Abstract
Hepcidin, master regulator of iron homeostasis, causes anemia under infectious and inflammatory conditions by reducing intestinal absorption of iron with decreased release of iron from macrophages and liver despite adequate iron stores leading to Anemia of Inflammation (AI). Many therapeutic trials have been carried out but none have been effective due to its adverse effects. In present study, we discover that Guanosine 5’-diphosphate (GDP) encapsulated in lipid vesicle (NH+) was found to inhibit NF-ҝB activation by limiting phosphorylation and degradation of IҝBα, thus, attenuating IL-6 secretion from macrophage cells. Moreover, the suppressed IL-6 levels down regulated JAK2/STAT3 pathway with decrease inflammation-mediated Hamp mRNA transcription (HepG2) and increase iron absorption (Caco2) in HepG2/Caco2 co-culture model. Analogous results were obtained in acute and chronic AI mice model thus, correcting haemoglobin level. These results proved NH + GDP as novel therapeutic agent to overcome limitations and suggests it as potential drug to ameliorate AI.
Highlights
The previous studies have reported that inflammatory disorders result in the secretion of pro-inflammatory cytokines such as IL-6, which binds to the IL-6 receptor on the membrane of hepatocytes to activate the JAK2/STAT3 pathway via phosphorylation[7]
Though uncovering all the molecular networks related to signalling pathway is critical, we have only focused on LPS-induced NF-ҝB activation along with IL-6 mediated JAK2/STAT3 pathway which is one major contributor in the regulation of hepcidin levels
We demonstrated the mechanism of NH + Guanosine 5’-diphosphate (GDP) attenuating NF-ҝB activation suppressing IL-6 secretion, which in turn decreases inflammation-mediated IL-6/JAK/STAT3 pathway (Fig. 7)
Summary
The previous studies have reported that inflammatory disorders result in the secretion of pro-inflammatory cytokines such as IL-6, which binds to the IL-6 receptor on the membrane of hepatocytes to activate the JAK2/STAT3 pathway via phosphorylation[7]. AMP-activated protein kinase[20], as a novel therapeutic target ameliorate AI by promoting suppressor of cytokine signalling 1(SOCS1) mediated JAK2 degradation. These approaches are limited with poor pharmacokinetics profile (AG490 and PpYLKT), lack of specificity, stability (STAT3 inhibitors), and competing iron chelating properties (curcumin) with decreased metabolic profile. GDP is a natural compound and earlier we reported that apart from directly binding and inhibiting hepcidin action, GDP attenuates inflammation-mediated IL-6/JAK//STAT3-hepcidin axis[21]. We aimed to investigate the underlying mechanism of NH + GDP on inflammation mediated NF-ҝB activation through IL-6/STAT3 hepcidin axis in in vitro and in vivo and assessed its therapeutic potential against AI
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