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    • Tubacin The glucocorticoid GR complex exerts wide spread cel

    2021-11-08

    The glucocorticoid-GR complex exerts wide-spread cellular effects through two distinct mechanisms categorized as genomic and non-genomic pathways [3,39]. Most non-genomic pathways originate from activation of mGR [40]. These actions of the GR appear to all play an important role in the regulation of the immune system. Although some studies have previously alluded to the existence of mGR in other cell types, including lymphoma Tubacin and peripheral blood mononuclear cells [41], their precise location is still unclear in teleosts. In the present study, we found ayu mGR (mPaGR) by immunofluorescence detection, and PaGR was expressed not only in the intracellular area but also in the plasma membrane. However, there is a limit to the immune regulation of mGR via non-genomic pathways in teleost fish. Here, we used cortisol-BSA, a membrane-impermeable agent, to verify the PaGR-non-genomic effect. Macrophages across all vertebrate species are typically one of the first cell types to encounter intruding pathogens and play critical roles in host protection and tissue homeostasis [[42], [43], [44]]. Cytokines are major regulators of macrophage activation [7,45,46]. Therefore, the highly-regulated balance between pro-inflammatory cytokines and anti-inflammatory cytokines plays an important role in immune responses against pathogens [8]. In fish macrophages, treatment with cortisol results in heightened anti-inflammatory cytokine expression (IL-10 and TGF-β) and decreased pro-inflammatory cytokine expression (IL-1β, TNF, and IL-6) [4,32]. In rainbow trout, Co-stimulation of cortisol with the inflammatory agents resulted in the up-regulated of IL-10, and the down-regulated of IL-6 and IL-8 in macrophage cell line [7]. Furthermore, cortisol does not show significant modulatory effects on cytokine expression induced by V. anguillarum bacteria in the rainbow trout macrophage cell line, while in sea bream cortisol did produce a clear inhibitory effect on both pro-inflammatory and anti-inflammatory cytokines by V. anguillarum bacterial infection in head kidney cells [11]. These results indicate that there are species differences in GR activity during immune regulation. A previous study has found that the teleost immune system is very diverse in different species [47]. In the present study, cortisol-induced activation of PaGR resulted in the down-regulation of IL-1β and TNF-α, and up-regulation of IL-10 and TGF-β mRNA expression after V. anguillarum infection in ayu MO/MΦ. However, there were no significant changes in cytokine expression between the cortisol-BSA treatment and the control. These data suggest that activation of PaGR is involved in the regulation of cytokine expression via a genomic pathway in ayu MO/MΦ during infection. Phagocytosis is a cellular process, a well-conserved innate defense mechanism that is important to the induction of antimicrobial responses and the regulation of adaptive immunity [45,48]. Phagocyte capacity has been described as an indicator of the health status of fish [49,50]. A previous study has shown that GR signaling is involved in regulating apoptosis and proliferation of B lymphocytes, inhibiting phagocytosis of tilapia leukocytes, and respiratory bursts in striped bass [51]. In addition, GR signaling promotes phagocytosis and bacteria killing in mammal monocytes [52,53]. In this study, we found that both cortisol and cortisol-BSA treatment could suppress phagocytosis in ayu MO/MΦ, but only cortisol treatment could enhance its bacterial killing capability. Furthermore, RU486 antagonized and nearly reversed the effects of cortisol and cortisol-BSA on ayu MO/MΦ. The results indicate that non-genomic pathway are involved in mediating the rapid suppression of phagocytosis by PaGR activation. The bacterial killing effect may be regulated by a genomic pathway. Our data suggested that PaGR could increase bacterial killing and reduce inflammatory responses to protect MO/MΦ during live V. anguillarum infection, and further support the GR's ability to modulate macrophage function via non-genomic pathways in an antagonistic way. However, further investigation is needed to determine the specific signaling pathways underlying the effect of PaGR on phagocytosis and bacterial killing.