IL-6: an early marker for outcome in acute ischemic stroke

Tanaka

J Cereb Blood Flow Metab

2008

213

177

Interleukin-6 (IL-6) is pleiotropic cytokine involved in many central nervous system disorders including stroke, and elevated serum IL-6 has been found in acute stroke patients. IL-6 is implicated in the inflammation, which contributes to both injury and repair process after cerebral ischemia. However, IL-6 is one of the neurotrophic cytokines sharing a common receptor subunit, gp130, with other neurotrophic cytokines, such as leukemia inhibitory factor (LIF) and ciliary neurotrophic factor. The expression of IL-6 is most prominently identified in neurons in the peri-ischemic regions, and LIF expression shows a similar pattern. The direct injection of these cytokines into the brain after ischemia can reduce ischemic brain injury. The cytokine receptors are localized on the neuron surface, suggesting that neurons are the cytokine target. The major IL-6 downstream signaling pathway is JAK-STAT, and Stat3 activation occurs mainly in neurons during postischemic reperfusion. Further investigation is necessary to clarify the exact role of Stat3 signaling in neuroprotection. Taken together, the information suggests that IL-6 plays a double role in cerebral ischemia, as an inflammatory mediator during the acute phase and as a neurotrophic mediator between the subacute and prolonged phases.

Section: Serum Interleukin-6 In Stroke Patientsmentioning

confidence: 99%

Ambivalent Aspects of Interleukin-6 in Cerebral Ischemia: Inflammatory versus Neurotrophic Aspects

Tanaka

J Cereb Blood Flow Metab

2008

213

177

“…Stroke elicits a systemic acute phase response and is associated with increased levels of circulating cytokines, acute phase reactants, and elevated neutrophil and total leukocyte counts, which correlate with poor clinical outcome (Muir et al, 1999;Emsley et al, 2003;Smith et al, 2004;Waje-Andreassen et al, 2005;Rallidis et al, 2006). A recent study further highlighted the marked activation of systemic immune pathways after experimental stroke, including induction of cytokines and chemokines in peripheral lymphoid organs (Offner et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Systemic Inflammatory Stimulus Potentiates the Acute Phase and CXC Chemokine Responses to Experimental Stroke and Exacerbates Brain Damage via Interleukin-1- and Neutrophil-Dependent Mechanisms

McColl¹,

Rothwell

Allan³

2007

J. Neurosci.

314

339

Systemic inflammatory stimuli, such as infection, increase the risk of stroke and are associated with poorer clinical outcome. The mechanisms underlying the impact of systemic inflammatory stimuli on stroke are not well defined. We investigated the impact of systemic inflammation on experimental stroke and potential mechanisms involved. Focal cerebral ischemia was induced by intraluminal filament occlusion of the middle cerebral artery (MCAo). Brain damage and neurological deficit 24 h after MCAo were exacerbated by systemic lipopolysaccharide (LPS) administration. This exacerbation was critically dependent on interleukin (IL)-1, because coadministration of IL-1 receptor antagonist abolished the effect of LPS on brain damage. Systemic administration of IL-1 increased ischemic damage to a similar extent as LPS and also exacerbated brain edema. IL-1 markedly potentiated circulating levels of the acute phase proteins, serum amyloid A and IL-6, and the neutrophil-selective CXC chemokines, KC and macrophage inflammatory protein-2. Neutrophil mobilization and cortical neutrophil infiltration were aggravated by IL-1 before changes in ischemic damage. Neutropenia abolished the damaging effects of systemic IL-1. These data show for the first time that an acute systemic inflammatory stimulus is detrimental to outcome after experimental stroke and highlight IL-1 as a critical mediator in this paradigm. Our data suggest IL-1-induced potentiation of neutrophil mobilization via CXC chemokine induction is a putative mechanism underlying this effect. Our results may help to explain the poorer outcome in stroke patients presenting with infection and may have implications for neurodegenerative diseases involving neurovascular alterations, such as Alzheimer's disease, in which systemic inflammation can modulate disease progression.

Therapeutic Hypothermia and Temperature Management

“…In previous studies, structural damage and an aggravated inflammatory response has been correlated with elevated IL-6 levels after brain injury (Howell et al, 2006;Yan et al, 2012). After stroke, for example, elevated levels of IL-6 are associated with the infarct size and poor outcome (Vila et al, 2000;Smith et al, 2004;Waje-Andreassen et al, 2005). In this regard, IL-6 levels are considered a highly specific biomarker of TBI severity and long-term outcome (van Griensven et al, 2003;Howell et al, 2006).…”

mentioning

confidence: 99%

Temporal Profile of Cerebrospinal Fluid, Plasma, and Brain Interleukin-6 After Normothermic Fluid-Percussion Brain Injury: Effect of Secondary Hypoxia

Chatzipanteli

Vitarbo

Alonso

et al. 2012

Interleukin-6 (IL-6) is a proinflammatory cytokine that may play multiple roles in the pathogenesis of traumatic brain injury (TBI). The present study determined time-dependent changes in IL-6 concentrations in vulnerable brain regions, cerebrospinal fluid (CSF) samples, and plasma after normothermic TBI. Because secondary insults are common in head injured patients, we also assessed the consequences of a post-traumatic secondary hypoxic insult on this pleiotropic cytokine. Male Sprague-Dawley rats were intubated, anesthetized, and underwent a moderate parasagittal fluid-percussion brain injury (1.8-2.1 atm, 37°C) followed by either 30 minutes of normoxic or hypoxic (pO 2 = 30-40 mmHg) gas levels. Rats were sacrificed 3, 6, or 24 hours after TBI or shamoperated procedures. Brain samples, including the ipsilateral cerebral cortex and hippocampus were dissected and analyzed. Plasma and CSF samples were collected at similar times and stored at -80°C until analysis. IL-6 levels were significantly increased ( p < 0.05) at 3, 6, and 24 hours in the cerebral cortex and at 6 hours in the hippocampus after TBI. IL-6 levels in the TBI normoxic group for both structures returned to control levels by 24 hours. Plasma levels of IL-6 were elevated at all time points, while CSF levels were high at 3 and 6 hours, but normalized by 24 hours. Post-traumatic hypoxia led to significantly elevated ( p < 0.05) IL-6 protein levels in the cerebral cortex at 24 hours compared to sham-operated controls. These findings demonstrate that moderate TBI leads to an early increase in IL-6 brain, plasma, and CSF protein levels. Secondary post-traumatic hypoxia, a common secondary injury mechanism, led to prolonged elevations in plasma IL-6 levels that may participate in the pathophysiology of this complicated TBI model.