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  • br Cer signaling roles that regulate cellular

    2018-11-15


    Cer signaling roles that regulate cellular functions The first demonstration of a Cer signaling role (to induce erythroblast maturation) was in 1974. The first barrier Cer studies, reported in 1975 by Gray and Yardley, initiated the field of skin Cer research. In contrast, Cer signaling studies were not further developed for some time. In early 1990, it was shown that increasing cellular Cer levels by sphinomyelinase activation induced cell cycle arrest and differentiation in leukemia cells in response to vitamin D or phorbol ester. A technical difficulty of Cer biological studies is the poor solubility of Cer in aqueous solution. The application of cell-permeable short-chain amide-linked fatty AGI-5198 cost (C2–C8) containing Cer, which substantially increased hydrophilicity, has led to more signaling Cer studies. Although such short-chain Cer is not synthesized in mammalian cells, it can be used as a precursor to synthesize natural, long-chain Cer in cells. Previous studies demonstrated that, in response to various stimuli, including ER stress, sphingomyelin hydrolysis by sphingomyelinase activation and/or de novo synthesis of Cer by ceramide synthase activation generate signaling Cer. Cer mechanisms that regulate cellular functions depend on cell types and/or stimuli. The following downstream mechanisms have been demonstrated in mammalian cells: In addition to these mechanisms, Cer physically affect cellular functions. Cer permeabilizes mitochondrial outer membranes, leading to mitochondrial-mediated apoptosis.
    Signaling roles of Cer metabolites in regulation of antimicrobial peptide production Skin deploys multiple barriers to protect cells and tissues from external perturbations—i.e., UV/oxidative stress, mechanical stress, and microbial infection. The antimicrobial peptide (AMP), an innate immune component, is a key constituent of the antimicrobial barrier. Microbial infection increases AMP production, whereas diverse types of external perturbations—such as epidermal permeability disruption, UV irradiation, and other types of oxidative stress—stimulate key epidermal AMP [cathelicidin antimicrobial peptide (CAMP), human beta-defensin (hBD) 1, hBD2 and hBD3 production]. Although all perturbations increase the risk of microbial infections, AMP production is increased in skin without infections following perturbations. Our recent studies demonstrate that acute epidermal permeability defects, as well as UVB/oxidative stress induce ER stress in keratinocytes. The ER is an intracellular organelle that synthesizes protein and lipid, and is a major storage place for Ca2+. ER stress occurs in cells when proteins are accumulated and Ca2+ is released from the ER. Three major transmembrane proteins—inositol-requiring enzyme 1 (IRE1 or ERN1, a kinase with ribonuclease activity), protein kinase RNA-like endoplasmic reticulum kinase (PERK; also known as PEK or EIF2AK3), and activating transcription factor 6—serve as sensors of ER stress and also induce rescue signals to restore cellular function, because ER stress causes deleterious cell effects, including apoptosis. However, high levels of ER stress levels cause apoptosis. We found that ER stress stimulates both CAMP and hBD2 and hBD3, but not hBD1, production. These studies demonstrate how different external perturbations can increase specific AMP production through one mechanism.
    Conclusion Cer and its metabolites exhibit multifunctions in mammalian cells, including keratinocytes. In contrast to barrier Cer, even a 1/1000 part of Cer concentration will suffice to generate signals to alter cellular function. Because such a small change occurs in certain cellular compartment(s) and/or basal Cer, S1P, and C1P levels are low, increased levels of Cer or its metabolites could have a great impact on cells. A rescue mechanism, metabolic conversion, against Cer-induced apoptosis enhances innate immunity through AMP production. Hormesis shows that low levels of external perturbations, including radiation, and oxidative stress, enhance the cellular antioxidant system (superoxide dismutase) and thioredoxin, a tumor suppressor gene p53, and heat shock proteins. Similarly, low levels of Cer and its metabolites could enhance defense against these external perturbants in cells.