play a critical role in the pathogenesis of chronic HBV and further indicate that ZFP36 may be an important target for anti-inflammatory therapy during chronic HBV infection

Differentiation, growth and morphogenesis: Acetabularia as a model system

The aim of this paper is to review the present knowledge of the main aspects of differentiation of Acetabularia, a unicellular, eukaryotic organism, and to underline the multiple control pathways modulated by circadian rhythmicity. Growth and morphogenesis are sequentially programmed. Timing of cap differentiation is highly dependent on external conditions. The importance of the sequence of processes is shown by experimental disregulation. The alga is a highly polarized cell, both in morphology and in the relative concentrations of a number of the molecules it contains. Apical cap differentiation is regulated at the post-transcriptional level and could also depend in part on polyamines and on proteolytic activity. Acetabularia displays a number of circadian rhythms (CR). These rhythms form an elaborate biological time structure (also called temporal morphology, or morphology in time as opposed to morphology in space): the distribution in the 24 h cycle of the peaks and troughs of the oscillating functions. The oscillations display fixed relations both with the other functions and with external conditions (such as the transition from dark to light). Interestingly, the CR modulate Acetabularia's development, which is influenced by photoperiod; we present preliminary experiments suggesting that disruption of temporal morphology is deleterious to morphogenesis. Induction of growth and of morphogenesis are totally dependent on blue light. However, blue light receptors in plants are probably multiple, but we present arguments suggesting that flavin-cytochrome b and the associated SHAM-sensitive molecule are present in Acetabularia plasma membrane and are involved in blue light perception. Agents interfering with different steps of signal perception and transduction show that at least some of these steps are temporally regulated. According to recent experiments from our laboratory, the existence of a redox signalling mechanism appears to be highly probable. The phytohormones (or plant regulators), auxin (indole acetic acid), abscisic acid and ethylene, exert cell-regulatory functions and are involved in Acetabularia differentiation. They also modulate at least some circadian rhythms. Finally, circadian rhythms intervene in differentiation and are proposed to have an integrative function.SCOPUS: re.jFLWINinfo:eu-repo/semantics/publishe