Cytokines in Periodontal Diseaase

CYTOKINES
Dr. Kritika Jangid
MDS- Periodontics

Cyto-cell.kine-movement
Cytokinesare lowmolecularweightsolublemediators(small
proteins)ofimmunitywhichare secretedbyactivated
immunocytesor somematrixcellsandpossesshighactivity
andvariousfunctions.

 Lymphokine: Made by activated
Lymphocytes especially TH cells, e.g.IL-2
 Monokine: Made by mononuclear
phagocytes, e.g.Mig/CXCL9
 Chemokine: Mediates chemotaxisbetween cells. e.g.IL-8, CXCL12
 Interleukin: interaction between leukocytes
IL-1, IL-8, IL-10, IL-13
 Named by activity: Tumor Necrosis Factor a (TNFa)
Colony Stimulation Facto(CSF)
Transforming Growth Factor b(TGFb)

 Low molecular weight proteins <30kd
 Active in pico-mole amounts
 Soluble mediators of immunity.
 Mechanism of leukocytes communication.
 Transient

 Produced by cells as part of normal cellular activity or the
result of environmentaltrigger
 Bind to receptors on cells
 Trigger signaltransduction pathways
 Initiatesynthesis of new proteins
 Only cells expressing receptors for specific cytokines can be
activated by them

 Autocrine
Affects the generating cell (self)
 Paracrine
Affects cells in the immediate vicinity
 Endocrine
Affects cells remote from the secreting cell

 PLEIOTROPISM
 REDUNDANCY
 SYNERGY
 ANTAGONISM
 CASCADE INDUCTION
 FORMACYTOKINE NETWORK.

 Abilityofonecytokinehavingdifferenteffectsondifferentcell.

 Thepropertyofmultiplecytokineshavingthesame or overlappingfunctional
effects.

 Thepropertyoftwoor morecytokineshavinggreater thanadditiveeffects.

 Theabilityofonecytokineinhibitingtheactionofanother.

 Actionofonecytokineona target cell
inducesthatcellto produce one or
more cytokines which induce other
target cellsto produce other
cytokines

 Onekindofcytokinescanbeproducedbydifferentcells.Onekindofcells
cansecretedifferentcytokines.
TH1
IL-2
IL-3,GM-
CSF,TNF-
IFN-γ,TNF-β
TH2
IL-4，6
IL-5

 Cytokinesinitiatetheiractionsby
bindingtospecificmembrane
receptorsontarget cells.

1. Pro-inflammatorycytokines
2. CytokineswithPredominantimmuno-regulatoryfunctions
3. Cytokinesthatregulatelymphocytegrowth,activationanddifferentiation
4. Cytokinesthathelpinhematopoiesis
5. Chemokines

 IL-1
 TNF
 INF
 IL-6
 IL-8
 Macrophagemigrationinhibitionfactor(MIF)

 2molecularforms-IL-1α, IL-1β
 Encodedby2separategenes
 20%homology
 MainsourceofIL-1 arethecellsofmonocyte-macrophagelineage
 IL-1αtendstoremainassociatedtomembranes
 IL-1β -synthesisedasan inactiveprecursor,releasedfromthecellafter being
processedpost-transitionallybyacysteine-asparageneprotease

 IL-1β isexpressedbymonocytes,macrophagesanddendriticcells.
 Itsignalsthrough2receptors-IL-1R1 andIL-1RII bothofwhichare shared
withIL-1α
 Itisa multifunctionalmoleculetheeffectsrangingfrominflammation,
immunityandhemopoiesis
 IL-1 hasdiversactivitiesandrolesin
 immunity,
 inflammation,
 tissue breakdown and
 tissue homeostasis

 Involvedininflammatoryandimmuneresponses
 Bothautocrineandparacrineinducerofother cytokineslikeIL-1, IL-6, IL-8,
PDGF,ecosanoids,plateletactivatingfactorsandgranulocytemonocyte
colonystimulatingfactor
 TNFissecretedbymacrophages,monocytes,neutrophils,T-cells,NK cells
followingtheir stimulationbybacteriallipo-polysaccharides
 CellsexpressingCD4secreteTNF-αwhileCD8cellssecretelittleor noTNFα

 Directeffectonthepathogenesisofperiodontaldisease
 Up-regulatestheproductionofotherclassicpro-inflammatoryinnate
immunitycytokineslikeIL-1βandIL-6
 TNF- β is commonly known as lymphotoxin

1. Metaboliceffects:AcutePhaseproteins-1-anti-trypsin,fibrinogen,CRP
2. Vasculareffects:Adherence.ExpressionofP-selectin,E-selectin
3. Endogenouspyrogen:DoesntcrossBBB, interactswitha groupofnucleiin
thehypothalamustocausefever

 Producedbyvarietyofcellslikemonocytes,fibroblasts,osteoblastsand
vascularendothelialcellsinresponsetoinflammatorychanges.
 Haspro-inflammatoryandhematopoieticactivity.
 Roleas a pro-inflammatorycytokineissimilartoIL-1 andTNF
 ActiononIL-6onB-cellsistheincreasedsecretionofIg-M
 InducesT-cellproliferation
 Pleiotropiccytokine

 Chemo-attractant for neutrophils
 Induced and secreted by monocytes, lymphocytes,
fibroblasts, epithelial and endothelial cells.
 Induces the adhesion of PMN to endothelial clls and
their trans-endothelial migration and release of
granulocyte enzymes from these cells
 Promotes angiogenesis
 Inhibits endothelial apoptosis

 Crucialroleintherecruitmentandactivationofmacrophagesas wellas in
helpingtokillthebacteria
 Alsoknownasglycosylation-inhibitingfactor(GIF)
 Innateimmuneresponses-TNF-α andTLR4expression,phagocytesand
intracellularkillingmechanisms
 Adaptiveimmuneresponses-Th1activationanddifferentiation

 IL-4
 IL-10
 IL-11
 IL-13
 IL-16
 TGF-β
 SolubleTNFreceptor
 SolubleIL-1 receptor

1. Pro- inflammatory cytokines
2. Cytokines with Predominant
immuno-regulatory functions
3. Cytokins that regulate lymphocyte growth, activation
and differentiation
4. Cytokines that help in hematopoiesis
5. Chemokines

 Interferons
 IL-12
 IL-18

 Anti-viraleffects
 IFN-α- producedbyleucocytes
 IFN-β- producedbyfibroblasts
 IFN-γ- producedbyCD4+cellsandNK cells
 AlongwithIL-1, itinducesan increaseintheexpressionofICAM-1onthe
cytoplasmicmembrane ofendothelialcells,enhancingT-lymphocyte
adherencetothevascularendothelium.

 Regulationcytokine-initiationandregulationofcellularimmuneresponses
 Linksinnateandadaptiveimmuneresponses
 GeneratedfromT andB-lymphocytes,NK cellsandmacrophages.
 TheproductionisofIL-12 isinhibitedbyIL-4andIL-10.

 Recentlydiscoveredinterleukin
 Initiallynamedas interferonγ-inducingfactor
 Ithassimilar roleslikeIL-1andIL-12
 IL-18 isproducedandreleased byAPCsanditsmaintargetsare Th0/Th1
CD4+TcellsandNK cells

2. Cytokines with Predominant immuno-regulatory
functions
3. Cytokines that regulate
lymphocyte growth, activation and
differentiation
5. Chemokines

 IL-2
 IL-4
 IL-5
 IL-12
 IL-15
 TGF-β

 Imp. for proliferation of T and B lymphocytes

 NecessaryforT celldevelopmentinthethymusforthe
maturationofa uniquesubsetofT cellsthatare termed as
regulatoryT-cells(T-regs)

• IL-4 isthemajorB-cellgrowthfactor
• VitalforimmunoglobulinclassswitchIgGtoIgEandinhibitsthesynthesisof
IgM andotherIgG subtypes
• IL-4 inducesexpressionofclassIImajor MHCmoleculesonB cells

 Suppresses the production of pro-inflammatory cytokines
 Suppresses the production of TNF-a, IL-1, IL-6 & IL-8
 Involved in the developmentof Th2 subset
 Involved in B-lymphocyte production
 Initiates growth of mast cells
 Stimulates synthesis of extracellularmatrix
 Cause the switching of antibody production to IgE and IgG

 RegulatesT cellandNK cellsactivationandproliferation
 ThenumberofCD8+memorycellsisshowntobecontrolledbya balance
betweenIL-15 andIL-12

functions
3. Cytokines that regulate lymphocyte growth,
activation and differentiation
4. Cytokines that help in
hematopoiesis
5. Chemokines

 Granulocyte- monocyte colony
stimulating factor
 IL-1
 IL-3 and Stem cell factor
 IL-6
 IL-7

 Majorcytokinestimulatinghaematopoiesis
 ReleasedbyactivatedT lymphocytes,stimulatinggranulocytesandmonocyte
cytotoxicactivityandexpressionofMHC-IImolecules
 Dendriticcellproliferationanddifferentiation
 B-cellproliferationanddifferentiation

 Actsas growthfactoronthebonemarrow
 Mobilisationofleukocyteswhichisreflectedintheperipheralbloodvessels
asleukocytosis
 Actsas growthfactorforearlybonemarrow progenitors
 ReleasedbyactivatedT-lymphocytes

 Imp. mediatoroftheosteoclastogenesisandbonelossininflammatory
conditionssuchasperiodontitis

functions
3. Cytokins that regulate lymphocyte growth, activation
and differentiation
5. Chemokines

 Cytokines that regulate the leukocyte movements

 2 groups depending on their structure- α and β
 α chemokine: Cys-X-Cys (CXC)
 β chemokine: CC

IL-8 (Neutrophil-Activatingfactor)
 ReleasedbyT-lymphocytesandmonocytesstimulatedwithTNFofIL-1
 Recruitsgranulocytestothearea ofinfection
 ChemotacticforT-lymphocytes

4 major cytokines which act predominantly on mononuclear cells
 RANTES (Regulated onactivation, normal T-cell expressed andsecreted): Released
by T-cells, attracts T cells with memoryphenotype, NK cells, eosinophils and mast
cells
 MacrophageInflammatory proteins (MIP): Released by monocytes and
macrophages and attracts eosinophils, lymphocytes and NK cells
 MacrophageChemotactic Proteins (MCP): Produced by monocytes and
macrophages and related cells and attracts monocytes, eosinophils and NK cells
 Eotaxin: Induced byIL-4 that recruits eosinophils and Th2 CD41 T cells to the site of
allergic inflammation

 IL-1α,IL-1βandTNF-α-stimulateboneresorptionandinhibitbone
formation
 Chungetal has showedelevatedIL-1βexpressioninGCF atsitesofrecent
boneandattachmentlossinptswithperiodontitis
(Subgingivalmicrofloraandgingivalcrevicularfluidcytokinesinrefractory
periodontitis.JCP1995,Vol22)

 Studiesdoneonnon-humanprimatemodelsusingIL-1 antagonist(IL-1R)
haveshownsignificantreductionininflammation,connectivetissue
attachmentlossandboneresorptioninducedbyperiodontalpathogens
comparedtocontrols
Delima et al. Inflammation and tissue loss caused by periodontal pathogens is
reducedbyIL-1 antagonists. JInft Dis 2002

 Acceleratedprogressionofperiodontitisinrat ligaturemodelonapplication
ofrhTNF-α
Gillespie. Impact of cytokines and T-lymphocytes upon osteoblast differentiation
and function. Arthritis Res Ther2007
 TNF-αreceptor knockoutmicedevelopedsignificantlylessinflammationand
alveolarbonelossinresponsetoA.a
Garlet et al. The dual role of p55 TNF-α receptor in A.a induced experimental
periodontitis. Clin ExpImmunol 2007

 Studieshavedemonstratedthatconc.ofIL-4 inGCF decreasedfrom
periodontalhealthtodisease.
Bozkurt et al. Anti-inflammatory cytokines in GCF in pts with periodontitis and RA:
a preliminary report. Cytokine 2006
Pradeepetal. GCF levels of monocyte chemoattractant protein 1 in periodontal
health and disease. Archives of Oral Biol 2009

 IL-6 higherininflammedgingivalfluid
Bartold. IL-6 in human gingival fibroblasts. JPR 1991
 GeneticallydeletedIL-6- decreasedboneloss
Bakret al. T-cells and the pro-inflammatory cytokines gammainterferon and IL-6
contribute to alveolar bone loss in mice. Infect Immunol 1999

 IL-8 conc.higherinpockets<3mmandlessin>6mm
McGee etal.The relationship between concentrations of proinflammatory
cytokines within gingiva and the adjacent sulcular depth. JOP 1998

IL-33-anti-inflammatoryandreparative responses
 TNF-αinducedIL-33 maylinkinflammationdirectlytotheIL-33-dependent
stimulationofTh2cytokineproducingcellswhichresultsinanti-
inflammatoryandreparativeresponses
Beklen etal. IL-1 superfamily memberIL-33 in periodontaln diseases. Biotech
Histochem April-2014

 Aggressive: IL-17
 Control: IL-11
IL-17 and IL-11 GCF levels in Aggressive and Chronic Periodontitis patients.
Shakeretal. Mediators of inflammation 2012

 Downregulationof expressionofosteoblastandosteocytemarkers in
periodontaltissuesassociatedwiththespontaneousalveolarbonelossofIL-
10knockoutmice
Claudino etal. European Journal ofOral Sciences 2010

 IL-18isincreasedinchronicperiodontitisafter bacterialinfectionvia T-cell
mediatedpathway
Yoshinaka et al. IncreasedIL-18 in gingival tissues evokes chronic periodontitis
after bacterial infection. The Tohoku Journal of Experimental Medicine 2014

 IL-29hasantiviralpropertiesandsmokingcausesimbalanceintheGCF ofIL-
29
Shivaprasad et al. Influence of smoking onIL-29 (IF-γ1) levels in GCF of Chronic
Periodontitis pts. Journal of dental Sciences.2014

 Carranza 10th and 11th editions
 Lindhe
 Perio 2000
 Periobasics.com
 Pubmed
 Google Scholar

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