PERIO

1. CYTOKINES
Arvind Nagaraj

2. CONTENTS
• Introduction
• Nomenclature
• Properties of Cytokines
• Categories of Cytokines
• Cytokine Receptors
• Some Important Cytokines
• Cytokines and Periodontal Disease
• Conclusion
• References

3. INTRODUCTION
• Inflammation, the response of tissues to injury, is characterized in the
acute phase by
1. increased blood flow
2. vascular permeability
3. accumulation of fluid, leukocytes and inflammatory mediators such as
cytokines.
• In the chronic phase, it is characterized by the development of specific
humoral and cellular immune responses to the pathogens present at the
site of tissue injury.
Wright, T. M. "Cytokines In Acute And Chronic Inflammation". Frontiers in Bioscience 2.4
(1997): d12-26. Web.

4. • During both acute and chronic inflammatory processes, a variety of
soluble factors are involved in leukocyte recruitment through increased
expression of cellular adhesion molecules and chemoattraction.
• The soluble factors that mediate these responses fall into four main
categories:
1. Inflammatory lipid metabolites such as platelet activating factor (PAF)
and the numerous derivatives of arachidonic acid (prostaglandins,
leukotrienes, lipoxins), which are generated from cellular phospholipids
2. Three cascades of soluble proteases/substrates (clotting, complement,
and kinins), which generate numerous pro-inflammatory peptides
3. Nitric oxide, a potent endogenous vasodilator
4. A group of cell-derived polypeptides, known as cytokines, which to a
large extent orchestrate the inflammatory response. They are major
determinants of the make-up of the cellular infiltrate, the state of cellular
activation, and the systemic responses to inflammation.

5. CYTOKINES
• Cytokines are proteins secreted by the cells of innate and adaptive
immunity that mediate many of the functions of these cells.
• Cytokines are produced In response to microbes and other antigens.
• Different cytokines stimulate diverse responses of cells involved in
immunity and inflammation.
• In the activation phase of adaptive immune responses, cytokines stimulate
the growth and differentiation of lymphocytes.
• ln the effector phases of innate and adaptive immunity, they activate
different effector cells to eliminate microbes and other antigens.
Abbas, Abul K et al. Cellular And Molecular Immunology. 1st ed. Print.

6. • Cytokines also stimulate the development of hematopoietic cells.
• In clinical medicine, cytokines are important as therapeutic agents and as
targets for specific antagonists in numerous immune and inflammatory
diseases.

7. NOMENCLATURE
• The nomenclature of cytokines is often based on their cellular sources.
• Cytokines that are produced by mononuclear phagocytes were originally
called monokines (CXCL 9), and those produced by Iymphocytes were
called Iymphokines (IL-2).
• With the development of anticytokine antibodies and molecular probes, it
became clear that the same protein may be synthesized by lymphocytes,
monocytes, and a variety of tissue cells, including endothelial cells and
some epithelial cells.
Therefore, the generic term cytokines is the preferred name for this class
of mediators.

8. • Cytokines made by leucocytes that act on other leucocytes are termed
Interleukins
Eg: IL-1, IL-10
• Cytokines with chemotactic activities are called chemokines
Eg: IL-8
• Based on Activity: Tumour Necrosis Factor α (TNF), Transforming Growth
Factor (TGF), Colony Stimulation Factor (CSF)

9. PROPERTIES
• Cytokines are polypeptides produced in response to microbes and other
antigens that mediate and regulate immune and inflammatory reactions.

10. • Cytokine secretion is a brief, self-limited event.
Cytokines are not usually stored as preformed molecules, and their
synthesis is initiated by new gene transcription as a result of cellular
activation.
Once synthesized, cytokines are rapidly secreted, resulting in a burst of
release when needed.
• Cytokine actions may be local and systemic.

11. • The actions of cytokines are often pleiotropic and redundant.

12. • Cytokines often influence the synthesis and actions of other cytokines.
The ability of one cytokine to stimulate production of others leads to
cascades in which a second or third cytokine may mediate the biologic
effects of the first.

13. • Two cytokines may antagonize each other's action, produce additive
effects, or, in some cases, produce greater than anticipated, or synergistic
effects.

14. • Cytokines initiate their actions by binding to specific membrane receptors
on target cells.
• External signals regulate the expression of cytokine receptors and thus the
responsiveness of cells to cytokines.
• The cellular responses to most cytokines consist of changes in gene
expression in target cells, resulting in the expression of new functions and
sometimes in the proliferation of the target cells.
• Cellular responses to cytokines are tightly regulated, and feedback
inhibitory mechanisms exist to turn down these responses.
Abbas, Abul K et al. Cellular And Molecular Immunology. 1st ed. Print.

15. Owen, Judith A et al. Kuby Immunology. 1st ed. New York: W.H. Freeman, 2013. Print.

16. CATEGORIES OF CYTOKINES
• Cytokines are categorized into three main functional categories based on
their principal biologic actions:
1. Mediators and regulators of innate immunity
2. Mediators and regulators of adaptive immunity
3. Stimulators of hematopoiesis

19. CYTOKINE RECEPTORS
• All cytokine receptors consist of one or more transmembrane proteins
whose extracellular portions are responsible for cytokine binding and
whose cytoplasmic portions are responsible for initiating intracellular
signaling pathways.
• The most widely used classification is based on structural homologies of
the extracellular cytokine-binding domains and shared intracellular
signaling mechanisms.

21. Pro-inflammatory
cytokines
IL-1 TNF IL-6 IL-8 MIF

22. INTERLEUKIN-1
• The principal function of lL-1 is as a mediator of the host inflammatory
response to infections and other stimuli.
• IL-1 works together with TNF in innate immunity and inflammation.
• The major cellular source of IL-1 is activated mononuclear phagocytes. IL-1
production by mononuclear phagocytes is induced by bacterial products
such as LPS and by other cytokines such as TNF.
• IL-1 is also produced by many cell types other than macro phages, such as
neutrophils, epithelial cells and endothelial cells.

23. • There are two forms of IL-1, called IL-1α and IL-1β.
These are less than 30% homologous to each other, but they bind to the
same cell surface receptors and have the same biologic activities.
• Both IL-1 polypeptides are synthesized as 33-kD precursors and are
secreted as 17-kD mature proteins.
• IL-1α has a diverse role in immunity, inflammation, tissue breakdown and
tissue homeostasis
• IL-1β plays a role in immunity, inflammation and haematopoiesis.
• The active form of IL-l β is the cleaved product, but IL-l α is active either as
the 33-kD precursor or as the smaller cleaved product.

24. • When secreted at low concentrations, IL-1 functions as a mediator of local
inflammation. It acts on endothelial cells to increase expression of surface
molecules that mediate leukocyte adhesion, such as ligands for integrins.
• When secreted in larger quantities, IL-1 enters the blood stream and
exerts endocrine effects.
Systemic IL-1 induces fever, synthesis of acute-phase plasma proteins by
the liver, directly and indirectly through stimulation of IL-6 production, and
neutrophil and platelet production by the bone marrow.

25. TUMOUR NECROSIS FACTOR
• TNF is the principal mediator of the acute inflammatory response to gram-
negative bacteria and other infectious microbes and is responsible for
many of the systemic complications of severe infections.
• TNF is also called TNF-α to distinguish it from the closely related TNF-β,
also called Iymphotoxin.
• Major source is activated mononuclear phagocytes.
Also released by macrophages, monocytes, neutrophils, T cells and non-
keratinocytes following their stimulation by bacterial lipopolysaccharides.
• The principal physiologic function of TNF is to stimulate the recruitment of
neutrophils and monocytes to sites of infection and to activate these cells
to eradicate microbes.

26. • TNF induces vascular endothelial cells to express adhesion molecules that
make the endothelial surface adhesive for leukocytes, initially for
neutrophils and subsequently for monocytes and lymphocytes. The most
important of these adhesion molecules
• TNF stimulates endothelial cells and macro phages to secrete chemokines
that enhance the affinity of leukocyte integrins for their ligands and
induce leukocyte chemotaxis and recruitment. TNF also acts on
mononuclear phagocytes to stimulate secretion of lL-1, which functions
much like TNF itself.
• TNF stimulates the microbicidal activities of neutrophils and macrophages.
• TNF also contributes to local inflammatory reactions that are injurious to
the host

27. • TNF also induces apoptosis of some cell types in vitro, however, the
physiologic role of this activity is not known.
• In severe infections, TNF is produced in large amounts and causes systemic
clinical and pathologic abnormalities.
If the stimulus for TNF production is sufficiently strong, the quantity of the
cytokine produced is so large that it enters the blood stream and acts at
distant sites as an endocrine hormone.
• Principal systemic effects of TNF are:
TNF acts on the hypothalamus to induce fever and is therefore called an
endogenous pyrogen.
Fever production in response to TNF (and IL-1) is mediated by increased
synthesis of prostaglandins by cytokine stimulated hypothalamic cells.
Prostaglandin synthesis inhibitors, such as aspirin, reduce fever by
blocking this action of TNF and IL-1.

28. • TNF acts on hepatocytes to increase synthesis of certain serum proteins,
such as serum amyloid A protein and fibrinogen.
• Prolonged production of TNF causes wasting of muscle and fat cells, called
cachexia.
Results from TNF-induced appetite suppression and reduced synthesis of
lipoprotein lipase, an enzyme needed to release fatty acids from
circulating lipoproteins so that they can be used by the tissues.
• When large amounts of TNF are produced, with serum concentrations
reaching 10-7 M or more, myocardial contractility and vascular smooth
muscle tone are inhibited, resulting in a marked fall in blood pressure, or
shock.
• TNF causes intravascular thrombosis, mainly as a result of loss of the
normal anticoagulant properties of the endothelium.

29. • High circulating levels of TNF cause severe metabolic disturbances, such as
a fall in blood glucose concentrations. This is due to overuse of glucose by
muscle and failure of the liver to replace the glucose.
• A complication of severe gram-negative bacterial sepsis is a syndrome
called septic shock.
Which is characterized by vascular collapse, disseminated intravascular
coagulation, and metabolic disturbances.
This syndrome is due to LPS-induced production of TNF and other
cytokines, including IL-12, IFN-γ, and IL-l.

31. INTERLEUKIN-6
• Pleiotropic cytokine
• Produced by monocytes, fibroblasts, osteoblasts and vascular endothelial
cells
• Has pro-inflammatory and haematopoietic activity
• Similar to IL-1 and TNF.
• Increased secretion of Ig-M
• T cell proliferation.
• A de-regulated production of IL-6 affects the pathogenesis of several
autoimmune and inflammatory diseases.

32. INTERLEUKIN-8
• Secreted by monocytes, lymphocytes, fibroblasts, epithelial and
endothelial cells.
• Causes neutrophil chemotaxis
• Induces PMN adhesion to endothelium, trans-endothelial migration and
enzyme release
• Also attract T cells
• Promotes angiogenesis and inhibits endothelial apoptosis

33. • Continuous extravasation of neutrophils can also contribute to tissue
destruction.
• In the presence of IL-3, IL-8 activates basophils to release leukotrienes and
histamine.
• Thus, IL-8 plays an important role in the innate immunity, providing a first
line of defense against invading pathogens

34. Anti-inflammatory
cytokines
IL-4 IL-10 IL-11 IL-13 IL-16 TGF-β

35. INTERLEUKIN-4
• IL-4 is the major stimulus for the production of IgE antibodies and for the
development of TH2 cells from naive CD4+ helper T cells.
• IL-4 is a member of the four-α-helical cytokine family.
The principal cellular sources of IL-4 are CD4+T lymphocytes of the TH2
subset as well as activated mast cells.
• IL-4 is the principal cytokine that stimulates B cell Ig heavy chain class
switching to the IgE isotype.
IgE is also the principal mediator of immediate hypersensitivity reactions,
and production of IL-4 is important for the development of allergies

36. • IL-4 stimulates the development of TH2 cells from naive CD4+ T cells and
functions as an autocrine growth factor for differentiated TH2 cells.
• IL-4, together with IL-13, contributes to an alternative form of macrophage
activation that is distinct from the macrophage response to IFN-γ.
The effects of IL-4 on macrophages include arginase induction leading to
collagen production, and increased mannose receptor expression, which
promotes the phagocytosis of microbes.

38. INTERLEUKIN-10
• IL-10 is an inhibitor of activated macrophages and dendritic cells and thus
involved in the control of innate immune reactions and cell-mediated
immunity.
• IL-10 is an inhibitor of host immune responses, particularly responses
involving macrophages.
• IL-10 is a member of a family of noncovalently linked dImeric cytokines,
each chain of which contains a six helix bundle domain that intercalates
with that of the other chain.
• The IL-10 receptor belongs to the type II cytokine receptor family.
• Other members of the family include IL-19, IL-20, IL-22, IL-24, and IL-26.

39. • IL-10 is produced mainly by activated macrophages and regulatory T cells.
It is both produced by and inhibits macrophage functions
IL-10 is also produced by some nonlymphoid cell types.
• IL-10 inhibits the production of IL-12 by activated macrophages and
dendritic cells. Because IL-12 is a critical stimulus for IFN-y secretion and is
an inducer of innate and cell-mediated immune reactions against
intracellular microbes, IL-10 functions to down-regulate all such reactions.
IL-10 was discovered as an inhibitor of IFN-y production.
• IL-10 inhibits the expression of costimulators and class II MHC molecules
on macrophages and dendritic cells.
Because of these actions, IL-10 serves to inhibit T cell activation and
terminate cell-mediated immune reactions.

40. INTERLEUKIN-13
• IL-13 is structurally and functionally similar to IL-4, and plays a key role in
defense against helminths and in allergic diseases.
• IL-13 is a member of the four-α-helical cytokine family
• IL-13 is produced mainly by CD4+ helper T cells of the TH2 subset.
Other cellular sources of IL-13 include basophils and eosinophils.
• lL-13 works together with lL-4 in producing biologic effects associated with
allergic inflammation.

41. • IL-13 promotes fibrosis as part of the tissue repair phase of chronic
inflammatory states.
The fibrogenic function of lL-13, which is not shared by lL-4, is due to
stimulation of fibroblasts and macro phages to synthesize collagen, in part
by inducing expression of the enzyme arginase-1
• IL-13 stimulates mucus production by lung epithelial cells. This property is
also not shared by lL-4, and also contributes to the pathogenesis of
asthma.
• IL-13 promotes inflammation by inducing expression of endothelial
adhesion molecules (e.g., VCAM-l) and chemokines, which mediate
recruitment of granulocytes and monocytes into tissues.
• The pro-inflammatory effects ofIL-13 may be protective against parasite
infections, and harmful in the case of asthma and other lung diseases.

42. TRANSFORMING GROWTH FACTOR-β
• The principal action of TGF- β in the immune system is to inhibit the
proliferation and activation of lymphocytes and other leukocytes.
• However, TGF- β can exert either anti-inflammatory or pro-inflammatory
effects depending on the timing of its appearance, the amount produced, and
systemic versus local expression.
• TGF- β was discovered as a tumor product that promoted the survival of cells
in semisolid culture media.
• TGF- β is a homodimeric protein that is synthesized and secreted by antigen-
stimulated T cells, LPS-activated mononuclear phagocytes, and many other
cell types.
Some regulatory T cells produce TGF- β, and the same cells may also produce
IL-10, which, like TGF- β, has immunosuppressive activities

43. • TGF- β inhibits the proliferation and effector functions of T cells and the
activation of macrophages.
TGF- β also acts on other cells, such as neutrophils and endothelial cells,
largely to counteract the effects of pro-inflammatory cytokines.
By these actions, TGF- β functions to inhibit immune and inflammatory
responses.
• TGF- β regulates differentiation of functionally distinct subsets of T cells.
• TGF- β regulates tissue repair after local immune and inflammatory
reactions subside.
This function is mediated by specific actions of TGF- β on collagen
synthesis and matrix-modifying enzyme production by macrophages and
fibroblasts, and by contributing to angiogenesis.

44. Cytokines with Predominant
immuno-regulatory functions
Interferon-γ IL-12 IL-18

45. INTERFERON - γ
• IFN- γ is the principal macrophage-activating cytokine and serves critical
functions in innate immunity and in adaptive cell-mediated immunity
against intracellular microbes.
• lFN- γ is a homodimeric protein produced by NK cells, CD4+ T cells, and
CD8+ T cells
• lFN- γ functions as a mediator of innate immunity.
In adaptive immunity, T cells produce lFN-y in response to antigen
recognition, and production is enhanced by IL-12 and lL-18.

46. • IFN-γ activates macrophages to kill phagocytosed microbes.
• IFN- γ promotes the differentiation of naive CD4+ T cells to the TH1 subset
and inhibits the differentiation of TH2 cells.
• IFN- γ stimulates expression of Class I and Class II MHC molecules and
costimulators on APCS
• The net effect of these activities is to promote macrophage-rich
inflammatory reactions while inhibiting IgE-dependent Eosinophil-rich
reactions

49. INTERLEUKIN-12
• IL-12 is a principal mediator of the early innate immune response to
intracellular microbes and is a key inducer of cell-mediated immunity, the
adaptive immune response to these microbes.
• The principal sources of IL-12 are activated dendritic cells and
macrophages.
• Production inhibited by IL-4 and IL-10
• IL-12 is critical for initiating a sequence of responses involving macro
phages, NK cells, and T lymphocytes that results in the eradication of
intracellular microbes.

50. • IL-12 stimulates the production of IFN-γ by NK cells and T lymphocytes.
• IL-12, together with IFN- γ, promotes the differentiation of CD4+ helper T
lymphocytes into IFN-γ producing TH1 cells.
• IL-12 enhances the cytotoxic functions of activated NK cells and CD8+
cytotoxic T lymphocytes
• IL-12 is an important link between innate and adaptive immunity, being
produced during early innate immune reactions against intracellular
microbes and promoting adaptive immune responses that protect the
host against these microbes.

52. Cytokines that regulate lymphocyte
growth, activation and
differentiation
IL-2 IL-4 IL-5 IL-12 IL-15 TGF-β

53. INTERLEUKIN-2
• IL-2 is a growth, survival, and differentiation factor for T lymphocytes, and
plays a major role in regulation of T cell responses through its actions on
regulatory T cells.
• Because of its ability to support proliferation of antigen stimulated T cells,
IL-2 was originally called T cell growth factor.
• IL-2 is produced mainly by CD4+ T lymphocytes.
• Secreted IL-2 is a 14- to 17-kD glycoprotein that folds into a globular
protein containing four a-helices. It is the prototype of the four-a-helical
cytokines that interact with type I cytokine receptors

54. • IL-2 is required for the survival and perhaps function of regulatory T cells,
which suppress immune responses against self and other antigens
• IL-2 stimulates the survival, proliferation, and differentiation of antigen-
activated T cells.
• IL-2 stimulates the survival, proliferation, and differentiation of antigen-
activated T cells.
• IL-2 acts on B cells both as a growth factor and as a stimulus for antibody
synthesis.
However, this action has only been observed in vitro

55. Cytokines that help in hematopoiesis
Granulocyte-
monocyte CSF
IL-1
IL-3 and Stem
Cell Factor
IL-6 IL-7

57. CHEMOKINES
• Chemokines are a large family of structurally homologous cytokines that
stimulate leukocyte movement and regulate the migration of leukocytes
from the blood to tissues.
• The name chemokine is a contraction of "chemotactic cytokine.“
• There are about 50 human chemokines, all of which are 8- to 12-kD
polypeptides that contain two internal disulfide loops.
• The chemokines are classified into four families on the basis of the
number and location of N-terminal cysteine residues.

58. • The two major families are the CC chemokines, in which the cysteine
residues are adjacent, and the CXC family, in which these residues are
separated by one amino acid.
• A small number of chemokines have a single cysteine (C family) or two
cysteines separated by three amino acids (CX3C).
• The chemokines of the CC and CXC subfamilies are produced by leukocytes
and by several types of tissue cells, such as endothelial cells, epithelial
cells, and fibroblasts.
Several CC chemokines are also produced by antigen stimulated T cells
• The receptors for chemokines are G protein-coupled receptors with seven-
transmembrane α-helical domains.

59. • Chemokines involved in inflammatory reactions are produced by
leukocytes in response to external stimuli, and chemokines that regulate
cell traffic through tissues are produced constitutively by various cells in
these tissues.
• Chemokines recruit the cells of host defense to sites of infection
• Chemokines regulate the traffic of lymphocytes and other leukocytes
through peripheral lymphoid tissues.
• Chemokines promote angiogenesis and wound healing.
• Chemokines are also involved in the development of diverse nonlymphoid
organs.

67. CYTOKINES AND PERIODONTAL
DISEASE

68. • Research on biological activities in normal periodontium and the
pathogenesis of periodontal diseases has clarified the involvement of
various cytokines in the biological activities observed in the sites.
• Cytokines play crucial roles in the maintenance of tissue homeostasis, a
process which requires a delicate balance between anabolic and catabolic
activities.
• Excessive and/or continuous production of cytokines in inflamed
periodontal tissues is responsible for the progress of periodontitis and
periodontal tissue destruction.
Particularly, inflammatory cytokines-such as IL-lox, IL-13, IL-6, and IL-8-are
present in the diseased periodontal tissues, and their unrestricted
production seems to play a role in chronic leukocyte recruitment and
tissue destruction.
Okada, H., and S. Murakami. "Cytokine Expression In Periodontal Health And Disease". Critical
Reviews in Oral Biology & Medicine 9.3 (1998): 248-266. Web.

70. • Various animal models showed that bacteria stimulate periodontal tissue
destruction but that this effect is mediated by the host response induced
by bacteria.
• By using inhibitors, it was shown that cytokines play an important role in
this process.
• The effects of cytokines that promote osteoclast formation and bone
resorption seem to be counteracted by other cytokines that are anti-
inflammatory.
• It is probable that the balance between stimulatory and inhibitory
cytokines, together with the regulation of their receptors and signaling
cascades, determines the level of periodontal tissue loss.
Graves, Dana. "Cytokines That Promote Periodontal Tissue Destruction". Journal of
Periodontology 79.8s (2008): 1585-1591. Web.

71. • Garlet, G. P. "Destructive And Protective Roles Of Cytokines In Periodontitis: A Re-Appraisal
From Host Defense And Tissue Destruction Viewpoints". Journal of Dental Research 89.12
(2010): 1349-1363. Web.

72. • IL-1 and TNF represent pro-inflammatory cytokines that stimulate a number of
events which occur during periodontal disease.
• These include induction of adhesion molecules and other mediators that
facilitate and amplify the inflammatory response, the stimulation of matrix
metalloproteinase, and bone resorption.
• The activity of these cytokines coincides with the critical events that occur
during periodontal disease, namely, loss of attachment and bone resorption.
• Much of the damage that occurs during tissue destruction can be attributed to
IL-1 and TNF activity.
Graves, D.T., and D. Cochran. "The Contribution Of Interleukin-1 And Tumor Necrosis Factor To
Periodontal Tissue Destruction". Journal of Periodontology 74.3 (2003): 391-401. Web.

74. CONCLUSION
• Cytokines are a family of proteins that mediate many of the responses of
innate and adaptive immunity.
• The same cytokines may be produced by many cell types, and individual
cytokines often act on diverse cell types.
• Cytokines are synthesized in response to inflammatory or antigenic stimuli
and usually act locally, in an autocrine or a paracrine fashion, by binding to
high-affinity receptors on target cells.
• Certain cytokines may be produced in sufficient quantity to circulate and
exert endocrine actions.
• For many cell types, cytokines serve as growth factors.

75. • Cytokines mediate their actions by binding with high affinity to receptors,
which belong to a limited number of structural families.
• Cytokines serve many functions that are critical to host defense against
pathogens and provide links between innate and adaptive immunity.
• Cytokines also regulate the magnitude and nature of immune responses
by influencing the growth and differentiation of lymphocytes.
• Cytokines provide important amplification mechanisms that enable small
numbers of lymphocytes specific for anyone antigen to activate a variety
of effector mechanisms to eliminate the antigen.
• Excessive production or actions of cytokines can lead to pathologic
consequences.

76. • The administration of cytokines or their inhibitors is a potential approach
for modifying biologic responses associated with immune and
inflammatory diseases
• Consistent experimental approaches must be undertaken to gain better
insight into the totality of cytokine networks and how they drive immune
responses in the periodontium.

77. REFERNCES
• Wright, T. M. "Cytokines In Acute And Chronic Inflammation". Frontiers in
Bioscience 2.4 (1997): d12-26.
• Abbas, Abul K et al. Cellular And Molecular Immunology. 1st ed. Print.
• Owen, Judith A et al. Kuby Immunology. 1st ed. New York: W.H. Freeman,
2013. Print.
• Okada, H., and S. Murakami. "Cytokine Expression In Periodontal Health
And Disease". Critical Reviews in Oral Biology & Medicine 9.3 (1998): 248-
266. Web.
• Graves, Dana. "Cytokines That Promote Periodontal Tissue
Destruction". Journal of Periodontology 79.8s (2008): 1585-1591. Web.
• Garlet, G. P. "Destructive And Protective Roles Of Cytokines In
Periodontitis: A Re-Appraisal From Host Defense And Tissue Destruction
Viewpoints". Journal of Dental Research 89.12 (2010): 1349-1363. Web.

78. • Graves, D.T., and D. Cochran. "The Contribution Of Interleukin-1 And
Tumor Necrosis Factor To Periodontal Tissue Destruction". Journal of
Periodontology 74.3 (2003): 391-401. Web.
• Preshaw, Philip M., and John J. Taylor. "How Has Research Into Cytokine
Interactions And Their Role In Driving Immune Responses Impacted Our
Understanding Of Periodontitis?". Journal of Clinical Periodontology 38
(2011): 60-84. Web.