The transcription factor CCAAT enhancer-binding protein a (C/EBPa) has an important role in granulopoiesis. The tumor suppressor function of C/EBPa is shown by the findings that loss of expression or function of C/EBPa in leukemic blasts contributes to a block in myeloid cell differentiation and to leukemia. C/EBPa mutations are found in around 9% of acute myeloid leukemia (AML) patients. The mechanism by which the mutant form of C/EBPa (C/EBPa-p30) exerts a differentiation block is not well understood. By using a proteomic screen, we have recently reported PIN1 as a target of C/EBPa-p30 in AML.In the present study, we show that C/EBPa-p30 induces PIN1 expression. We observed elevated PIN1 expression in leukemic patient samples. Induction of C/EBPa-p30 results in recruitment of E2F1 in the PIN1 promoter. We show that the inhibition of PIN1 leads to myeloid differentiation in primary AML blasts with C/EBPa mutations. Overexpression of PIN1 in myeloid cells leads to block of granulocyte differentiation. We also show that PIN1 increases the stability of the c-Jun protein by inhibiting cJun ubiquitination, and c-Jun blocks granulocyte differentiation mediated by C/EBPa. Our data suggest that the inhibition of PIN1 could be a potential strategy of treating AML patients with C/EBPa mutation.
A hallmark of acute inflammation involves the recruitment of polymorphonuclear leukocytes (neutrophils) to infected or injured tissues. The processes underlying this recruitment are complex, and include multiple mechanisms of intercellular communication between neutrophils and the inflamed tissue. In recent studies of the systemic and pulmonary vasculature, interest has increased in novel forms of intercellular communication, such as microparticle exchange and gap junctional intercellular communication. To understand the roles of these novel forms of communication in the onset, progression, and resolution of inflammatory lung injury (such as acute respiratory distress syndrome), we review the literature concerning the contributions of microparticle exchange and gap junctional intercellular communication to neutrophilalveolar crosstalk during pulmonary inflammation. By focusing on these cell-cell communications, we aim to demonstrate significant gaps of knowledge and identify areas of considerable need for further investigations of the processes of acute lung inflammation.Keywords: neutrophil; connexin; gap junction; microparticles; acute lung injury Although investigations of acute respiratory distress syndrome (ARDS) have yet to yield an efficacious pathophysiologytargeted therapy, they have provided important insights into the intercellular communications regulating neutrophil activation and alveolar transmigration. These communications include juxtacrine and paracrine (e.g., chemokines, cytokines, and proteinases), crosstalk between neutrophils and lung parenchymal cells, and the signaling conducted through cell-surface receptors such as leukocyte integrins and cognate adhesion molecules (e.g., intercellular adhesion molecules) expressed by lung parenchymal cells (1). The past decade has seen an increasing recognition of alternative forms of intercellular communications during the onset and resolution of inflammatory lung disease. These communications include microparticle exchange as well as gap junctional intercellular communication (GJIC). This Perspective will focus on these alternative forms of communication between neutrophils and lung parenchymal cells during the genesis of ARDS, highlighting opportunities for further investigations. MICROPARTICLE EXCHANGEMicroparticles are spherical, lipid bilayer-encapsulated extracellular bodies ranging from 50-1,000 nm in diameter. Microparticles can be secreted by almost every cell type, including lung parenchymal cells and inflammatory cells. Multiple forms of microparticles exist, reflecting different modes of production. "Exosomes" and "shedding vesicles" are derived from living cells, whereas "apoptotic bodies" are secreted by apoptotic and/or necrotic cells (2). Exosomes have an endosomal origin, and are stored as intraluminal vesicles within multivesicular bodies (3). Upon stimulation, exosomes are secreted by fusion with the cell membrane, forming a relatively homogenous group of microparticle sizes (50-150 nm). In contrast, shedding vesicles and apoptotic ...
The earth rotates on its axis around the sun, creating a day and night cycle, that caused the development of circadian rhythms. The circadian rhythm is primarily entrained by light, which is detected by the retina. Retinal ganglion cells project to a part of the hypothalamus termed suprachiasmatic nucleus. Here, we find the master molecular clock, composed of a transcription-translation-loop at its core. The master clock indirectly influences the innate immune system via different biological systems. Also, the master clock controls the peripheral clocks, which are present in innate immune cells. Here, circadian rhythm proteins influence the response of immune cells to pathogens. Furthermore, the master clock influences our sleep-pattern, the most important restorative physiological function. In critically ill patients the circadian rhythm is substantially altered, supporting a dysfunctional innate immune response. This review discusses recent basic science findings on the interaction of the circadian rhythm and the innate immune system. Furthermore we give an outlook on potential future therapeutic strategies.
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