Cytokines in Periodontal Diseaase
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Transcript of Cytokines in Periodontal Diseaase
CYTOKINES
Dr. Kritika JangidMDS- Periodontics
DEFINITIONCyto-cell. kine-movement
Cytokines are low molecular weight soluble mediators(small proteins) of immunity which are secreted by activated immunocytes or some matrix cells and possess high activity and various functions.
CYTOKINES Lymphokine: Made by activatedLymphocytes especially TH cells, e.g. IL-2
Monokine: Made by mononuclear
phagocytes, e.g. Mig/CXCL9
Chemokine: Mediates chemotaxis between 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)
PROPERTIESLow molecular weight proteins <30kdActive in pico-mole amountsSoluble mediators of immunity. Mechanism of leukocytes communication. Transient
PROPERTIESProduced by cells as part of normal
cellular activity or the result of environmental trigger
Bind to receptors on cells
Trigger signal transduction pathways
Initiate synthesis of new proteins
Only cells expressing receptors for specific cytokines can be activated by them
AutocrineAffects the generating cell (self)
ParacrineAffects cells in the immediate vicinity
EndocrineAffects cells remote from the secreting cell
EFFECTS OF CYTOKINESPLEIOTROPISM
REDUNDANCY
SYNERGY
ANTAGONISM
CASCADE INDUCTION
FORM A CYTOKINE NETWORK.
PLEIOTROPISM Ability of one cytokine having different effects
on different cell .
REDUCTANCYThe property of multiple cytokines having the
same or overlapping functional effects.
SYNERGYThe property of two or more cytokines having
greater than additive effects.
ANTAGONISMThe ability of one cytokine inhibiting the
action of another.
CASCADE INDUCTION
Action of one cytokine on a target cell induces that cell to produce one or more cytokines which induce other target cells to produce other cytokines
One kind of cytokines can be produced by different cells. One kind of cells can secrete different cytokines.
TH1
IL-2
IL-3,GM-CSF,TNF-
IFN-γ,TNF-β
TH2
IL-4， 6
IL-5
Cytokines initiate their actions by binding to specific membrane receptors on target cells.
1. Pro- inflammatory cytokines
2. Cytokines with Predominant immuno-regulatory functions
3. Cytokines that regulate lymphocyte growth, activation and differentiation
4. Cytokines that help in hematopoiesis
5. Chemokines
CLASSIFICATION OF CYTOKINES
1. Pro- inflammatory cytokines
2. Cytokines with Predominant immuno-regulatory functions
3. Cytokines that regulate lymphocyte growth, activation and differentiation
4. Cytokines that help in hematopoiesis5. Chemokines
CLASSIFICATION OF CYTOKINES
IL-1
TNF
INF
IL-6
IL-8
Macrophage migration inhibition factor (MIF)
2 molecular forms- IL-1α, IL-1βEncoded by 2 separate genes20% homologyMain source of IL-1 are the cells of monocyte-
macrophage lineage
IL-1α tends to remain associated to membranes
IL-1β - synthesised as an inactive precursor, released from the cell after being processed post- transitionally by a cysteine-asparagene protease
IL-1
IL-1β is expressed by monocytes, macrophages and dendritic cells.
It signals through 2 receptors- IL-1R1 and IL-1RII both of which are shared with IL-1α
It is a multifunctional molecule the effects ranging from inflammation, immunity and hemopoiesis
IL-1 has divers activities and roles in immunity,inflammation, tissue breakdown and tissue homeostasis
Involved in inflammatory and immune responses
Both autocrine and paracrine inducer of other cytokines like IL-1, IL-6, IL-8, PDGF, ecosanoids, platelet activating factors and granulocyte monocyte colony stimulating factor
TNF is secreted by macrophages, monocytes, neutrophils, T-cells, NK cells following their stimulation by bacterial lipo-polysaccharides
Cells expressing CD4 secrete TNF-α while CD8 cells secrete little or no TNFα
TNF- α
Direct effect on the pathogenesis of periodontal disease
Up-regulates the production of other classic pro-inflammatory innate immunity cytokines like IL-1β and IL-6
TNF- β is commonly known as lymphotoxin
1. Metabolic effects: Acute Phase proteins- 1-anti-trypsin, fibrinogen, CRP
2. Vascular effects: Adherence. Expression of P-selectin, E-selectin
3. Endogenous pyrogen: Does nt cross BBB, interacts with a group of nuclei in the hypothalamus to cause fever
IL-1 and TNF have effects at 3 different levels...
Produced by variety of cells like monocytes, fibroblasts, osteoblasts and vascular endothelial cells in response to inflammatory changes.
Has pro-inflammatory and hematopoietic activity.
Role as a pro-inflammatory cytokine is similar to IL-1 and TNF
Action on IL-6 on B-cells is the increased secretion of Ig-M
Induces T-cell proliferationPleiotropic cytokine
IL-6
Chemo-attractant for neutrophilsInduced 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 angiogenesisInhibits endothelial apoptosis
IL-8
Crucial role in the recruitment and activation of macrophages as well as in helping to kill the bacteria
Also known as glycosylation-inhibiting factor (GIF)
Innate immune responses- TNF-α and TLR4 expression, phagocytes and intracellular killing mechanisms
Adaptive immune responses- Th1 activation and differentiation
Macrophage Migration Inhibition Factor (MIF)
IL-4IL-10IL-11IL-13IL-16TGF-βSoluble TNF receptorSoluble IL-1 receptor
Anti-inflammatory cytokines
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 hematopoiesis5. Chemokines
CLASSIFICATION OF CYTOKINES
Interferons
IL-12
IL-18
Anti-viral effectsIFN-α- produced by leucocytesIFN-β- produced by fibroblastsIFN-γ- produced by CD4+ cells and NK cells
Along with IL-1, it induces an increase in the expression of ICAM-1 on the cytoplasmic membrane of endothelial cells, enhancing T-lymphocyte adherence to the vascular endothelium.
Interferons
Regulation cytokine- initiation and regulation of cellular immune responses
Links innate and adaptive immune responses
Generated from T and B-lymphocytes, NK cells and macrophages.
The production is of IL-12 is inhibited by IL-4 and IL-10.
IL-12
Recently discovered interleukin
Initially named as interferon γ-inducing factor
It has similar roles like IL-1 and IL-12
IL-18 is produced and released by APCs and its main targets are Th0/Th1 CD4+ T cells and NK cells
IL-18
1. Pro- inflammatory cytokines2. Cytokines with Predominant immuno-
regulatory functions
3. Cytokines that regulate lymphocyte growth, activation and differentiation
4. Cytokines that help in hematopoiesis5. Chemokines
CLASSIFICATION OF CYTOKINES
IL-2IL-4IL-5IL-12IL-15TGF-β
Imp. for proliferation of T and B lymphocytes
IL-2
Necessary for T cell development in the thymus for the maturation of a unique subset of T cells that are termed as regulatory T-cells (T-regs)
IL-4
• IL-4 is the major B-cell growth factor
• Vital for immunoglobulin class switch IgG to IgE and inhibits the synthesis of IgM and other IgG subtypes
• IL-4 induces expression of class II major MHC molecules on B cells
Suppresses the production of pro-inflammatory cytokinesSuppresses the production of TNF-a, IL-1, IL-6 &
IL-8Involved in the development of Th2 subsetInvolved in B-lymphocyte productionInitiates growth of mast cells
Stimulates synthesis of extracellular matrixCause the switching of antibody production
to IgE and IgG
Regulates T cell and NK cells activation and proliferation
The number of CD8+ memory cells is shown to be controlled by a balance between IL-15 and IL-12
IL-15
1. Pro- inflammatory cytokines2. Cytokines with Predominant immuno-
regulatory functions3. Cytokines that regulate lymphocyte growth,
activation and differentiation
4. Cytokines that help in hematopoiesis
5. Chemokines
CLASSIFICATION OF CYTOKINES
Granulocyte- monocyte colony stimulating factor
IL-1IL-3 and Stem cell factorIL-6IL-7
Major cytokine stimulating haematopoiesis
Released by activated T lymphocytes, stimulating granulocytes and monocyte cytotoxic activity and expression of MHC-II molecules
Dendritic cell proliferation and differentiation
B-cell proliferation and differentiation
Granulocyte- monocyte colony stimulating factor
Acts as growth factor on the bone marrow
Mobilisation of leukocytes which is reflected in the peripheral blood vessels as leukocytosis
IL-1
IL-3Acts as growth factor for early bone marrow
progenitors
Released by activated T-lymphocytes
Imp. mediator of the osteoclastogenesis and bone loss in inflammatory conditions such as periodontitis
IL-7
1. Pro- inflammatory cytokines2. Cytokines with Predominant immuno-
regulatory functions3. Cytokins that regulate lymphocyte growth,
activation and differentiation4. Cytokines that help in hematopoiesis
5. Chemokines
CLASSIFICATION OF CYTOKINES
Cytokines that regulate the leukocyte movements
2 groups depending on their structure- α and β
α chemokine: Cys-X-Cys (CXC)β chemokine: CC
Chemokines
IL-8 (Neutrophil- Activating factor)Released by T-lymphocytes and monocytes
stimulated with TNF of IL-1Recruits granulocytes to the area of infectionChemotactic for T-lymphocytes
α Chemokines
4 major cytokines which act predominantly on mononuclear cells
RANTES (Regulated on activation, normal T-cell expressed and secreted): Released by T-cells, attracts T cells with memory phenotype, NK cells, eosinophils and mast cells
Macrophage Inflammatory proteins (MIP): Released by monocytes and macrophages and attracts eosinophils, lymphocytes and NK cells
Macrophage Chemotactic Proteins (MCP): Produced by monocytes and macrophages and related cells and attracts monocytes, eosinophils and NK cells
Eotaxin: Induced by IL-4 that recruits eosinophils and Th2 CD41 T cells to the site of allergic inflammation
β-Chemokines
CYTOKINES IN PERIODONTAL
DISEASE
IL-1α, IL-1β and TNF-α- stimulate bone resorption and inhibit bone formation
Chung et al has showed elevated IL-1β expression in GCF at sites of recent bone and attachment loss in pts with periodontitis(Subgingival microflora and gingival crevicular fluid cytokines in refractory periodontitis. JCP 1995, Vol 22)
Established Evidences
Studies done on non-human primate models using IL-1 antagonist (IL-1R) have shown significant reduction in inflammation, connective tissue attachment loss and bone resorption induced by periodontal pathogens compared to controlsDelima et al. Inflammation and tissue loss caused
by periodontal pathogens is reduced by IL-1 antagonists. J Inft Dis 2002
Accelerated progression of periodontitis in rat ligature model on application of rhTNF-αGillespie. Impact of cytokines and T-lymphocytes
upon osteoblast differentiation and function. Arthritis Res Ther 2007
TNF-α receptor knockout mice developed significantly less inflammation and alveolar bone loss in response to A.aGarlet et al. The dual role of p55 TNF-α receptor
in A.a induced experimental periodontitis. Clin Exp Immunol 2007
TNF-α stimulates bone resorption
Studies have demonstrated that conc. of IL-4 in GCF decreased from periodontal health to disease.Bozkurt et al. Anti-inflammatory cytokines in GCF
in pts with periodontitis and RA: a preliminary report. Cytokine 2006
Pradeep et al. GCF levels of monocyte chemoattractant protein 1 in periodontal health and disease. Archives of Oral Biol 2009
IL-4 has anti-inflammatory properties
IL-6 higher in inflammed gingival fluid Bartold. IL-6 in human gingival fibroblasts. JPR
1991
Genetically deleted IL-6- decreased bone lossBakr et al. T-cells and the pro-inflammatory
cytokines gamma interferon and IL-6 contribute to alveolar bone loss in mice. Infect Immunol 1999
IL-6: proinflammatory cytokine
IL-8 conc. higher in pockets <3 mm and less in >6mmMcGee et al. The relationship between
concentrations of proinflammatory cytokines within gingiva and the adjacent sulcular depth. JOP 1998
IL-8 is a chemotactic for leukocytes
IL-33- anti-inflammatory and reparative responses
TNF-α induced IL-33 may link inflammation directly to the IL-33- dependent stimulation of Th2 cytokine producing cells which results in anti-inflammatory and reparative responses Beklen et al. IL-1 superfamily member IL-33 in
periodontaln diseases. Biotech Histochem April-2014
Recent Evidences
Aggressive: IL-17Control: IL-11
IL-17 and IL-11 GCF levels in Aggressive and Chronic Periodontitis patients. Shaker et al. Mediators of inflammation 2012
IL-17 and IL-11
Downregulation of expression of osteoblast and osteocyte markers in periodontal tissues associated with the spontaneous alveolar bone loss of IL-10 knockout miceClaudino et al. European Journal of Oral Sciences
2010
IL-10
IL-18 is increased in chronic periodontitis after bacterial infection via T-cell mediated pathwayYoshinaka et al. Increased IL-18 in gingival tissues
evokes chronic periodontitis after bacterial infection. The Tohoku Journal of Experimental Medicine 2014
IL-18
IL-29 has antiviral properties and smoking causes imbalance in the GCF of IL-29Shivaprasad et al. Influence of smoking on IL-29
(IF-γ1) levels in GCF of Chronic Periodontitis pts. Journal of dental Sciences. 2014
IL-29
Carranza 10th and 11th editionsLindhePerio 2000Periobasics.comPubmedGoogle Scholar
References
