No abstract

One of the mitogen-activated protein kinases (MAPKs), c-Jun NH2-terminal protein kinase (JNK) plays an important role in regulating cell fate, such as proliferation, differentiation, development, transformation, and apoptosis. Its activity is induced through the interaction of MAPK kinase kinases (MAP3Ks), MAPK kinases (MAP2Ks), and various scaffolding proteins. Because of the importance of the JNK cascade to intracellular bioactivity, many studies have been conducted to reveal its precise intracellular functions and mechanisms, but its regulatory mechanisms remain elusive. In this review, we discuss the molecular characterization, activation process, and physiological functions of mitogen-activated protein kinase kinase 7 (MKK7), the MAP2K that most specifically controls the activity of JNK. Understanding the role of MKK7/JNK signaling in physiological conditions could spark new hypotheses for targeted anticancer therapies.

Although Morinda citrifolia (noni) has long been used in traditional medicines for human diseases, its molecular and cellular mechanism of immunostimulatory ability to improve human health under normal healthy conditions is not fully elucidated. This study aimed to investigate the in vitro and in vivo immunostimulatory activity of M. citrifolia fruit water extract treated with enzymes (Mc‐eWE). In vitro studies revealed that Mc‐eWE stimulated the cells by inducing nitric oxide (NO) production and the expression of inflammatory cytokines, such as interleukin (IL)‐1β, IL‐6, IL‐12, tumor necrosis factor‐alpha (TNF‐α), and interferon‐gamma (IFN‐γ). The immunostimulatory activity was mediated by activation of NF‐κB and AP‐1. Ex vivo studies showed that Mc‐eWE stimulated splenocytes isolated from mice by inducing NO production and expression of immunostimulatory cytokines and by downregulating the expression of the immunosuppressive cytokine IL‐10 without cytotoxicity. In vivo demonstrated that Mc‐eWE induced immunostimulation by modulating populations of splenic immune cells, especially by increasing the population of IFN‐γ+ NK cells. Mc‐eWE enhanced the expression of inflammatory genes and immunostimulatory cytokines and inhibited the expression of IL‐10 in the mouse splenocytes and sera. Taken together, these results suggest that Mc‐eWE plays an immunostimulatory role by activating innate and adaptive immune responses.

Interferon regulatory factor (IRF)-3 is known to have a critical role in viral and bacterial innate immune responses by regulating the production of type I interferon (IFN). Thymoquinone (TQ) is a compound derived from black cumin (Nigella sativa L.) and is known to regulate immune responses by affecting transcription factors associated with inflammation, including nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). However, the role of TQ in the IRF-3 signaling pathway has not been elucidated. In this study, we explored the molecular mechanism of TQ-dependent regulation of enzymes in IRF-3 signaling pathways using the lipopolysaccharide (LPS)-stimulated murine macrophage-like RAW264.7 cell line. TQ decreased mRNA expression of the interferon genes IFN-α and IFN-β in these cells. This inhibition was due to its suppression of the transcriptional activation of IRF-3, as shown by inhibition of IRF-3 PRD (III-I) luciferase activity as well as the phosphorylation pattern of IRF-3 in the immunoblotting experiment. Moreover, TQ targeted the autophosphorylation of TANK-binding kinase 1 (TBK1), an upstream key enzyme responsible for IRF-3 activation. Taken together, these findings suggest that TQ can downregulate IRF-3 activation via inhibition of TBK1, which would subsequently decrease the production of type I IFN. TQ also regulated IRF-3, one of the inflammatory transcription factors, providing a novel insight into its anti-inflammatory activities.