The role of interleukin-6 signaling in nervous tissue

Rothaug, Michelle; Becker-Pauly, Christoph; Rose-John, Stefan

doi:10.1016/j.bbamcr.2016.03.018

Cited by 498Cytokine Signaling Pathways and InteractionsNeuroinflammation and Neurodegeneration MechanismsTryptophan and brain disorders

The role of interleukin-6 signaling in nervous tissue

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Rothaug, Michelle, Becker-Pauly, Christoph, Rose-John, Stefan·2016·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

DOI 10.1016/j.bbamcr.2016.03.018

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Abstract

The cytokine interleukin-6 (IL-6) plays a critical role in the pathogenesis of inflammatory disorders and in the physiological homeostasis of neural tissue. Profound neuropathological changes, such as multiple sclerosis (MS), Parkinson's and Alzheimer's disease are associated with increased IL-6 expression in brain. Increased nocturnal concentrations of serum IL-6 are found in patients with impaired sleep whereas IL-6-deficient mice spend more time in rapid eye movement sleep associated with dreaming. IL-6 is crucial in the differentiation of oligodendrocytes, regeneration of peripheral nerves and acts as a neurotrophic factor. It exerts its cellular effects through two distinct pathways which include the anti-inflammatory pathway involving the membrane-bound IL-6 receptor (IL-6R) expressed on selective cells, including microglia, in a process known as classical signaling that is also critical for bacterial defense. In classical signaling binding of IL-6 to the membrane-bound IL-6R activates the β-receptor glycoprotein 130 (gp130) and subsequent down-stream signaling. The alternative, rather pro-inflammatory pathway, shown to mediate neurodegeneration in mice, termed trans-signaling, depends on a soluble form of the IL-6R that is capable of binding IL-6 to stimulate a response on distal cells that express gp130. A naturally occurring soluble form of gp130 (sgp130) has been identified that can specifically bind and neutralize the IL-6R/IL-6 complex. Thus, trans-signaling is blocked but classical signaling is completely unaffected. A modified, recombinant dimerized version of sgp130 (sgp130Fc) has successfully been used to block inflammatory processes in mice and may also be used in the clarification of IL-6 trans-signaling in neurological diseases.

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Numerous studies have reported that intracranial IL6 and IL6 signaling using non-canonical trans-signaling modalities impact behavior.
“Numerous studies have reported that intracranial IL6 and IL6 signaling using non-canonical trans-signaling modalities impact behavior (Rothaug et al., 2016).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Rothaug et al., 2016

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Inflammation as a central mechanism in Alzheimer's disease
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Interleukin-6 Signaling Pathway and Its Role in Kidney Disease: An Update
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Repopulating Microglia Promote Brain Repair in an IL-6-Dependent Manner
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Transformation of Astrocytes to a Neuroprotective Phenotype by Microglia via P2Y1 Receptor Downregulation
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Role of IL-6 in the regulation of neuronal development, survival and function
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Neuroinflammation and Proinflammatory Cytokines in Epileptogenesis
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IL-6 Improves Energy and Glucose Homeostasis in Obesity via Enhanced Central IL-6 trans-Signaling
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On inflammatory hypothesis of depression: what is the role of IL-6 in the middle of the chaos?
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Deep insight into cytokine storm: from pathogenesis to treatment
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Associations of Immunological Proteins/Traits with Schizophrenia, Major Depression and Bipolar Disorder: A Bi-Directional Two-Sample Mendelian Randomization Study
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Interleukin-6 as a Multifunctional Regulator: Inflammation, Immune Response, and Fibrosis
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Inflammation and Oxidative Stress in Multiple Sclerosis: Consequences for Therapy Development
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Single-nucleus multiregion transcriptomic analysis of brain vasculature in Alzheimer’s disease
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Inflammation in Post-Traumatic Stress Disorder (PTSD): A Review of Potential Correlates of PTSD with a Neurological Perspective
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The Influence of Fluorine on the Disturbances of Homeostasis in the Central Nervous System
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Prenatal interleukin 6 elevation increases glutamatergic synapse density and disrupts hippocampal connectivity in offspring
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Sarcopenia and Cognitive Function: Role of Myokines in Muscle Brain Cross-Talk
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Nanoparticle-induced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes
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Neurobiological basis of stress resilience
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“Hypothalamic Microinflammation” Paradigm in Aging and Metabolic Diseases
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Depression and Interleukin-6 Signaling: A Mendelian Randomization Study
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Cytokine signaling in multiple sclerosis: Lost in translation
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The Obese Brain: Mechanisms of Systemic and Local Inflammation, and Interventions to Reverse the Cognitive Deficit
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Neuroinflammation in Huntington’s Disease: A Starring Role for Astrocyte and Microglia
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Shared pathways for neuroprogression and somatoprogression in neuropsychiatric disorders
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Muscle-to-Brain Signaling Via Myokines and Myometabolites
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Interleukin 6 in diabetes, chronic kidney disease, and cardiovascular disease: mechanisms and therapeutic perspectives
Kreiner, F. F., Kraaijenhof, J. M., von Herrath, M., Hovingh, G. K., & von Scholten, B. J. (2022) · Expert Review of Clinical Immunology · doi:10.1080/1744666x.2022.2045952 · Cited by 105 · see citing works
Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease
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Inflammation at the crossroads of COVID-19, cognitive deficits and depression
Silva, N. M. L. E., Barros‐Aragão, F. G. Q., Felice, F. G. D., & Ferreira, S. T. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109023 · Cited by 93 · see citing works
Understanding the Immunologic Characteristics of Neurologic Manifestations of SARS-CoV-2 and Potential Immunological Mechanisms
Mohammadi, S., Moosaie, F., & Aarabi, M. H. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-02094-y · Cited by 88 · see citing works
The impact of interleukin-6 (IL-6) and mesenchymal stem cell-derived IL-6 on neurological conditions
Kerkis, I., da Silva, Á. R. D. B. P., & Araldi, R. P. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1400533 · Cited by 89 · see citing works
How inflammation dictates diabetic peripheral neuropathy: An enlightening review
Cheng, Y., Chen, Y., Li, K., Liu, S., Pang, C., Gao, L., Xie, J., Wenjing, L. V., Yu, H., & Deng, B. (2023) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.14477 · Cited by 98 · see citing works
The hormetic and hermetic role of IL-6
Forcina, L., Franceschi, C., & Musarò, A. (2022) · Ageing Research Reviews · doi:10.1016/j.arr.2022.101697 · Cited by 85 · see citing works
Microglia-orchestrated neuroinflammation and synaptic remodeling: roles of pro-inflammatory cytokines and receptors in neurodegeneration
Yang, G., Xu, X., Gao, W., Wang, X., Zhao, Y., & Xu, Y. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2025.1700692 · Cited by 85 · see citing works
The cytokine network in the pathogenesis of major depressive disorder. Close to translation?
Petralia, M. C., Mazzon, E., Fagone, P., Basile, M. S., Lenzo, V., Quattropani, M. C. A., Nuovo, S. D., Bendtzen, K., & Nicoletti, F. (2020) · Autoimmunity Reviews · doi:10.1016/j.autrev.2020.102504 · Cited by 86 · see citing works
Chemokine and cytokine levels in the lumbar cerebrospinal fluid of preterm infants with post-hemorrhagic hydrocephalus
Habiyaremye, G., Morales, D. M., Morgan, C. D., McAllister, J. P., CreveCoeur, T. S., Han, R. H., Gabir, M., Baksh, B. S., Mercer, D., & Limbrick, D. D. (2017) · Fluids and Barriers of the CNS · doi:10.1186/s12987-017-0083-0 · Cited by 83 · see citing works
Aging triggers an upregulation of a multitude of cytokines in the male and especially the female rodent hippocampus but more discrete changes in other brain regions
Porcher, L., Bruckmeier, S., Burbano, S. D., Finnell, J. E., Gorny, N., Klett, J., Wood, S. K., & Kelly, M. P. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02252-6 · Cited by 78 · see citing works
What are the links between hypoxia and Alzheimer’s disease?
Lall, R., Mohammed, R., & Ojha, U. (2019) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s203103 · Cited by 78 · see citing works
Cost-effective and disposable label-free voltammetric immunosensor for sensitive detection of interleukin-6
Cancelliere, R., Tinno, A. D., Lellis, A. M. D., Contini, G., Micheli, L., & Signori, E. (2022) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2022.114467 · Cited by 77 · see citing works
Neuroprotective effects associated with immune modulation by selected lactic acid bacteria in a Parkinson's disease model
Visñuk, D. P., de Giori, G. S., LeBlanc, J. G., & de LeBlanc, A. D. M. (2020) · Nutrition · doi:10.1016/j.nut.2020.110995 · Cited by 76 · see citing works
The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives
Alexaki, V. I. (2021) · Cells · doi:10.3390/cells10071584 · Cited by 83 · see citing works
Neuroinflammation in psychiatric disorders: An introductory primer
Dunn, G. A., Loftis, J. M., & Sullivan, E. L. (2020) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2020.172981 · Cited by 73 · see citing works
Anti-inflammatory role of GM1 and other gangliosides on microglia
Galleguillos, D., Wang, Q., Steinberg, N., Zaidi, A. K., Shrivastava, G., Dhami, K., Daskhan, G. C., Schmidt, E. N., Dworsky-Fried, Z., Giuliani, F., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02374-x · Cited by 74 · see citing works
Disentangling the Hypothesis of Host Dysosmia and SARS-CoV-2: The Bait Symptom That Hides Neglected Neurophysiological Routes
Briguglio, M., Bona, A. R., Porta, M., Dell’Osso, B. M., Pregliasco, F. E., & Banfi, G. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00671 · Cited by 69 · see citing works
Defining the Role of Anti- and Pro-inflammatory Outcomes of Interleukin-6 in Mental Health
García‐Juárez, M., & Camacho‐Morales, A. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.03.020 · Cited by 67 · see citing works
Cellular and Molecular Mediators of Neuroinflammation in Alzheimer Disease
Yang, S. (2019) · International Neurourology Journal · doi:10.5213/inj.1938184.092 · Cited by 69 · see citing works
Posthemorrhagic hydrocephalus associates with elevated inflammation and CSF hypersecretion via activation of choroidal transporters
Lolansen, S. D., Rostgaard, N., Barbuskaite, D., Capion, T., Olsen, M. H., Nørager, N. H., Vilhardt, F., Andreassen, S. N., Toft‐Bertelsen, T. L., Ye, F., et al. (2022) · Fluids and Barriers of the CNS · doi:10.1186/s12987-022-00360-w · Cited by 67 · see citing works
Linking APOE-ε4, blood-brain barrier dysfunction, and inflammation to Alzheimer's pathology
Riphagen, J. M., Ramakers, I. H. G. B., Freeze, W. M., Pagen, L. H. G., Hanseeuw, B. J., Verbeek, M. M., Verhey, F. R. J., & Jacobs, H. I. L. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.09.020 · Cited by 65 · see citing works
IL-1β Induced Cytokine Expression by Spinal Astrocytes Can Play a Role in the Maintenance of Chronic Inflammatory Pain
Gajtkó, A., Bakk, E., Hegedűs, K., Ducza, L., & Holló, K. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.543331 · Cited by 65 · see citing works
DNA Methylation Profiles of Selected Pro-Inflammatory Cytokines in Alzheimer Disease
Nicolia, V., Cavallaro, R. A., López‐González, I., Maccarrone, M., Scarpa, S., Ferrer, I., & Fuso, A. (2017) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlw099 · Cited by 65 · see citing works
Increased IL-6 expression in astrocytes is associated with emotionality, alterations in central amygdala GABAergic transmission, and excitability during alcohol withdrawal
Roberts, A. J., Khom, S., Bajo, M., Vlkolinský, R., Polis, I. Y., Cates‐Gatto, C., Roberto, M., & Gruol, D. L. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.08.185 · Cited by 65 · see citing works
Neuroprotective Metabolites of Hericium erinaceus Promote Neuro-Healthy Aging
Roda, E., Priori, E. C., Ratto, D., Luca, F. D., Iorio, C. D., Angelone, P., Locatelli, C., Desiderio, A., Goppa, L., Savino, E., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22126379 · Cited by 65 · see citing works
IL-6 and its role in IgA nephropathy development
Groza, Y., Jemelková, J., Kafkova, L. R., Malý, P., & Raška, M. (2022) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2022.04.001 · Cited by 64 · see citing works
Activation of STAT3 Regulates Reactive Astrogliosis and Neuronal Death Induced by AβO Neurotoxicity
Toral-Ríos, D., Patiño‐López, G., Gómez‐Lira, G., Gutiérrez, R., Becerril-Pérez, F., Rosales-Córdova, A., León‐Contreras, J. C., Hernández‐Pando, R., León‐Rivera, I., Soto‐Cruz, I., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207458 · Cited by 63 · see citing works
Astrocytic STAT3 activation and chronic itch require IP3R1/TRPC-dependent Ca2+ signals in mice
Shiratori‐Hayashi, M., Chiharu, Y., Eguchi, K., Shiraishi, Y., Kohno, K., Mikoshiba, K., Inoue, K., Nishida, M., & Tsuda, M. (2020) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2020.06.039 · Cited by 62 · see citing works
Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling
Billing, U., Jetka, T., Nortmann, L., Wundrack, N., Komorowski, M., Waldherr, S., Schaper, F., & Dittrich, A. (2019) · Communications Biology · doi:10.1038/s42003-018-0259-4 · Cited by 64 · see citing works
Inflammatory Markers in Cerebrospinal Fluid from Patients with Hydrocephalus: A Systematic Literature Review
Lolansen, S. D., Rostgaard, N., Oernbo, E. K., Juhler, M., Simonsen, A. H., & MacAulay, N. (2021) · Disease Markers · doi:10.1155/2021/8834822 · Cited by 58 · see citing works
Increased Levels of Plasma Tumor Necrosis Factor-α Mediate Schizophrenia Symptom Dimensions and Neurocognitive Impairments and Are Inversely Associated with Natural IgM Directed to Malondialdehyde and Paraoxonase 1 Activity
Maes, M. H. J., Sirivichayakul, S., Matsumoto, A. K., Maes, A., Michelin, A. P., Semeão, L. D. O., Pedrão, J. V. D. L., Moreira, E. G., Barbosa, D. S., Geffard, M., et al. (2020) · Molecular Neurobiology · doi:10.1007/s12035-020-01882-w · Cited by 56 · see citing works
Involvement of Spinal IL-6 Trans-Signaling in the Induction of Hyperexcitability of Deep Dorsal Horn Neurons by Spinal Tumor Necrosis Factor-Alpha
König, C., Morch, E., Eitner, A., Möller, C., Turnquist, B. P., Schaible, H., & Ebersberger, A. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.4159-15.2016 · Cited by 43 · see citing works
Interleukin-6 in Traumatic Brain Injury: A Janus-Faced Player in Damage and Repair
Ciryam, P., Gerzanich, V., & Simard, J. M. (2023) · Journal of Neurotrauma · doi:10.1089/neu.2023.0135 · Cited by 54 · see citing works
Neuroinflammation in the Cerebellum and Brainstem in Friedreich Ataxia: An [ 18F ]‐ FEMPA PET Study
Khan, W., Corben, L. A., Bilal, H., Vivash, L. E., Delatycki, M. B., Egan, G. F., & Harding, I. H. (2021) · Movement Disorders · doi:10.1002/mds.28825 · Cited by 54 · see citing works
Novel Phosphodiesterase 4 Inhibitor FCPR03 Alleviates Lipopolysaccharide-Induced Neuroinflammation by Regulation of the cAMP/PKA/CREB Signaling Pathway and NF-κB Inhibition
Zou, Z., Chen, J., Feng, H.-F., Cheng, Y., Wang, H., Zhou, Z., Guo, H., Zheng, W., & Xu, J. (2017) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.116.239608 · Cited by 55 · see citing works
Low-Dose Pulsatile Interleukin-6 As a Treatment Option for Diabetic Peripheral Neuropathy
Cox, A., Sagot, Y., Hédou, G., Grek, C. L., Wilkes, T., Vinik, A. I., & Ghatnekar, G. S. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00089 · Cited by 53 · see citing works
Lupeol inhibits LPS-induced neuroinflammation in cerebellar cultures and induces neuroprotection associated to the modulation of astrocyte response and expression of neurotrophic and inflammatory factors
Oliveira-Junior, M. S., Pereira, É. P. L., de Amorim, V. C. M., Reis, L. T. C., do Nascimento, R. P., da Silva, V. D. A., & Costa, S. L. (2019) · International Immunopharmacology · doi:10.1016/j.intimp.2019.02.055 · Cited by 53 · see citing works
Expression pattern of perilipins in human brain during aging and in Alzheimer's disease
Conte, M., Medici, V., Malagoli, D., Chiariello, A., Cirrincione, A., Davin, A., Chikhladze, M., Vasuri, F., Legname, G., Ferrer, I., et al. (2021) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12756 · Cited by 52 · see citing works
Beneficial potential of intravenously administered IL-6 in improving outcome after murine experimental stroke.
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Authors: Rothaug, M., Becker-Pauly, C., & Rose-John, S.
Affiliations: Christian-Albrechts-Universität zu Kiel (DE)
Venue: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Publisher: Elsevier BV
Published: 2016-06
Volume: 1863
Issue: 6
Pages: 1218-1227
ISSN: 0167-4889 (ISSN-L)
DOI: 10.1016/j.bbamcr.2016.03.018
OpenAlex: W2308447553
Cited by: 491
References: 170
Citations by year: 2026: 30 · 2025: 51 · 2024: 44 · 2023: 54 · 2022: 89 · 2021: 74 · 2020: 59 · 2019: 37 · 2018: 22 · 2017: 23 · 2016: 8
FWCI: 3.02
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 365 d)
Locations: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
PubMed (publishedVersion)
Funders: Deutsche Forschungsgemeinschaft (SFB 654)
Proteolysis as a Regulatory Event in Pathophysiology (SFB 877)
Topics: Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords: interleukin-6, IL-6 signaling, neuroinflammation, multiple sclerosis, Parkinson's disease, Alzheimer's disease, sleep, REM sleep, oligodendrocyte differentiation, peripheral nerve regeneration, neurotrophic factors, soluble IL-6 receptor, gp130, trans-signaling, sgp130Fc, neurodegeneration, microglia
MeSH terms: Animals, Central Nervous System, Humans, Models, Biological, Protein Binding, Signal Transduction, Interleukin-6, Neurodegenerative Diseases, Receptors, Interleukin-6, Cytokine Receptor gp130

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The role of interleukin-6 signaling in nervous tissue

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