1. CYTOKINES
Cytokines are small secreted proteins released by
cells have a specific effect on the interactions and
communications between cells.
These are group of low molecular weight
polypeptides or proteins which are secreted by
activated immunocytes or some matrix cells and
possess high activity and various functions.
2. Their major functions are to mediate and regulate immune
response and inflammatory reactions.
Release of Cytokines :
Peripherally through
Mast cell
Glial cell
Monocyte
Macrophage
lymphocyte
Centrally through
Non neural cells
Microglia
Astrocytes
Schwan cells
3. Cytokine is a general name.other names include
Lymphokine -cytokines made by lymphocytes,
Monokine -cytokines made by monocytes,
Chemokine -cytokines with chemotactic activities, and
Interleukin -cytokines made by one leukocyte and acting on
other leukocytes.
4. Cytokines may act on the cells
that secrete them (autocrine
action), on nearby cells
(paracrine action), or in some
instances on distant cells
(endocrine action).
5. It is common for different cell types
to secrete the same cytokine or for a
single cytokine to act on several
different cell types called pleiotropy.
6. Cytokines are
redundant in their
activity, meaning
similar functions can be
stimulated by different
cytokines
7. One cytokine stimulates its target cells to make additional
cytokine
Cytokines are made by many cell populations, but the
predominant producers are helper T cells (Th) and
macrophages.
10. Cytokines have been classified on the basis of their
biological responses into pro or anti-inflammatory
cytokines depending on their effect on immunocytes
Major cytokines include:-
interleukins(IL)
Monokines
Interferons(IFN)
Colony stimulating factor(CSF)
Tumour necrosis factor(TNF)
11. Other types are
Type 1 cytokine
Produced by Th
1-Helper cells
Include IL-2 ,
IFN-GAMMA ,
IL-12 , TNF-
BETA
Type 2 cytokine
Produced by Th-
2 Helper cells
Include IL-4 ,
IL-5 , IL-6 , IL-
10 , IL-13
12. Mediators of Natural
immunity are:- TNF APLA
,IL-1 ,10,12,IFN (ALPHA ,
BETA, GAMMA)
Chemokines.
Meditors of adaptive
immunity are IL-
2,4,5,10,TGF-BETA,IFN-
GAMMA
13. INTERLEUKINS -1
produced by monocytes and macrophages
Their main cellular sources are mononuclear phagocytes, fibroblasts,
keratinocytes, and T and B lymphocytes. Previous synonyms--
endogenous pyrogen (EP), mononuclear cell factor, and lymphocyte-
activating factor (LAF)--emphasize the role of IL-1 in inflammation.
Both IL-1α and IL-1β can trigger fever by enhancing prostaglandin E2
(PGE2) synthesis by the vascular endothelium of the hypothalamus and
can stimulate T cell proliferation.
In addition, IL-1 elicits the release of histamine from mast cells at the
site of inflammation. Histamine then triggers early vasodilation and
increase of vascular permeability
The pro-inflammatory effects of IL-1 can be inhibited by IL-1 receptor
antagonist (IL-1Ra) produced by immune complex- or IL-4-stimulated
macrophages and by TNF
14. INTERLEUKIN -2
IL-2 is a glycoprotein originally known as T cell growth
factor (TCGF).
It is secreted mainly by activated T helper cells.
It acts as a growth factor/activator for T cells, NK cells,
and B cells and promotes the development of lymphokine-
activated killer (LAK) cells. It therefore plays a critical
role in regulating both cellular and humoral chronic
inflammatory responses.
Binding of IL-2 to the IL-2 receptor on T lymphocytes
leads to cell proliferation, increased lymphokine
secretion, and enhanced expression of class II MHC
molecules.
15. INTERLEUKIN-3
IL-3, also called multi-CSF.
produced by activated T cells and mast cells.
It stimulates eosinophils and B cell
differentiation while it inhibits lymphokine-
activated killer (LAK) cell activity,
16. INTERLEUKIN-4
IL- 4 is produced by CD4+ (TH) cells, mast cells, and basophils. It induces CD4+ T
cells to differentiate into TH2 cells while suppressing the development of TH1
cells. It also acts as a B cell, T cell, and mast cell growth factor, it enhances class II
MHC expression on B cells, and it promotes immunoglobulin class switching to
IgG1 and IgE.
Itis necessary forIgE response induction
It-4 has marked inhibitory effects on the expression and release of the
proinflammatory cytokines.
It is able to block or suppress the monocyte-derived cytokines, including IL-1,
TNF-α , IL-6, IL-8, and macrophage inflammatory protein (MIP)-1α.
It induces a potent cytotoxic response against tumors.
may act by stabilizing disease and modifying tumor growth rates in addition to
inducing tumor shrinkage and cell death without causing severe side effects,
suggesting a possible adjuvant role for IL-4 in the treatment of malignant diseases.
17. INTERLEUKIN-5
Also known as B cell growth factor II (BCGFII) and T cell
replacing factor (TRF), is produced by CD4+ T helper cells
as well as NK cells.
IL-5 is involved in eosinophil differentiation and
activation and stimulation of immunoglobulin class
switching to IgA.
Other properties of IL-5 include increased activation of B
cell proliferation, and enhancement of T cell cytotoxicity.
The combined production of IL-4 and IL-5 by CD4+ TH2
cells therefore results in IgE and IgA production and mast
cell and eosinophil stimulation.
18. INTERLEUKIN-6
IL-6 acts as a growth factor for mature B cells and
induces their final maturation into
antibodyproducing plasma cells.
It is involved in T cell activation and
differentiation, and participates in the induction of
IL-2 and IL-2 receptor expression.
Some of the regulatory effects of IL-6 involve
inhibition of TNF production, providing negative
feedback for limiting the acute inflammatory
response.
19. INTERLEUKIN-7
IL-7 is a cytokine known as a pre-B cell growth factor,
is a bone marrow and thymic stromal cell product.
It stimulates the development of pre-B and pre-T
cells and acts as a growth factor for B cells, T cells,
and early thymocytes.
20. INTERLEUKIN-8/CHEMOKINES
IL-8 and other low molecular weight chemokines
(e.g. platelet factor 4, macrophage inflammatory
protein (MIP)-1α and β, MIP-2, monocyte
chemoattractant protein-1 (MCP- 1/JE),
RANTES) belong to a chemotactic cytokine
family and are responsible for the chemotactic
migration and activation of neutrophils and
other cell types (such as monocytes, lymphocytes,
basophils, and eosinophils) at sites of
inflammation.
21. INTERLEUKIN-9
IL-9 is another cytokine produced by CD4+ T helper
(TH2) cells as well as some B lymphomas first
described in the mouse, IL-9 was known as mast
cell growth-enhancing activity (MEA) and murine
Tcell growth factor P40.
Its production is IL-4 and IL-10, and thus IL-2-
dependent.
IL-9 is regulatory in nature in that it inhibits
lymphokine production by IFN-γ producing CD4+ T
cells and enhances the growth of CD8+ T cells.
22. INTERLEUKIN-10
IL-10 is also referred to as B cell-derived T cell
growth factor and cytokine synthesis inhibitory
factor (CSIF) because it inhibits IFN-γ.
produced by a variety of cell types, including
CD4+ T cells, activated CD8+ T cells, and
activated B cells.
Itconsidered a T cell cross-regulatory factor and
has thus been referred to as an "anticytokine.
23. INTERLEUKIN-11
IL-11is produced by bone marrow stromal
cells and by some fibroblasts.
It is a functional homologue of IL-6
It is physiologically active in localized areas of
inflammation, such as inflammatory arthritis
or inflammatory bowel disease.
24. INTERLEUKIN-12
IL-12, previously known as natural killer cell stimulatory
factor (NKSF) and cytotoxic lymphocyte maturation factor
(CLMF), was originally isolated from Epstein-Barr virus
transformed B cells.
Its biological activities include enhancement of cytotoxic T
cells and lymphokine activated killer (LAK) cell generation
and activation, increased natural killer (NK) cell
cytotoxicity, induction of activated T cell and NK cell
proliferation, induction of IFN-γ production by NK cells and
T cells, and inhibition of IgE synthesis
25. INTERLEUKIN-13
IL-13 exhibits anti-inflammatory activities by inhibiting
the production of inflammatory cytokines, such as IL-1β,
TNF-α, IL-8, and IL-6, by human peripheral blood
monocytes induced with lipopolysaccharide.
Inhibition of inflammatory cytokine production is also a
characteristic of two other cytokines produced by TH2
lymphocytes, namely IL-4 and IL-10.
In addition, IL- 13 enhances monocyte and B
lymphocyte differentiation and proliferation, increases
CD23 expression, and induces IgG4 and IgE class
switching.
26. INTERLEUKIN-14
A product of malignant B and T cells as well as
normal T cells, B-cell growth factor (BCGF).
Like IL-4, IL-14 has been shown to induce B cell
proliferation.
However, IL-14 inhibits immunoglobulin secretion.
It has been suggested to play an important role in the
aggressive form of B-cell type non-Hodgkin’s
lymphoma.
27. INTERLEUKIN-15
IL-15 is a cytokine of a T cell stimulatory
activity produced by activated monocytes,
epithelial cells, and fibroblasts.
It stimulates T lymphocyte and NK cell
proliferation.
It enhances B cell expansion and
immunoglobulin production.
28. INTERLEUKIN-16
IL-16 was originally identified as a chemotactic
factor known as lymphocyte chemoattractant factor
or lymphotactin.
It is an unusual cytokine in that preformed IL-16 is
stored in CD8+ lymphocytes and is secreted upon
stimulation with histamine or serotonin.
It induces chemotaxis of CD4+ T lymphocytes
29. INTERLEUKIN-17
IL-17 is a product of activated T
lymphocytes and its biologic activities
include stimulation of IL-6 and IL-8
30. TUMOUR NECROSIS FACTOR(TNF)
Tumor necrosis factors-(TNF) α and β are cytokines that
bind to common receptors on the surface of target cells
and exhibit several common biological activities.
TNF-α, or cachectin, exists as a trimer and is one of the
products of activated macrophages/monocytes,
fibroblasts, mast cells, and some T and natural killer
(NK) cells.
TNF-α and IL-1 share several proinflammatory
properties. Like IL-1, TNF- α can induce fever, either
directly via stimulation of PGE2 synthesis by the
vascular endothelium of the hypothalamus, or indirectly
by inducing release of IL-1.
31. EOTAXIN
Eotaxin is a specific chemoattractant for
eosinophils. It is produced by cytokine-
stimulated epithelial and endothelial cells
as well as IL-3- stimulated eosinophils.
32. COLONY STIMULATING FACTOR(CSF)
Colony stimulating factors (CSF) are named according to the
target cell type whose colony formation in soft agar cultures of
bone marrow.
Granulocyte-CSF (G-CSF) and granulocyte macrophage-CSF
(GM-CSF) participate in acute inflammation.
Monocytes, T cells, fibroblasts and endothelial cells activated
by macrophage products such as IL-1 or TNF, can produce G-
CSF and GM-CSF.
Both CSF's can stimulate neutrophils, while GM-CSF can also
activate effector functions of eosinophils and mononuclear
phagocytes.
33. TRANSFORMING GROWTH FACTOR-BETA
The transforming growth factor- β (TGF-β) family of
cytokines includes three isoforms, TGF-β1, β2, and
β3 which are encoded by separate genes yet bind to
the same high affinity receptor.
It is produced by T cells, platelets, and monocytes.
TGF-β inhibits T cell and NK cell proliferation and
activation and may play an important role in
inflammation.
At a site of injury, TGF-β stored in platelets is
released upon degranulation.
TGF-β then attracts monocytes and other
leukocytes to the site, thus participating in the
initial step of chronic inflammation.
34. INTERFERONS
The interferons are a group of cytokines originally
identified by and named for their anti-viral activity.
Type I interferons include IFN-α, an 18-20 kDa product
of leukocytes, and IFN-β, a product of fibroblasts. They
exhibit anti-viral as well as antiproliferative properties
and upregulate MHC class I expression.
Type II interferon, immune interferon or IFN-γ, is a
homodimer produced by activated T cells and NK cells.
IFN-γ is known to enhance MHC class I and II
expression on nucleated cells and to stimulate many of
the effector functions of mononuclear phagocytes.
35. IFN-GAMMA INDUCING FACTOR
An IFN-γ-inducing activity was identified in murine
Kupffer cells and activated macrophages and referred
to as IFN-γ-inducing factor (IGIF).
IGIF induces IFN-γ production more potently than
does IL- 12 and is involved in the development of TH1
cells.
36. CYTOKINE EXPRESSION IN PERIODONTAL HEALTH
The regulations of migration, proliferation, and
differentiation of resident cells and of the production of
tissue matrix in a healthy state are major aspects of
periodontal tissue homeostasis.
two major pathways that control the balance of
gingival tissue and bone remodeling and the
subsequent control of periodontal bone loss.
37. The first encompasses the interactions with osteoblasts and
stroma that couple between bone formation and resorption
during physiological bone remodeling processes. Through the
network of autocrine and paracrine regulations, a range of
growth factors, such as platelet derived growth factor, basic
fibroblast growth factor and insulin-like growth factor, exert
their activities through their receptors on osteoblasts to
stimulate the formation of new bone .
38. The second pathway deals with the inflammatory or ⁄ and
osteoclastogenic cytokines ⁄ mediators that are produced
during local tissue inflammation and trauma or systemic
assaults and are thus responsible for bone loss under
pathological conditions where bone remodeling becomes
imbalanced or dysregulated as a result of increased
osteoclast number and activity, resulting in irreversible bone
loss .
39. CYTOKINES IN PATHOGENSIS OF PERIODONTAL DISEASE:-
periodontal diseases are initiated by bacteria, the host
response is believed to play an essential role in the breakdown
of connective tissue and bone. Microbial antigens and
virulence factors elicit an inflammatory and immune reaction,
in which both innate and adaptive immune responses are,
involved .
The host response to the bacterial challenge includes the
action and stimulation of various inflammatory cell types as
well as of resident cells of the tissue.
40. Through a cascade of events, mast cells are stimulated to release vasoactive
amines and preformed tumor necrosis factor α (TNFα), which increases
vascular permeability and the expression of adhesion molecules such as
intercellular adhesion molecule-1 (ICAM-1) and P-selection on endothelial cell
surfaces.
which increases vascular permeability and the expression of
adhesion molecules such as intercellular adhesion molecule-1
(ICAM-1) and P-selection on endothelial cell surfaces.
41. This process recruits PMNs into the tissue, where they release lysosomal
enzymes, which contribute to tissue degradation.
At this stage, the gingival tissues damage is still reversible and
it is possible to repair and remodel the damaged tissue .If it fails
to repair due to environmental factors , inflammation fails to
resolve.
results in connective tissue breakdown and irreversible bone
loss.
42. In this situation, macrophages form pre-osteoclasts which,
after maturing into osteoclasts, are capable of degrading
alveolar bone.
Without active resolution of inflammation, the bacterial antigens
ultimately encounter antigen presenting cells for instance dendritic
cells, macrophages and B cell
43. CD4 T helper cells (Th0) with antigen presenting cells, naïve T
cells differentiate into various subsets of cells including Th1, Th2,
Th17 and regulatory T cells (Tregs)
Th1 cells initiate the cell-mediated immune response and secrete interferon-γ
(IFN-γ), transforming growth factor-β (TGF-β), interleukin-2 (IL-2) and TNFα in
the presence of IL-12.
whereas
Th2 cells derive the humoral immune response and produce the cytokines IL-4,
IL-5, IL-6, L-10, IL-13 and TGF-β in the presence of IL-4.
44. An inflammatory cytokine is a cytokine which is induced during the
course of an inflammatory response and is closely associated with
its onset and/or progression.
IL-1α, IL-1β, IL-6, IL-8 and TNF-α are classified as
proinflammatory cytokines enhance the bactericidal capacity of
phagocytes, recruit additional innate cell populations to sites of
infection, induce dentritic cell maturation and direct the
subsequent specific immune response to the invading microbes .
Anti-inflammatory cytokines block this process or at least suppress
the intensity of the cascade. IL-4, IL-10, IL-13 and transforming
growth factor (TGF) -β suppress the production of IL1, TNF,
chemokines such as IL-8, and vascular adhesion molecules .
45. In periodontal disease, the balance between pro- and
antiinflammation is directed towards proinflammatory
activity.
Three proinflammatory cytokines, interleukin-1 (IL-1), IL-6,
and tumor necrosis factor-α (TNF-α), appear to have a central
role in periodontal tissue destruction .
46. IL-1 stimulates the proliferation of keratinocytes, fibroblasts and endothelial cells of
the periodontal tissues. Additionally it enhances fibroblast synthesis of type I
procollagen, collagenase, hyaluronate, fibronectin, and prostaglandin E2I.
IL-1 is a critical component in the homeostasis of periodontal tissues and its
unrestricted production may lead to tissue damage.
IL-1β upregulates matrix metalloproteinases and downregulates tissue inhibitors of
metalloproteinase production and it is also an effective stimulator of bone resorption.
Prostaglandin E2 (PGE2) is one of the main mediators in the periodontal
inflammation by stimulating the suppression of lymphocyte production, decreasing
the collagen synthesis by fibroblasts and influencing osteoclastic bone resorption .
IL-6 is secreted by a number of cells comprising monocytes/ macrophages, activated T-
cells, endothelial cells, adipocytes and fibroblasts .
IL-6 synthesis and secretion are stimulated by two major proinflammatory cytokines,
IL-1β and TNF-α, but the fact that IL-6 remains considerably longer in the plasma
makes this molecule a good marker of inflammation .
47. IL-6 is produced locally in the inflamed tissues following
cellular activation by bacterial lipopolysaccharide (LPS) or
other cytokines such as IL-1β or TNF-α .
significant correlations have been found between
periodontal pocket depth and IL-6 -content in gingival
crevicular fluid.
Tumor necrosis factor has the potential to stimulate the
production of secondary mediators, including chemokines
or cyclooxygenase products.
48.
49. DIAGNOSTIC USE OF CYTOKINES IN PERIODONTAL
DISEASE:-
Individuals with periodontal infections have elevated
concentrations of circulating inflammatory markers and the
severity of periodontal destruction directly correlates with serum
concentrations of inflammatory markers .
Numerous cytokines and chemokines have been detected in the
gingival crevicular fluid (GCF), exudates collected at the gingival
margin, and in gingival tissue from patients with periodontitis.
50. higher expression of IL-6 was reported in diseased gingival
tissues when compared with healthy tissue in periodontitis
patients similarly, increased circulating systemic levels of IL-6
decreased after nonsurgical periodontal therapy resulting in
clinical improvement of the periodontal status.
A significant correlation exists between the IL-1β levels of
gingival crevicular fluid (GCF) and periodontal parameters such
as probing pocket depth and attachment level .
51. THERAPEUTIC USE OF CYTOKINES IN
PERIODONTAL DISEASE:-
The modification of destructive host response against
Periodontopathogens by inhibition of pro-inflammatory
cytokines has a potential therapeutic means in the treatment
of periodontitis.
NSAIDs include a suppressing effect of prostaglandin
synthesis via COX- 1 and COX- 2 and may act as inhibitor of
gingival inflammation and bone destruction.
Detection of elevated levels of PGE2 and IL-1β in gingival
tissue may be recognized as indicator for activity of
periodontitis and may provide the evaluation of recurrence and
progression of disease.
52. REFERENCES:-
1. Cytokines, Inflammation and Pain Jun-Ming Zhang, MSc, MD1 and Jianxiong An, MSc,
MD2 1Department of Anesthesiology, University of Cincinnati, NIH Public Access Author
Manuscript .
2. Role of Cytokines M.M. Khan, Immunopharmacology, C Springer Science+Business
Media, LLC 2008.
3. Cytokines & their physiologic and pharmacologic functions in inflammation: A review P.
Zuber Shaikh Sinhgad College of Pharmacy, Pune, (MH) – India, INTERNATIONAL
JOURNAL OF PHARMACY & LIFE SCIENCES .
4. Review Article Proinflammatory Cytokines and Periodontal Disease, Review Article
Proinflammatory Cytokines and Periodontal Disease ,Nada Tawfig* Department of
periodontology, Faculty of Dentistry, University of Khartoum, Sudan , Journal of Dental
Problems and Solutions. 04 May, 2016.
5. Cytokines in periodontal disease: where to from here? Gregory J. Seymour and Erica
Gemmell Oral Biology and Pathology, School of Dentistry, University of Queensland,
Brisbane, Australia.