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, 24 (2), 95-102

Control of Inflammatory Responses: A New Paradigm for the Treatment of Chronic Neuronal Diseases


Control of Inflammatory Responses: A New Paradigm for the Treatment of Chronic Neuronal Diseases

Joo Hong Woo et al. Exp Neurobiol.


The term 'inflammation' was first introduced by Celsus almost 2000 years ago. Biological and medical researchers have shown increasing interest in inflammation over the past few decades, in part due to the emerging burden of chronic and degenerative diseases resulting from the increased longevity that has arisen thanks to modern medicine. Inflammation is believed to play critical roles in the pathogenesis of degenerative brain diseases, including Alzheimer's disease and Parkinson's disease. Accordingly, researchers have sought to combat such diseases by controlling inflammatory responses. In this review, we describe the endogenous inflammatory stimulators and signaling pathways in the brain. In particular, our group has focused on the JAK-STAT pathway, identifying anti-inflammatory targets and testing the effects of various anti-inflammatory drugs. This work has shown that the JAK-STAT pathway and its downstream are negatively regulated by phosphatases (SHP2 and MKP-1), inhibitory proteins (SOCS1 and SOCS3) and a nuclear receptor (LXR). These negative regulators are controlled at various levels (e.g. transcriptional, post-transcriptional and post-translational). Future study of these proteins could facilitate the manipulation of the inflammatory response, which plays ubiquitous, diverse and ambivalent roles under physiological and pathological conditions.

Keywords: JAK-STAT; MKP-1; inflammation; liver X receptor; nuclear receptor; post-transcriptional regulation.


Fig. 1
Fig. 1. Endogenous inflammatory mediators in the brain. Brain inflammation can be caused by: aggregated proteins, such as prions, amyloid-β and α-synuclein; cell membrane components, including gangliosides and chromogranin (which are released from damaged nerve cells); and blood components, such as thrombin, prothrombin, plasminogen and tissue plasminogen activator (which can leak through a rupture of the blood brain barrier). In addition, oxidative stress due to intermittent hypoxia is accompanied by chronic inflammation.
Fig. 2
Fig. 2. JAK-STAT signaling as an anti-inflammatory target. JAK-STAT signaling mediates the brain inflammation induced by LPS, IFN-γ, ganglioside and thrombin. Curcumin activates SH2-containing phosphatase 2 (SHP2), while rosiglitazone and 15d-PGJ2 increase the expressions of SOCS1 and SOCS3. SHP2 and the SOCS proteins are typical negative feedback molecules of the JAK-STAT pathway.
Fig. 3
Fig. 3. Schematic of the anti-inflammatory mechanisms of LXR ligands in IFN-γ-stimulated astrocytes (18). IFN-γ triggers an early response in which STAT1 is phosphorylated and translocated to the nucleus, thereby inducing inflammatory gene expression. Synthetic and oxysterol derivatives of LXR ligands trigger the formation of PIAS1 (or HDAC4)-pSTAT1-LXR β (or LXR α) trimers, a process mediated by the differential conjugation of SUMO (Su) to individual LXRs. This blocks the binding of STAT1 to the promoters of its target genes.
Fig. 4
Fig. 4. MKP-1 as an anti-inflammatory target. The expression of MCP-1, a crucial molecule in initiating inflammatory responses, is regulated by JNK. MKP-1 dephosphorylates and inactivates JNK, suppressing MCP-1 expression. 15d-PGJ2, ETYA, and 22(R)-hydroxycholesterol (22R-HC) induce MKP-1 expression via HuR-dependent post-transcriptional regulation.

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