Molecular mediators in periodontal pathology

Molecular mediators in
periodontal pathology
Copyright ©2021 Periowiki.com

Contents
-Introduction
- Overview of the pathogenesis of periodontitis
- Classification of inflammatory mediators
- Cytokines
- Arachidonic acid metabolites
- Matrix metallo proteinases
-Conclusion
-References

The inflammatory response is vital for our survival and occurs throughout
many processes in our bodies. Among other things, inflammation is a
necessary component for our defence against pathogens and in wound
healing.
In response to an injury or infection, acute inflammation occurs
immediately and is usually short-lived.
However, when inflammation remains unresolved, it evolves into chronic
inflammation because host immune and inflammatory responses are
insufficient to remove or clear the microbial challenge which initiates and
perpetuates the disease.
“In chronic inflammation, tissue destruction and healing usually occur at the
same time, but the balance is delicate and can tilt towards destruction”
Introduction

Primary hallmark of periodontitis, the destruction of
periodontal tissue, is widely accepted to be a result of the
host immune inflammatory response caused by periodontal
microorganisms.
microorganisms
Page, R.C. and Kornman, K.S. (1997) The pathogenesis of human periodontitis: an introduction. Periodontology 2000 14, 9-11.

Overview of the pathogenesis of periodontitis

Inflammatory mediators in the pathogenesis
of periodontitis

Inflammatory mediators are soluble, diffusible
molecules that act locally at the site of tissue damage
and infection, and at more distant sites.

I
Classification of inflammatory mediators
Exogenous Endogenous
Bacterial endotoxins
Bacterial peptides
Plasma
derived
Cell
derived
Clotting system
Fibrinolytic system
Kinin system
Complementary system
Lipid mediators
. Arachidonic acid
metabolites
. Platelet activating
factor.
Cytokines
Vasoactive amines
Neuropeptides
ROS
Neutrophil activation
& mediators produced

I
1.Exogenous – bacterial products
1.Bacterial Endotoxin (lipopolysaccharide)
a.Stimulates neutrophils and macrophages. Triggers
production of cytokines (TNF, IL-1).
b. Increases neutrophil adhesion to endothelium.
c. Activates Hageman factor and complement system.
2. Bacterial Peptides (containing N-formyl methionine) –
chemotactic factors.

Plasma derived
• Proteins circulate in
plasma as inactive
precursors and
undergo proteolytic
cleavage to become
active.
Cell derived
• Cell stimulation can
result in secretion
of preformed
mediators and/or
synthesis and
secretion of new
mediators.
2. Endogenous – produced internally by host

PLASMA-DERIVED MEDIATORS – Series of inactive proteins circulating
in the plasma that are converted to proteolytic enzymes that activate other
proteins.
I. Clotting System – results in production of thrombin, factor Xa and
formation of fibrinopeptides.
1.Thrombin cleaves fibrinogen to form fibrin and enhances
leukocyte adhesion.
2.Fibrinopeptides are chemotactic and increase vascular
permeability.
3.Factor Xa increases vascular permeability and leukocyte
emigration.
II. Fibrinolytic System – results in formation of the proteolytic
enzyme, plasmin. Plasmin cleaves fibrin to form fibrin degradation
products (increase vascular permeability) and complement fragments
(anaphylatoxins).

PLASMA-DERIVED MEDIATORS
III. Kinin System – results in bradykinin formation (nonapeptide)
Bradykinin is a vasodilator, increases vascular permeability,
bronchial smooth muscle contraction, pain. It is short-lived
(inactivated by kininases).
IV. Complement System – series of plasma proteins (C1-C9) that play
a role in inflammation and immune defense against microorganisms.

Important inflammatory mediators in complement system:
C3a, C5a – Increase vascular permeability and cause vasodilation by
binding to mast cells and inducing histamine release
(anaphylatoxins).
C5a – Chemotactic for neutrophils, monocytes, eosinophils, and
basophils.
Increases adhesiveness of neutrophils to endothelium.
Stimulates synthesis and secretion of arachidonic acid
metabolites.
C3b -Opsonin, binds to microbial surface and promotes phagocytosis.

CELL DERIVED INFLAMMATORY MEDIATORS

Cytokines
Any of numerous hormone like, low-molecular-
weight proteins, secreted by various cell types, which regulate the
intensity and duration of immune response and mediate cell-to-
cell communication.
Medical Dictionary for the Dental Professions © Farlex 2012

Classification of cytokines
In the absence of a unified classification system, cytokines are variously
identified by : -
1) Numeric order of discovery (currently interleukin [IL]-1 through IL-
35),
2) A given functional activity (e.g. tumor necrosis factor [TNF],
granulocyte colony-stimulating factor),
3) Kinetic or functional role in inflammatory responses (early or late,
innate or adaptive, proinflammatory or anti-inflammatory),
4) Primary cell of origin (monokine = monocyte derivation; lymphokine
= lymphocyte derivation),
5) Structural homologies shared with related molecules. molecules.

Tumor necrosis factor
Tumor necrosis factor “family” includes two structurally and
functionally types:
TNF-a or cachectin, mainly produced by monocytes and / or
macrophages.
TNF-β or lymphotoxin, a product of lymphoid cells.
Kull and Jacobs have reported that there are about 1000 to 3000
receptors virtually on all cells. TNF-a once produced and secreted,
will bind to TNF receptor present in all plasma membrane of most of
the cells throughout the body.

Role of TNF-a in periodontal disease
- TNF-a is a proinflammatory cytokine.
- Induces the secretion of collagenase by fibroblasts, resorption of cartilage
and bone, and has been implicated in the destruction of periodontal tissues
in periodontitis (Van Dyke TE, Lester MA, Shapira L. 1993).
- Induces the synthesis of IL–1 and PGE 2, also activates osteoclasts and
thus induces the bone resorption (Bertolini DR, Glenn EN, Bringman TS,
Smith DD, Mundy GR).
- TNF-a has synergistic effects with the bone resorptive actions of IL– 1b.
- The systemic elevation of TNF-a level is extremely toxic to the host and
hence has been termed as the "Suicide hormone” (Offenbacher S 1996).

Role of TNF-a in periodontal disease
-TNF-α (10 ng/mL) upregulates levels of MMP-3, -10, and -13 in human
PDL cells.
(Su-Jin Ahn, Eun-Mi Rhim, Ji-Yoen Kim, Kyung-Hee Kim, Hyeon-
Woo Lee, Eun-Cheol Kim, and Sang Hyuk Park 2014).
-TNF-α also inhibits insulin transduction and contributes to insulin
resistance in diabetes mellitus (Zou C, Shao J 2008).
- A profound impact of diabetes and smoking on salivary TNF-α in chronic
periodontitis subjects in comparison to healthy subjects. Moreover, diabetes
status increased TNF-α significantly in comparison to smoking in chronic
periodontitis patients (Pritma Singh, Narender Dev Gupta, Afshan
Bey, and Saif Khan 2014).

Colony stimulating factors
The CSFs were named for their ability to induce the development of distinct
cell lines. IL-3 is a CSF known as multiCSF.
It stimulates the formation of all nonlymphocyte blood cells. Granulocyte
macrophage- CSF (GM-CSF) stimulates cells of the granulocyte and
macrophage lineage to differentiate and acts at a later stage than IL-3.
Macrophage – CSF (M-CSF) and granulocyte-CSF (G-CSF) more
specifically promote the differentiation of macrophages and granulocytes.

-Colony-stimulating factors can stimulate differentiation of osteoclast
precursors into mature osteoclast.
-Colony-stimulating factors may mediate their effects on osteoclast
formation indirectly. For example, early studies showed that colony-
stimulating factor stimulates IL-1 production, which stimulates
prostaglandin synthesis (Metcalf D, Begley CG, Williamson DJ, Nice EC, De Lamarter
J, Mermod JJ, Thatcher D, Schmidt A 1987) .
-HPDL cells are capable of secreting M-CSF and expressing RANKL in
response to TNF-alpha. The upregulation of M-CSF is possibly one of the
mechanisms essential for periodontal tissue destruction in response to
inflammatory cytokines (Yongchaitrakul T, Lertsirirangson K, Pavasant P
2006).

- Hart et al. (1988), who reported that the combination of GM-CSF and
LPS (E. coli) induced synergistic IL-1 release by THP-1 cells and human
monocytes. In combination with E. coli LPS, GM-CSF was reported to
be a weak inducer of monocyte IL-1β activity.
- Activation and differentiation of THP-1 cells by oral LPS in the
presence of GM-CSF may suggest a role for human macrophages in
acute and chronic periodontal diseases (A. A. M. A. Baqui, Timothy F. Meiller,
Jennifer J. Chon, Been-Foo Turng, and William A. Falkler, Jr 1998).

Interferons
-The IFNs are a large family of multifunctional secreted proteins involved
in antiviral defence, cell growth regulation and immune activation.
-The IFNs may be classified into two distinct types. Type I IFNs are
produced in direct response to virus infection and consist of the products
of the IFN-α multigene family, which are predominantly synthesized by
leukocytes, and the product of the IFN-β gene, which is synthesized by
most cell types but particularly by fibroblasts.
-Type II IFN consists of the product of the IFN-γ gene and, rather than
being induced directly by virus infection, is synthesized in response to the
recognition of infected cells by activated T lymphocytes and natural killer
(NK) cells (reviewed in Vilcek & Sen, 1996).

Interferons in periodontal disease
-Low ratio of IL-4 to IFN-gamma levels might be involved in the
destruction (diseased sites) of periodontal tissue, whereas an increased
ratio of IL-4 to IFN-gamma levels could be related to the improvement of
clinical periodontal health (Tsai CC, Ku CH, Ho YP, Ho KY, Wu
YM, Hung CC 2007).

Gamma interferon :
-Is a multifunctional cytokine, which has effects similar to tumor necrosis factor a
or IL-1 in most biological systems (Mann GN, Jacobs TW, Buchinsky FJ,
Armstrong EC, Li M, Ke HZ, Ma YF, Jee WS, Epstein S. 1994).
- However, it has an effect on bone resorption that is opposite that of IL-1 and
tumor necrosis factor alpha.
-Gamma interferon is more effective in inhibiting bone resorption induced by IL-1
or tumor necrosis factor a than systemic hormones like parathyroid hormone or
1,25-(OH)2D3F.
-Further, it has been found in long term marrow cell cultures in which interferon
gamma inhibits the formation of cells with the osteoclast phenotype.
( ZVI SCHWARTJZOS, EF GOULTSCHIND,A VIDD . DEAN& BARBARAD . BOYAN 1997).

Interleukins
-Secreted proteins that bind to their specific receptors and play a
role in the communication among leukocytes are named ILs.

Interleukins
Cytokine Role of cytokine Source Functions
IL 1alpha Pro – inflammatory Gingival fibroblasts, basal
layer of oral mucosal
epithelium
- Destruction on cementum & alveolar
bone.
IL 1Beta Pro – inflammatory Monocytes, fibroblasts
Stimulates bone resorption.
Stimulates neutrophil degranulation.
Recruits neutrophils.
Stimulates T-cell proliferation.
Stimulates prostaglandin release from
fibroblasts.
Stimulates cytokine release from
fibroblasts.
Stimulates proteinase release from
various cells.

Cytokine Role of cytokine Source Function
IL 2 Pro – inflammatory Peripheral blood
lymphocytes.
Autocrine factor for T cells.
Stimulates B cells.
IL 3 Pro – inflammatory Monocytes, fibroblasts
Stimulates bone resorption.
Stimulates neutrophil degranulation.
Recruits neutrophils.
Stimulates T-cell proliferation.
Stimulates prostaglandin release from
fibroblasts.
Stimulates cytokine release from
fibroblasts.
Stimulates proteinase release from
various cells.

IL 4 Anti – inflammatory T cells, Mast cells,
basophils
- Induces Th2 cell differentiation.
-Inhibits interleukin 2- and interferon y-induced
activities.
- Inhibits IL- 12 production.
- Induces proliferation and differentiation of B
cells induces proliferation of T cells.
-Downregulates monocyte production of IL 1,
TNF alpha and IL – 6.
-L.ShapiraT.E.Van DykeT.C.Hart (1992):
hypothesize that, in the case of Adult
periodontitis, a localized lack of the regulatory
cytokine interleukin-4 (IL-4) in the gingival
tissues predisposes susceptible individuals to
progress from gingivitis to periodontitis.
IL 5 Pro – inflammatory
Th2 cells
Gingival
mononuclear cells
B cells
-Eosinophil differentiation .
- Regulate B cell development to plasma cells.

IL 6 Pro –and Anti-
inflammatory
Fibroblasts - B-cell differentiation
- 1L-2 release from fibroblasts
- Stimulates osteoclast formation
- Stimulates T-cell formation
IL 7 Pro – inflammatory Bone marrow Mediator of osteoclastogenesis.

IL 8 Pro – inflammatory
Chemokine
Fibroblasts -Stimulates neutrophil recruitment
- Stimulates neutrophil activation
IL 9 Pro-inflammatory T cells -Appears to enhance the IL-8 stimulation and
proliferation of bone marrow-derived mast
cells.

IL 10 Anti – inflammatory Fibroblasts - B-cell differentiation
T and B cells,
Monocytes and
Macrophages.
- Promotes Th2 responses while suppressing Thl
cell-mediated responses.
- Suppresses proliferation and cytokhe production
by activated T cells.
- Suppresses macrophage function and IL 12
production.
- Inhibits macrophage-derived IL 1 alpha, IL 6 &
IL 8
- Enhances IL 1ra production
-Enhances B-cell proliferation and differentiation.
IL 11 Both pro- and anti-
inflammatory
Human PDL
cells
Mechanical loading appears to control
proliferation and osteoblastic/ cementoblastic
differentiation of human PDL stem/progenitor cells
through the regulation of Ang II and AT2 by IL-11.
(S. Monnouchi et al 2011)

IL 12 Pro – inflammatory Fibroblasts - B-cell differentiation
IL 13 Anti – inflammatory Th2 cells -Similar functions to interleukin 4 although
more restricted.
- Downregulates IL12 production.
-Acts as a co-stimulatory signal for human B
cells but does not affect T cells.
-Modulates monocyte and macrophage
function including inhibition of cytokine
production.

IL 14 T-lymphocytes and
malignant B-
lymphocytes
Enhances the proliferation of activated B-cell.
Hyperproduction of IL-14 together with IL-6
and IL-10 has been reported in systemic lupus
erythematosus.
IL 15 Anti – inflammatory Monocytes,
epithelium and
muscles
Johnson RB , Serio FG (2007) -
IL-15 concentration correlated inversely with
the adjacent gingival sulcular depth (P <0.001).
Relatively low IL-15 concentrations within
diseased gingiva suggest that IL-15 might have
anti-inflammatory properties.
May play a role in the pathogenesis of Cs-
induced gingival overgrowth due to its
interaction with Cs and its role in inflammation
and apoptosis (Buduneli E, Genel F, Atilla G,
Kütükçüçler N. 2003)

IL 16 Pro – inflammatory Eosinophils and
CD8+T cells
- Can cause the high affinity of IL-2 receptors
on CD4+ cells and is chemotaxis to Th1 cells
and CD4+ T cells.
-IL-16 can stimulate monocytes to produce
proinflammatory cytokines and is highly
associated with inflammation including
arthritis, enteritis and allergic rhinitis.
Tsai IS et al 2006.
-May be related to periodontal disease severity
in alcohol drinkers/smokers. The concentration
and total amount of IL-16 both are raised in
alcohol consumers and cigarette smokers with
periodontal disease. Deeper probing pocket
depths are found in alcoholics as well as
smokers.
IL 17 Pro - inflammatory T cell - Stimulates Osteoclastic resorption.

IL 18 Pro – inflammatory Macrophages - IFN gamma inducing factor .
-- Induces release of IL – 1, MMP – 9, IL 1Beta.
- Associated with development of insulin
resistance.
Parag Hadge , Happy Daisy , A.R. Pradeep, M.V.
Ramachandra Prasad 2011.
IL 19 Anti-inflammatory Monocytes
T& B lymphocytes
-Upregulates the expression of heme oxygenase-
1 (HO-1) and reduces reactive oxygen species in
human vascular smooth muscle cells.
-Neuroprotection.
-Can induce angiogenic potential of Endothelial
cells.

IL 20 Pro- and Anti-
inflammatory effects
Activated
keratinocytes,
monocytes
regulates proliferation and differentiation of
keratinocytes during inflammation,
particularly inflammation associated with the
skin.
IL 21 Can exert both
inflammatory and anti-
inflammatory effects,
the latter linked to the
induction of IL-10, a
counter-regulatory
cytokine expressed at
high levels both in
BXSB-Yaa mice and in
human SLE patients.
CD4+ T cells
NK T cells
key role in B cell differentiation to plasma cells,
induces a functional programme in CD8+ T
cells that leads to enhanced survival, antiviral
activity and antitumour activity.

IL 22 Pro and Anti –
inflammatory
Th 17 cells
NK cells
-Acts on non-immune cells to induce anti-
microbial responses, protection from tissue
damage, and enhance cell regeneration.
-Induced gene expressions of RUNX2, MSX2
and osteocalcin in PDL cells, suggesting that
IL-22 enhances the mineralized matrix-
forming activities of PDL cells.
Kato-Kogoe N 2012
IL 23 Pro – inflammatory Macrophages and
dendritic cells
-Controls the differentiation of T-helper Th17
cells and induces the production of IL-17 in
this T-cell subtype.

IL 24 Anti-inflammatory Monocytes, T & B
cells.
IL 24, RANTES and CCR5 polymorphisms
investigated are not associated with chronic
periodontitis (L Savarrio et al 2007).
IL 25 Th2 cells,
dendritic cells,
macrophages,
mast cells,
basophils,
eosinophils,
epithelial cells and
Paneth cells
- induce NF-κB activation, and stimulate the
production of IL-8 (named also CXCL8),
which is the major chemotactic substance of
neutrophils’.
-Drives the expression of IL-4, IL-5, and IL-13,
thereby contributing to allergic disease. On the
other hand, recent studies have shown a novel
anti-inflammatory role for IL-25 as a key
factor in the attenuation of IL-17-mediated
inflammation, such as in colitis,
encephalomyelitis, and diabetes mellitus. Thus,
IL-25 and IL-17, being members of the same
cytokine family, seem to play opposing roles in
the pathogenesis of autoimmune diseases .
-This cytokine also plays a role in creation of
allergic inflammation in asthma and
autoimmune diseases as well as in treatment of
cancer.

IL 26 Pro-inflammatory
member of IL-10
cytokine family
Th17 cells It acts on epithelial cells and intestinal
epithelial cells.
It induces IL-10 expression, stimulates the
production of IL-1-beta, IL-6, and IL-8 and
causes Th17 cell generation.
IL 27 Pro – and anti-
inflammatory
T cells Concluded - IL-35 and IL-17, but not IL-27,
may play important roles in the pathogenesis of
periodontitis (Mitani A et al 2015).
IL-27 stimulates IL-10 production. It is a pro-
inflammatory molecule and upregulates type-2
interferon synthesis by natural killer cells.

IL 28 Regulatory T cells IL-28 and IL-29 may protect humans from
viral infection by inducing an anti-viral state
and by modulating the immune response.
Enhances keratinocyte capacity to recognize
pathogens in the healthy skin.
IL 29 Pro – inflammatory virus-infected
cells, dendritic
cells, and
regulatory T-cells
-Has antiviral properties , is induced by herpes
virus.

IL 30 Anti-inflammatory Monocytes Monocytes mainly produce IL-30 in response
to TLR agonists including bacterial LPS.
It acts on monocytes, macrophages, dendritic
cells, T and B lymphocytes, natural killer cells,
mast cells, and endothelial cells
IL 31 Pro – inflammatory Th2 cells and
dendritic cells.
-IL-31 produced by mast cells in response to P.
gingivalis infection causes gingival epithelial
barrier dysfunction, which may contribute to
the chronic inflammation observed in
periodontitis (Hiroyuki Tada et al 2019).

IL 32 Anti – inflammatory Human gingival
fibroblasts
Down regulates IL – 8 production .
(Ouhara K et al 2012) .
IL 33 Anti – inflammatory Human gingival
fibroblasts
-TNF alpha induced IL 33, induces
lymphocytes resulting in protective, anti-
inflammatory and reparative responses
(Beklen A 2014).

IL 34 Pro – inflammatory Gingival
fibroblasts
-Can be substituted for M-CSF in RANKL-
induced osteoclastogenesis. IL-34 may
contribute to inflammation and
osteoclastogenesis in bone-degenerative
diseases such as periodontitis. (Bostrom EA
and Lundberg P 2013) .
IL 35 Anti-inflammatory Regulatory B cells -Plays an important role in immune regulation
through the suppression of effector T-cell
populations, including T-helper 17 (Th17) cells.
Mitani A et al 2015-Concluded- IL-35 and IL-
17, but not IL-27, may play important roles in
the pathogenesis of periodontitis.
Schmidlin, P.R., Dehghannejad, M. & Fakheran,
O. 2012 - results of observatory human studies
confirmed the presence of high levels of IL-35
in saliva, GCF, serum, and gingival biopsies of
patients suffering from inflammatory
periodontal disease. Moreover, two included
clinical trials showed that non-surgical
periodontal therapy could downregulate IL-35
production in chronic periodontitis patients.

IL 36 is a group of cytokines
in the IL-1 family
with pro-inflammatory
effects.
Phagocytes Kurşunlu SF , Oztürk VÖ , Han B , Atmaca
H,Emingil G 2015 – High levels of IL-36-β in
the AgP group in comparison to CP group
might suggest that periodontitis in the
aggressive form could be related to the increase
in GCF IL-36β.
Babaloo AR, Shirmohammadi A,
Sandoghchian S, Kamalzadeh A, Ghasemi S
(2018)-concluded that IL-36γ concentrations
increased in periodontitis, which could trigger
MAPK and TLR4 pathways.
IL 37 (IL-1F7),
Anti-inflammatory.
Phagocytes and
organs including
the uterus, testis,
and thymus
M. Sağlam, S. Köseoğlu, L. Savran, T.
Pekbağriyanik, G. Sağlam2 and R. Sütçü 2014-
Expressed in all bio fluids. Not involved in
periodontal diseases.

Cytokine Role of
cytokine
Source Function
IL 38 Anti-
inflammatory
placenta,
tonsil's B lymphocytes,
spleen,
skin,
thymus
-Acts on T cells and inhibits the synthesis of IL-
17 and IL-22 (Justiz Vaillant AA, Qurie A.
2021)
- IL-38 is the most recent member of the IL-1
superfamily and has anti-inflammatory
properties similar to those of IL-37 but through
different receptors. However, limited evidence
exists regarding the role of IL-37 and IL-38 in
periodontitis (Papathanasiou E, Conti P,
Carinci F, Lauritano D, Theoharides TC.
2020).
IL 39 B lymphocytes -It acts on neutrophils inducing their
differentiation or expansion.
-IL 39 is a novel member of IL-12 family and
has been reported to play a pro-inflammatory
role in lupus-like mice.
-Can exacerbate ConA-induced hepatitis and
may be a therapeutic target in inflammatory
liver disease.

Cytokine Role of
cytokine
Source Function
IL 40 bone marrow, fetal liver,
and by activated B cells.
-plays a vital role in the development of humoral
immune responses.
- Remarkably, it is not structurally related to any
other cytokine family, indicating that it likely has
unique evolutionary history (Catalan-Dibene J,
McIntyre LL, Zlotnik A)
- human B cell lymphoma cell lines (OCI-Ly1)
constitutively express IL-40, suggesting a
potential role of IL-40 in human B cell-
associated diseases (Catalan-Dibene J,
McIntyre LL, Zlotnik A)

Induction of Thl and Th2 cells and their possible involvement in
periodontal tissue destruction.
Both ThI and Th2 cells are thought to go through a common intermediate stage, ThO. IL-4
stimulates differentiation of ThO cells into Th2 cells, whereas IL-i 2, IFN--y, and TGFl
enhance differentiation into ThI cells.
Macrophages are thought to play a central role in the production of IL-12, which stimulates
Thl cell generation.
Furthermore, cellular functions of both ThI and Th2 cells are mutually regulate. IFN-y,
secreted by Thl cells, selectively inhibits proliferation of Th2 cells; IL-1 0, secreted by Th2
cells, inhibits cytokine synthesis by ThI cells.
Recent observations have demonstrated that IL-10 can be secreted by Thl and Th2 cells
(Gerosa et aI., 1996; Windhagen et a/., 1996).
This hypothesis suggests the possible involvement of unrestricted activation of Thl or Th2
cells in periodontal tissue destruction.

Matrix metallo proteinases
Matrix metalloproteinases represent a family of dependent metal ions
endopeptidases that are capable of degrading all extracellular matrix
components, including several types of collagen and basement
membrane components (Birkedal-Hansen H. 1993; Woessner Jr JF).
They are secreted as inactive proenzymes (zymogens) and their
activation occur in the tissue by cleavage of the N-terminal propeptide
domain by other proteinases (Murphy G, Knäuper V. 1997).

Matrix metallo proteinases
Cytokines Action on MMPs
IL-1b and TNF-1a
By periodontal fibroblasts.
Upregulate –
collagenase (MMP-1).
gelatinase-A (MMP-2).
stromelysin- 1 (MMP-3)
MMP 13.
IL -6 Upregulate –
Osteoblast gelatinase (MMP- 2).
IL- 8 recruits neutrophils to inflammatory sites
and it is able to promote neutrophil
degranulation that releases large amounts of
gelatinase-B (MMP-9) into periodontitis sites.
TGF – 1 beta Represses the transcription of most MMPs
but upregulates MMP-2.

Arachidonic acid metabolites
Leucotrienes
Prostanoids
Arachidonic acid pathway activated by IL-1 and TNF alpha

Leucotrienes in periodontal disease
Functions
Leukotriene B4 (LTB4) Pro – inflammatory Recruit neutrophils to
areas of tissue damage,
though it also helps
promote the production of
inflammatory cytokines
by various immune cells.
- Induce bone resorption.

Leucotriene B4 in periodontal disease
-Pradeep AR , Manjunath SG , Swati PP , Shikha C, Sujatha PB 2007 –
Assessed the relationship between clinical parameters and concentrations of
LTB(4) within gingival crevicular fluid (GCF) from inflamed gingiva and
periodontitis sites before and after the treatment of periodontitis in 60
patients
Concluded that, there is substantial increase in GCF LTB(4) concentrations
with the severity of periodontal disease and a concomitant decrease in its
level following SRP in subjects with periodontitis suggest a possible role for
LTB(4) in the progression of periodontal disease.

- G. A. Sánchez, V. A. Miozza, A. Delgado and L. Busc 2013 –
Performed a study to explore the role of LTB4 in 81 subjects distributed into
four groups, namely, clinically healthy, mild, moderate and severe
periodontitis,
Concluded that, the close relation between salivary LTB4 and mucin levels
suggested that LTB4 might be involved in the defence mechanism of the oral
cavity. The correlation of LTB4 with the alveolar bone level indicates that
they are one of the mediators responsible for bone resorption.
Leucotriene B4 in periodontal disease

Leucotrienes in periodontal disease
Resolvin E1 Anti- inflammatory
- Inhibit osteoclast growth and bone resorption
by interfering with osteoclast differentiation.
- Restore impaired phagocytic activity in
macrophages from the blood of patients with
aggressive periodontitis.
- Inhibited LTB4-induced production of the
antimicrobial peptide LL-37 from PMNs, thus
terminating the LL-37/LTB4 proinflammatory
circuit.
- Specialized pro-resolving lipid mediators are
dual functioning because they limit neutrophil
accumulation and stimulate non-phlogistic
activation of macrophages in vivo.
The lipoxygenases are critical enzymes for the formation of LXA4 as well as the
omega-3 EPA and DHA derived resolvins, protectins and maresins.

Resolvin E1 in periodontal disease
Gabrielle Fredman, Sungwhan F. Oh , Srinivas Ayilavarapu , Hatice Hasturk ,
Charles N. Serhan, Thomas E. Van Dyke 2011 –
In their study concluded that, macrophages from LAP subjects exhibit reduced
phagocytosis. The pro-resolving lipid mediator, Resolvin E1 (0.1–100 nM), rescues
the impaired phagocytic activity in LAP macrophages.
These abnormalities suggest compromised resolution pathways, which may
contribute to persistent inflammation resulting in establishment of a chronic
inflammatory lesion and periodontal disease progression.

Prostaglandins in periodontal disease
Actions
PGE2
(Produced by
osteoblasts)
Proinflammatory
- Stimulation of inflammatory mediators and
MMPs, as well as
- osteoclast formation via receptor activator of
nuclear factor-κB ligand (RANKL).
- PGE2 has been shown both to inhibit and
stimulate OPG expression (Refs 54, 171), a
contradiction which may be the result of differing
incubation times, as has been suggested for the
effect of PGE2 on osteoclast formation (Ref. 123).

-Scott W. Garrison, S. C. Holt, and Frank C. Nichols 1988 –
-Study findings demonstrate that, the potency of the LPS preparations is
tentatively ranked as follows: Wolinella ≥ Salmonella > A. a. > B. intermedius ≥ B.
gingivalis.
-These findings demonstrate that LPS preparations from suspected periodontal
pathogens are capable of stimulating PGE2 release from human monocytes.
-The high potency and prolonged stimulation of PGE2 release with Wolinella LPS
suggests unusual toxic properties that may exert a greater influence in the
pathogenesis of destructive periodontal diseases.

Jun Nukaga et al 2004 –
-Investigated the regulatory effects of interleukin-1β (IL-1β) and prostaglandin E2
(PGE2) on expression of RANKL in human periodontal ligament (HPDL) cells
and the mechanisms involved in the PGE2 effect.
-Concluded that Human periodontal ligament cells activated with inflammatory
factors such as IL-1β and PGE2 may directly stimulate osteoclastogenesis through
RANKL, which is stimulated to express by these factors.
Xiaohui Rausch-Fan et al 2005 –
-Gingival fibroblasts (GFB) may produce prostaglandin E2 (PGE2) in response to
proinflammatory cytokines.
- Concluded that, PGE2 is a potent stimulator of bone resorption, and production of
PGE2 and COX-2 protein is augmented by glycine.

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