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Review
. 2012;8(9):1254-66.
doi: 10.7150/ijbs.4679. Epub 2012 Oct 25.

Interleukin-6, a major cytokine in the central nervous system

María Erta  1 , Albert Quintana, Juan Hidalgo
Affiliations
Review

Interleukin-6, a major cytokine in the central nervous system

María Erta et al. Int J Biol Sci. 2012.

Abstract

Interleukin-6 (IL-6) is a cytokine originally identified almost 30 years ago as a B-cell differentiation factor, capable of inducing the maturation of B cells into antibody-producing cells. As with many other cytokines, it was soon realized that IL-6 was not a factor only involved in the immune response, but with many critical roles in major physiological systems including the nervous system. IL-6 is now known to participate in neurogenesis (influencing both neurons and glial cells), and in the response of mature neurons and glial cells in normal conditions and following a wide arrange of injury models. In many respects, IL-6 behaves in a neurotrophin-like fashion, and seemingly makes understandable why the cytokine family that it belongs to is known as neuropoietins. Its expression is affected in several of the main brain diseases, and animal models strongly suggest that IL-6 could have a role in the observed neuropathology and that therefore it is a clear target of strategic therapies.

Keywords: Alzheimer's disease; Gliogenesis; Multiple Sclerosis; Neurogenesis; Neuroinflammation; Neuropoietin; Stroke; Trauma..

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Conflict of interest statement

Competing Interests: The authors declare that no competing interest exists.

Figures

Figure 1
Figure 1
IL-6 is produced by different brain cells and may signal in a complex manner. Neurons, astrocytes, microglia and endothelial cells the essential sources of IL-6 in the CNS. All of them may produce some amounts of IL-6, but upon proper stimuli such as injury copious amounts of IL-6 will be secreted. IL-6 can bind to the membrane-bound IL-6 receptor (mIL-6R, expressed in limited cells) or to the soluble form of the receptor (sIL-6R), which is known as trans-signaling; both of them can properly signal upon interaction with the sgp130 protein (expressed ubiquitously). A releasable form of gp130 can also be found in biological fluids, which will exert inhibitory actions on trans-signaling.
Figure 2
Figure 2
IL-6 has a major role in the response of the brain to injury. To some extent the response of the brain to trauma and stroke is similar. Stroke may be caused by an embolus/thrombus occlusion, an hemorrhage or a vasospasm, resulting in ischemia. Hypoxia initiates a biochemical cascade leading towards cell death, involving excitotoxicity, oxidative stress and apoptosis in which IL-6 has a protective effect. In the early response, neutrophils extravasate to nervous parenchyma involving a process of rolling, activation and transmigration due to an upregulation of P and E-selectin, followed then by an upregulation of ICAM and VCAM. Neutrophils are a rich source of sIL-6R, and damaged resident cells produce IL-6, TNF-α, IL-1β and chemokines, enhancing leukocyte migration toward parenchyma. TNF-α and IL-1β lead to neutrophil degranulation and tissue destruction by means of metalloproteinase (MMP) and TGF-β, while IL-6 inhibits TNF-α and neutrophils' diapedesis. Moreover, it induces apoptosis in neutrophils in a negative feedback loop. In the late phase of this response, IL-6 orchestrates the transition between innate and adaptive immune response, not only inhibiting neutrophils but recruiting monocytes and T-cells for a late inflammatory response. Besides, it induces astrogliosis and angiogenesis needed for the tissue remodelation and recovering. On the other hand, IL-6 exhibits a detrimental effect for instance in relation with body temperature increase, critical in the patient outcome. If deregulated, chronic IL-6 may cause significant brain damage.
Figure 3
Figure 3
Role of IL-6 in CNS diseases. IL-6 has been related to many brain diseases. In Multiple Sclerosis (MS) IL-6 influences T-cell function inducing its proliferation and infiltration into CNS by upregulation of VCAM-1 on the vascular endothelial cells. In the presence of TGF-β, it also induces T-cells differentiation into Th17 cells, which secrete IL-17 that stimulates IL-6 production in astrocytes in a positive feedback loop. Besides, T-cell direct contact induces production of IL-6, reactive oxygen species (ROS) and nitric oxide (NO) in astrocytes, which contribute to damaging myelin sheath and neurons that will led to ascending paralysis and, as long as IL-23 is present, the fully development of MS. In Alzheimer's disease, Amyloid-β peptide (Aβ) produced by cleavage of amyloid precursor protein (APP), induces microgliosis, astrogliosis and triggers IL-6 production in both types of cells which upregulates APP and hyperphosphorylates tau in neurons. Aβ is accumulated in the extracellular space forming senile plaques and inducing neuronal death. However, IL-6 can play a protective role differentiating microglia into phagocytic macrophages capable of degrading Aβ. Mutant Huntingtin (mHtt), associated with Huntington's disease , is a CAG expansion translated into intracellular polyglutamine inclusions which are toxic for the cell due to different pathways: increase in intracellular Ca2+ due to NMDA receptor binding, increase mitochondrial dysfunction with ROS production, and axonal transport disruption due to mHtt/HAP1 complexes. Elevated intracellular Ca2+ activates caspases and calpains, which cleave mHtt into toxic N-terminal fragments triggering apoptosis in a positive feed-back loop. Furthermore, calpain causes autophagy inhibition resulting in high levels of mHtt in another positive feed-back loop. Moreover, microglia cells expressing mHtt also contribute to neuronal cells degeneration. Parkinson's disease (PD) is considered a synucleinopathy due to an abnormal intracellular accumulation of insoluble alpha-synuclein aggregations (aα-syn) in the form of Lewy bodies in dopaminergic (DA) neurons due to a mutation, a toxic or an idiopathic form. Its etiopathogenesis remains unclear but, like HD, neuronal death is thought to be as a result of mitochondrial dysfunction with ROS production, an intracellular increase of Ca2+, oxidative stress and alterations in the ubiquitinproteasomal system (UPS) that become incapable to degrade aα-syn, which triggers microglia to produce ROS. All together produce neurodegeneration and PD symptomatology. MPTP is metabolized into MPP+ by glial cells and primarily kills DA neurons, by interfering with mitochondrial metabolism, producing PD symptoms and being able to model a toxic PD in animals. In both diseases, IL-6 protects against Ca2+ and ROS excitotoxicity decreasing neuronal death.
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References

    1. Hirano T, Taga T, Nakano N, Yasukawa K, Kashiwamura S, Shimizu K. et al. Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2) Proc Natl Acad Sci U S A. 1985;82:5490–4. - PMC - PubMed
    1. Yasukawa K, Hirano T, Watanabe Y, Muratani K, Matsuda T, Nakai S. et al. Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene. EMBO J. 1987;6:2939–45. - PMC - PubMed
    1. Yamasaki K, Taga T, Hirata Y, Yawata H, Kawanishi Y, Seed B. et al. Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science. 1988;241:825–8. - PubMed
    1. Kishimoto T, Akira S, Narazaki M, Taga T. Interleukin-6 family of cytokines and gp130. Blood. 1995;86:1243–54. - PubMed
    1. Wang X, Lupardus P, Laporte SL, Garcia KC. Structural biology of shared cytokine receptors. Annu Rev Immunol. 2009;27:29–60. - PMC - PubMed

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