Human β‐defensin 3 induces STAT1 phosphorylation, tyrosine phosphatase activity, and cytokine synthesis in T cells

[摘要] TheAMPhBD‐3stimulatesnumerousimmuneeffectorfunctionsinmyeloidcellsandkeratinocytes,predominantlythroughtheMAPKsignalingcascade.Incontrast,hBD‐3wasreportedtoneutralizetheactivationofTcellsbyantagonizingMAPKsignalinginitiatedbySDF‐1αthroughCXCR4.Withtheuseofcomplementaryproteomicandimmunochemicalapproaches,weinvestigatedpossiblestimulatoryeffectsofhBD‐3onTcellsanddemonstratethathBD‐3inducesSTAT1tyrosinephosphorylationwithin5minyetisunabletoinduceMAPKactivation.InclusionofaPTPaseinhibitorincreasedhBD‐3‐inducedphosphorylationdramatically,suggestingthathBD‐3alsostimulatesPTPaseactivityconcurrently.TheincreaseinPTPaseactivitywasconfirmedbydemonstratingthathBD‐3suppressesIFN‐γ‐inducedSTAT1tyrosinephosphorylationbutnotSTAT1serineandERK1/2threoninephosphorylationandstimulatesthetranslocationofSHP‐2intothenucleuswithin15min.ThesignalingpathwaysinitiatedbyhBD‐3mayleadtotheobservedenhancementofdistinctTcelleffectorfunctionsduringTCRactivation,suchastheincreaseinIL‐2andIL‐10,butnotIFN‐γsecretion.Thus,hBD‐3initiatesdistinctlineage‐specificsignalingcascadesinvariouscellsinvolvedinhostdefenseandinducesaconcurrenttyrosinekinaseandtyrosinephosphatasesignalingcascadethatmayactivatesimultaneouslythetargetedTcellsandinhibittheirresponsetootherimmunemediators.Furthermore,theseresultssuggestthatthisevolutionarilyconservedpeptide,whichexhibitsabroadspectrumofantimicrobialandimmunomodulatoryactivities,servestointegrateinnateandadaptiveimmunity...

[学科分类] 生理学

[关键词] T lymphocyte;antimicrobial peptides;signal transduction;IL‐2;IL‐10;IFN‐γ