Association of Proinflammatory Cytokine Levels with Stroke Severity, Infarct Size, and Muscle Strength in the Acute Phase of Stroke



      Patterns of cytokine levels and their association with stroke severity, infarct size, and muscle strength are obscure. We aimed to analyze the immune mediators linked to T helper (Th)1, Th2, Th17, and regulatory T cell patterns and their association with stroke severity, infarct size, and muscle strength.

      Materials and methods

      We included patients with acute stroke (n = 15) and healthy non-disabled individuals (n = 20) aged > 18 years. The dependent variables were stroke severity according to the National Institute of Health Stroke Scale (NIHSS), infarct size on computed tomography, handgrip strength by dynamometry, and global muscle strength according to the Medical Research Council (MRC) scale. The independent variables were the circulating cytokine levels. The cytokine levels were compared between the groups, and correlations between the clinical data were verified.


      The stroke group had higher interleukin (IL)-6 (p < 0.0001) and IL-10 (p < 0.0001) levels, but lower tumor necrosis factor (TNF)-α (p = 0.036) levels than the control group. IL-10 and soluble tumor necrosis factor receptor (sTNF-RII) levels were correlated with each other (r = 0.533; p = 0.042) and infarct size (r = 0.653; p = 0.033 and r = 0.689; p = 0.018, respectively). MRC scores were positively and negatively correlated with handgrip strength of the affected side (r = 0.78; p = 0.001) and NIHSS scores (r = -0.87; p < 0.0001), respectively.


      Plasma levels of some cytokines were associated with changes in the acute phase of stroke, and IL-10 and sTNF-RII levels are potential biomarkers of infarct size.

      Graphical abstract

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Stroke and Cerebrovascular Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Bernhardt J.
        • Zorowitz R.D.
        • Becker K.J.
        • et al.
        Advances in Stroke 2017.
        Stroke. 2018; 49: e174-e199
        • Hankey G.J.
        Lancet. 2017; 389: 641-654
        • Langhorne P.
        • Wu O.
        • Rodgers H.
        • et al.
        A very early rehabilitation trial after stroke (AVERT): a phase III, multicentre, randomized controlled trial.
        Health Technol Assess. 2017; 21: 1-120
        • Bernhardt J.
        • Hayward K.S.
        • Kwakkel G.
        • et al.
        Agreed definitions and a shared vision for new standards in stroke recovery research: the stroke recovery and rehabilitation roundtable taskforce.
        Int J Stroke. 2017; 12: 444-450
        • Rafii M.S.
        • Hillis AE.
        Compendium of cerebrovascular diseases.
        Int Rev Psychiatry. 2006; 18: 395-407
        • Scherbakov N.
        • von Haehling S.
        • Anker S.D.
        • et al.
        Stroke induced sarcopenia: muscle wasting and disability after stroke.
        Int J Cardiol. 2013; 170: 89-94
        • Ramiro L.
        • Simats A.
        • García-Berrocoso T.
        • et al.
        Inflammatory molecules might become both biomarkers and therapeutic targets for stroke management.
        Ther Adv Neurol Disord. 2018; 111756286418789340
        • Dolati S.
        • Ahmadi M.
        • Khalili M.
        • et al.
        Peripheral Th17/Treg imbalance in elderly patients with ischemic stroke.
        Neurol Sci. 2018; 39: 647-654
        • Jiang C.
        • Kong W.
        • Wang Y.
        • et al.
        Changes in the cellular immune system and circulating inflammatory markers of stroke patients.
        Oncotarget. 2017; 8: 3553-3567
        • Hu Y.
        • Zheng Y.
        • Wu Y.
        • et al.
        Imbalance between IL-17A-producing cells and regulatory T cells during ischemic stroke.
        Mediat Inflamm. 2014; 2014813045
        • Lou Z.
        • Wang A.P.
        • Duan X.M.
        • et al.
        Upregulation of NOX2 and NOX4 mediated by TGF-β signaling pathway exacerbates cerebral ischemia/reperfusion oxidative stress injury.
        Cell Physiol Biochem. 2018; 46: 2103-2113
        • Oliveira D.M.G.
        • Aguiar L.T.
        • de Oliveira Limones M.V.
        • et al.
        Aerobic training efficacy in inflammation, neurotrophins, and function in chronic stroke persons: a randomized controlled trial protocol.
        J Stroke Cerebrovasc Dis. 2019; 28: 418-424
        • Jin R.
        • Liu L.
        • Zhang S.
        • et al.
        Role of inflammation and its mediators in acute ischemic stroke.
        J Cardiovasc Transl Res. 2013; 6: 834-851
        • Zaremba J.
        • Losy J.
        Early TNF-alpha levels correlate with ischaemic stroke severity.
        Acta Neurol Scand. 2001; 104: 288-295
        • Jørgensen L.
        • Jacobsen B.K.
        Changes in muscle mass, fat mass, and bone mineral content in the legs after stroke: a 1 year prospective study.
        Bone. 2001; 28: 655-659
        • Costamagna D.
        • Costelli P.
        • Sampaolesi M.
        • et al.
        Role of inflammation in muscle homeostasis and myogenesis.
        Mediators Inflamm. 2015; 2015805172
        • Malone K.
        • Amu S.
        • Moore A.C.
        • et al.
        The immune system and stroke: from current targets to future therapy.
        Immunol Cell Biol. 2019; 97: 5-16
        • Gandolfi M.
        • Smania N.
        • Vella A.
        • et al.
        Assessed and emerging biomarkers in stroke and training-mediated stroke recovery: state of the art.
        Neural Plast. 2017; 20171389475
        • Coelho Junior H.J.
        • Gambassi B.B.
        • Diniz T.A.
        • et al.
        Inflammatory mechanisms associated with skeletal muscle sequelae after stroke: role of physical exercise.
        Mediat Inflamm. 2016; 20163957958
        • Brennan P.M.
        • Murray G.D.
        • Teasdale GM.
        Simplifying the use of prognostic information in traumatic brain injury. Part 1: the GCS-pupils score: an extended index of clinical severity.
        J Neurosurg. 2018; 128: 1612-1620
        • Cincura C.
        • Pontes-Neto O.M.
        • Neville I.S.
        • et al.
        Validation of the National Institutes of Health Stroke Scale, modified Rankin Scale and Barthel Index in Brazil: the role of cultural adaptation and structured interviewing.
        Cerebrovasc Dis. 2009; 27: 119-122
        • Bohannon R.W.
        • Peolsson A.
        • Massy-Westropp N.
        • et al.
        Reference values for adult grip strength measured with a Jamar dynamometer: a descriptive meta-analysis.
        Physiotherapy. 2006; 92: 11-15
        • Aguiar L.T.
        • Martins J.C.
        • Lara E.M.
        • et al.
        Dynamometry for the measurement of grip, pinch, and trunk muscles strength in subjects with subacute stroke: reliability and different number of trials.
        Braz J Phys Ther. 2016; 20: 395-404
        • Zhang X.H.
        • Liang HM.
        Systematic review with network meta-analysis: diagnostic values of ultrasonography, computed tomography, and magnetic resonance imaging in patients with ischemic stroke.
        Medicine. 2019; 98 (Baltimore): e16360
        • Demeestere J.
        • Wouters A.
        • Christensen S.
        • et al.
        Review of perfusion imaging in acute ischemic stroke: from time to tissue.
        Stroke. 2020; 51: 1017-1024
        • Lambertsen K.L.
        • Biber K.
        • Finsen B.
        Inflammatory cytokines in experimental and human stroke.
        J Cereb Blood Flow Metab. 2012; 32: 1677-1698
        • Lambertsen K.L.
        • Finsen B.
        • Clausen B.H.
        Post-stroke inflammation-target or tool for therapy?.
        Acta Neuropathol. 2019; 137: 693-714
        • Sairanen T.
        • Carpén O.
        • Karjalainen-Lindsberg M.L.
        • et al.
        Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke.
        Stroke. 2001; 32: 1750-1758
        • Emsley H.C.
        • Smith C.J.
        • Gavin C.M.
        • et al.
        Clinical outcome following acute ischaemic stroke relates to both activation and autoregulatory inhibition of cytokine production.
        BMC Neurol. 2007; 7: 5
        • Fassbender K.
        • Rossol S.
        • Kammer T.
        • et al.
        Proinflammatory cytokines in serum of patients with acute cerebral ischemia: kinetics of secretion and relation to the extent of brain damage and outcome of disease.
        J Neurol Sci. 1994; 122: 135-139
        • Ormstad H.
        • Aass H.C.
        • Lund-Sørensen N.
        • et al.
        Serum levels of cytokines and C-reactive protein in acute ischemic stroke patients, and their relationship to stroke lateralization, type, and infarct volume.
        J Neurol. 2011; 258: 677-685
        • Wytrykowska A.
        • Prosba-Mackiewicz M.
        • Nyka W.M.
        IL-1β, TNF-α, and IL-6 levels in gingival fluid and serum of patients with ischemic stroke.
        J Oral Sci. 2016; 58: 509-513
        • Intiso D.
        • Zarrelli M.M.
        • Lagioia G.
        • et al.
        Tumor necrosis factor alpha serum levels and inflammatory response in acute ischemic stroke patients.
        Neurol Sci. 2004; 24: 390-396
        • Sun B.
        • Liang L.F.
        • Li J.
        • et al.
        A meta-analysis of interleukin-6 as a valid and accurate index in diagnosing early neonatal sepsis.
        Int Wound J. 2019; 16: 527-533
        • Lasek-Bal A.
        • Jedrzejowska-Szypulka H.
        • Student S.
        • et al.
        The importance of selected markers of inflammation and blood-brain barrier damage for short-term ischemic stroke prognosis.
        J Physiol Pharmacol. 2019; 70: 209-217
        • Kimura A.
        • Kishimoto T.
        IL-6: regulator of Treg/Th17 balance.
        Eur J Immunol. 2010; 40: 1830-1835
        • Zenewicz L.A.
        • Flavell R.A.
        Recent advances in IL-22 biology.
        Int Immunol. 2011; 23: 159-163
        • Kim O.Y.
        • Chung J.Y.
        • Song J.
        Effect of resveratrol on adipokines and myokines involved in fat browning: Perspectives in healthy weight against obesity.
        Pharmacol Res. 2019; 148104411
        • Erta M.
        • Quintana A.
        • Hidalgo J.
        Interleukin-6, a major cytokine in the central nervous system.
        Int J Biol Sci. 2012; 8: 1254-1266
        • Mengel A.
        • Ulm L.
        • Hotter B.
        • et al.
        Biomarkers of immune capacity, infection and inflammation are associated with poor outcome and mortality after stroke - the PREDICT study.
        BMC Neurol. 2019; 19: 148
        • Grønhøj M.H.
        • Clausen B.H.
        • Fenger C.D.
        • et al.
        Beneficial potential of intravenously administered IL-6 in improving outcome after murine experimental stroke.
        Brain Behav Immun. 2017; 65: 296-311
        • Chang L.T.
        • Yuen C.M.
        • Liou C.W.
        • et al.
        Link between interleukin-10 level and outcome after ischemic stroke.
        Neuroimmunomodulation. 2010; 17: 223-228
        • Nayak A.R.
        • Kashyap R.S.
        • Purohit H.J.
        • et al.
        Evaluation of the inflammatory response in sera from acute ischemic stroke patients by measurement of IL-2 and IL-10.
        Inflamm Res. 2009; 58: 687-691
        • Kulesh A.A.
        • Kuklina E.M.
        • Shestakov V.V.
        The relationship between serum and liquor Il-1β, Il-6, TNFα, Il-10 levels and clinical, cognitive and functional characteristics in acute ischemic stroke.
        Klin Med. 2016; 94 (Mosk): 657-662
        • Corey S.
        • Abraham D.I.
        • Kaneko Y.
        • et al.
        Selective endovascular cooling for stroke entails brain-derived neurotrophic factor and splenic IL-10 modulation.
        Brain Res. 2019; 1722146380
        • Conway S.E.
        • Roy-O'Reilly M.
        • Friedler B.
        • et al.
        Sex differences and the role of IL-10 in ischemic stroke recovery.
        Biol Sex Differ. 2015; 6: 17
        • Chen M.
        • Yang Y.
        A meta-analysis on associations of IL-6 and IL-10 polymorphisms with susceptibility to ischemic stroke.
        J Neuroimmunol. 2019; 335577004
        • Zhou K.
        • Zhong Q.
        • Wang Y.C.
        • et al.
        Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3β/PTEN axis.
        J Cereb Blood Flow Metab. 2017; 37: 967-979
        • Daneman R.
        • Prat A.
        The blood-brain barrier.
        Cold Spring Harb Perspect Biol. 2015; 7a020412
        • Sekerdag E.
        • Solaroglu I.
        • Gursoy-Ozdemir Y.
        Cell death mechanisms in stroke and novel molecular and cellular treatment options.
        Curr Neuropharmacol. 2018; 16: 1396-1415
        • Wang P.
        • Wu P.
        • Siegel M.I.
        • Egan R.W.
        • Billah M.M.
        Interleukin (IL)-10 inhibits nuclear factor KB (NF-KB) activation in human monocytes.
        J Biol Chem. 1995; 270: 9558-9563
        • Rodrigo R.
        • Fernández-Gajardo R.
        • Gutiérrez R.
        • et al.
        Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities.
        CNS Neurol Disord Drug Targets. 2013; 12: 698-714
        • Clausen B.H.
        • Wirenfeldt M.
        • Høgedal S.S.
        • et al.
        Characterization of the TNF and IL-1 systems in human brain and blood after ischemic stroke.
        Acta Neuropathol Commun. 2020; 8: 81
        • Pergola V.
        • Di Salvo G.
        • Martiniello A.R.
        • et al.
        TNF alpha and heart failure.
        Minerva Cardiol Angiol. 2000; 48: 475-484