ERK1-2, MEK1-2 and p38 downstream signalling molecules impaired in CD56dimCD16 and CD56brightCD16dim-− natural killer cells in Chronic Fatigue Syndrome-Myalgic Encephalomyelitis patientsReportar como inadecuado

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Journal of Translational Medicine

, 14:97

Immunobiology and immunotherapy


BackgroundNatural Killer NK cell effector functions are dependent on phosphorylation of the mitogen-activated protein kinases MAPK pathway to produce an effective immune response for the clearance of target cells infected with viruses, bacteria or malignantly transformed cells. Intracellular signals activating NK cell cytokine production and cytotoxic activity are propagated through protein phosphorylation of MAPKs including MEK1-2, ERK1-2, p38 and JNK. Reduced NK cell cytotoxic activity is consistently reported in Chronic Fatigue Syndrome-Myalgic Encephalomyelitis CFS-ME patients and intracellular signalling by MAPK in NK cells remains to be investigated. Therefore, the purpose of this paper was to investigate MAPK downstream signalling molecules in NK cell phenotypes from CFS-ME patients.

MethodsFlow cytometric protocols were used to measure phosphorylation of the MAPK pathway in CD56CD16 and CD56CD16 NK cells following stimulation with K562 tumour cells or phorbol-12-myristate-13-acetate plus ionomycin. NK cell cytotoxic activity, degranulation, lytic proteins and cytokine production were also measured as markers for CD56CD16 and CD56CD16 NK cell function using flow cytometric protocols.

ResultsCFS-ME patients n = 14 had a significant decrease in ERK1-2 in CD56CD16 NK cells compared to the non-fatigued controls n = 11 after incubation with K562 cells. CD56CD16 NK cells from CFS-ME patients had a significant increase in MEK1-2 and p38 following incubation with K562 cells.

ConclusionsThis is the first study to report significant differences in MAPK intracellular signalling molecules in CD56CD16 and CD56CD16 NK cells from CFS-ME patients. The current results highlight the importance of intracellular signalling through the MAPK pathway for synergistic effector function of CD56CD16 and CD56CD16 NK cells to ensure efficient clearance of target cells. In CFS-ME patients, dysfunctional MAPK signalling may contribute to reduced NK cell cytotoxic activity.

KeywordsNatural killer Cytotoxic Cytokine Intracellular signalling Mitogen-activated protein kinase signalling Chronic Fatigue Syndrome-Myalgic Encephalomyelitis AbbreviationsAPCallophycocyanin

AFalexa fluor


BVbrilliant violet

CDcluster of differentiation

CFcyanin-based fluorescent dye

CFS-MEChronic Fatigue Syndrome-Myalgic Encephalomyelitis

ERKextracellular signal-regulated kinases

E:Teffector to target

FBSfetal bovine serum

FITCfluorescein isothiocyanate

GM-CSFgranulocyte–macrophage colony-stimulating factor

Iκβinhibitory kappa beta


IFN-γinterferon gamma


JNKJun N-terminal kinase

mABsmonoclonal antibodies

MAPKmitogen-activated protein kinase

MFImedian fluorescence intensity

NKnatural killer

NFCnon-fatigued control

NF-κβnuclear factor kappa beta

PBMCsperipheral blood mononuclear cells



PerCP-Cyperidinin chlorophyll protein-cyanine


p38p38 mitogen-activated protein kinase

RPMIRoswell Park Memorial Institute

Statsignal transducer and activator of transcription

TNFtumour necrosis factor


Electronic supplementary materialThe online version of this article doi:10.1186-s12967-016-0859-z contains supplementary material, which is available to authorized users.

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Autor: Teilah Kathryn Huth - Donald Staines - Sonya Marshall-Gradisnik


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