Effect of astrocyte‐targeted production of IL‐6 on traumatic brain injury and its impact on the cortical transcriptome

Seo

Korean J Physiol Pharmacol

et al. 2010

The present study demonstrates the effect of fibrates, agonists of PPARα on cytokines-induced proliferation in primary cultured astrocytes. Alone or combination treatment with cytokines, such as IL-1β (10 ng/ml), IFNγ (10 ng/ml), and TNF-α (10 ng/ml) cause a significant increase of cell proliferation in a time-dependent manner. Treatment of astrocytes with bezafibrate and fenofibrate (0, 5, and 10 μ M) reduced the IFNγ and IL-1β-induced cell proliferation in a dose-dependent manner. To address the involvement of IL-6 on the IFNγ and IL-1β-induced cell proliferation, released IL-6 level was measured. IFNγ and IL-1β cause an increase of released IL-6 protein level in a time-dependent manner. Furthermore, pretreatment with IL-6 antibody (0, 0.1, 1, 2.5, and 5 ng/ml) dose-dependently inhibited the IFNγ and IL-1β-induced cell proliferation. However, bezafibrate and fenofibrate did not affect increased mRNA and protein levels of IL-6 in IFNγ and IL-1β-stimulated astrocytes. Taken together, these results clearly suggest that activation of PPARα attenuates the IFNγ and IL-1β-induced cell proliferation through IL-6 independent pathway.

Section: Discussionmentioning

confidence: 88%

Activation of PPARα Attenuates IFNγ and IL-1β-induced Cell Proliferation in Astrocytes: Involvement of IL-6 Independent Pathway

Seo

Korean J Physiol Pharmacol

et al. 2010

Mechanisms of Neuroinflammation

“…Corresponding to the results seen in IL-6 knockout mice, GFAP-IL-6 mice, which overexpress IL-6 in the CNS, showed faster recovery and healing after TBI [215,216]. Transcriptome analyses of IL-6 knockout versus wildtype [217] and GFAP-IL-6 mice [218] post-TBI via cryoinjury, showed that multiple pathways involving inlammation, apoptosis and oxidative stress were afected by IL-6. For example, IL-6 knockouts had lower expression of the gene producing suppressor of cytokine signaling (SOCS), an inhibitory protein transcribed by the JAK/STAT pathway after IL-6 activation [217].…”

Section: Il-6 In Tbimentioning

confidence: 66%

“…brain-derived neurotrophic factor, early growth response 1) post-injury [217]. Injured GFAP-IL-6 mice expressed higher levels of complement component 4 and other inlammatory mediator genes in addition to lower levels of select pro-apoptotic genes and oxidative stress-related genes in comparison to injured wildtype mice [218].…”

Section: Il-6 In Tbimentioning

confidence: 99%

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Dugue¹,

Nath²,

Dugue³

et al. 2017

This chapter will introduce the reader to the pathophysiology of two devastating neurologic events, traumatic brain injury (TBI) and acute ischemic stroke (AIS). Here we focus on the role of key pro-inlammatory and anti-inlammatory cytokines. Several experimental interventions have been found to modulate cytokine production and brain injury after AIS or TBI. Here minocycline, biological response modiiers, hormonal therapies, omega-3 faty acids, N-acetylcysteine, and cannabinoids will be discussed. In addition, the role of cytokine-induced inlammasomes in both TBI and AIS will be addressed and followed by discussion of pro-inlammatory cytokines (e.g., TNF-α, IL-1β, IL-18, and IFN-γ). Finally, the main anti-inlammatory cytokines, IL-33, IL-10, IL-6, and IL-4, will be discussed in the context of both TBI and AIS. It should be noted that the role of these cytokines is diverse and the dichotomization of classically pro-versus anti-inlammatory cytokines is being re-examined, as many of these cytokines have been found to play dual roles in TBI and AIS brain injury.Keywords: traumatic brain injury, ischemic stroke, cytokines, interleukins, inlammasome Pathophysiology of traumatic brain injuryTraumatic brain injury (TBI) is a major cause of death and disability worldwide [1,2]. It is one of the most commonly diagnosed neurological disorders in the United States, impacting people of a variety of ages and segments of society [3]. In Europe, the economic cost of © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.TBI is over 33 billion euros per year [4]. Continued surveillance and research is being done to reduce primary and secondary TBI [as well as acute ischemic stroke(AIS)]-induced brain injury [1].The pathophysiology of TBI begins with the initial brain trauma (i.e., the primary injury). This primary injury results from mechanical damage that disrupts the blood-brain barrier (BBB), alters the vasculature and damages brain tissue. The resulting injured glia and neurons release their intracellular contents (i.e., damage-associated molecular paterns; (DAMPs)) into the extracellular space and activate neighboring glia and neurons. Activated glia and neurons then produce molecular signals that can both exacerbate and mend the acute injury and contribute to long-term recovery [5][6][7][8][9]. These downstream molecular and cellular processes (i.e., the secondary injury in TBI) are the focus of many pre-clinical and clinical therapeutic studies. Secondary injury in TBI involves a host of molecular and cellular responses to the The pathophysiology of AIS and TBI share common mechanisms. The initial insult in AIS, an occlusion of blood low resulting in a core infarct zone surrounded by a poorly perfused penumbra, versus the initial primary physical impact in TBI both result in pe...

“…IL-6 KO mice had a substantially different response at 1 day after injury compared to WT controls, with a tendency for attenuated upregulation of multiple transcription factors; the authors suggest it is this early transcriptional difference that underscores the later poor recovery from TBI [86] . Mice producing IL-6 in astrocytes had increased expression of inflammatory genes compared to WT controls, as expected; they also had decreased expression of pro-apoptotic genes and changes in genes associated with a wide range of processes including oxidative stress, synaptic activity, and cell migration and proliferation [87] , thus demonstrating the pervasive nature of IL-6 signalling following injury. In another example, recent studies have conducted microarray analyses of TBI using mouse models of Alzheimer's disease [88,89] .…”

Section: Traumatic Brain Injurymentioning

confidence: 70%

“…Two studies have examined the transcriptome response to cryolesion in mice which have altered levels of the cytokine interleukin-6 (IL-6), an inflammatory mediator known to have significant and wide-ranging effects on the response to neurotrauma. The first used IL-6 KO mice which have a worse than usual response to TBI [86] , and the second used transgenic mice which produce IL-6 in astrocytes and are known to have less cell death and increased repair after TBI [87] . IL-6 KO mice had a substantially different response at 1 day after injury compared to WT controls, with a tendency for attenuated upregulation of multiple transcription factors; the authors suggest it is this early transcriptional difference that underscores the later poor recovery from TBI [86] .…”

Section: Traumatic Brain Injurymentioning

confidence: 99%

Current and Future Applications of Transcriptomics for Discovery in CNS Disease and Injury

Munro

Perreau²

2009

Neurosignals

The central nervous system (CNS) displays heterogeneity at regional, cellular and subcellular levels, making analysis of transcriptomic events accompanying neural injury particularly challenging. Microarray technology provides methods for elucidating global changes in neural gene expression and discovery of signalling pathways within this complex biological network. The lack of suitable and sufficient human CNS tissue along with its inherent variability means that diverse animal models of both multiple sclerosis and neurotrauma are vital for examining the pathophysiological changes accompanying neural injury resulting from disease or trauma. Gene expression profiling of these models is providing valuable information about mechanisms of damage, repair and regeneration and candidate treatments. In vitro models of neural injury are also proving useful, and transcriptomics is enhancing our understanding of the properties of neural stem cells with a view to their therapeutic application in neural repair. Thoughtful experimental design and analysis of microarray experiments is crucial for extracting biological meaning from the vast amount of data produced. In this review we discuss the current and emerging application of transcriptomics for the study of neural function in health, disease and injury.