Download 12/01/08

Cytokines
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Low molecular weight glycoproteins, which
are transiently produced by almost any
nucleated cell
A group of regulatory molecules, which
function as important mediators of cell
communication under normal as well as
pathological conditions and also have
therapeutic potential
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Cytokines
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Exert their biological activities at picomolar
concentrations via interaction with specific
cell surface receptors, which are expressed at
relatively low numbers by respective cell (10
to 10,000 per cell)
Multiple overlapping activities:
– they may induce each other
– interfere with the expression of their receptors,
and thus can affect cell function in a synergistic,
additive, or antagonistic way
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1. Interleukins
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IL-1, IL-6, and IL-8
– multifunctional nonspecific mediators
– early host defense mediators released shortly after
injury by a variety of cells
– regulate proliferation as well as differentiation of
inflammatory and noninflammatory cells
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IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, and IL-10
– more specific factors
– mainly produced by lymphocytes
– responsible for T and B cell proliferation as well as
differentiation
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2. Tumor Necrosis Factors
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TNF- (cachectin) may be involved in the
down regulation of the induction of contact
hypersensitivity
TNF- (lymphotoxin) is lymphocyte-derived
cytotoxic factor
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3. Colony Stimulating Factors
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Keratinocytes are able to produce all types of
CSF
IL-3 (multi-CSF) affects the formation of
bone marrow stem cell colonies
Granulocyte/macrophage-CSF (GM-CSF)
Granulocyte-CSF (G-CSF)
Macrophage-CSF (M-CSF)
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4. Interferons
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Mediators protecting cells from viral
infection
Exhibit various effects on cell proliferation
and differentiation
INF-, INF-, and INF-
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5. Growth Factors
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Involved in cell proliferation, in cell surface
alteration, and immunoregulation
Transforming growth factor- (TGF)
Transforming growth factor- (TGF)
Acidic fibroblast growth factor (aFGF)
Basic fibroblast growth factor (bFGF)
Platelet derived growth factor (PDGF)
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Autocrine and Paracrine Effects
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Normal skin produces and releases a large
variety of growth factors and chemotactic
substances that are involved in autocrine and
paracrine regulation of skin function
– e.g., EGF, FGF, TGF-, TGF-, interleukins,
parathyroid hormone-like growth factor
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All major epidermal and dermal cells
participate in the response following cytokine
release
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Keratinocytes produce two forms of IL-1
– IL-1 and IL-1
– IL-1 receptor expression is autoinduced by IL-1
stimulation
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induces the production of various cytokines and helps
coordinate the response to injury
increased production of cytokines
– IL-1, IL-6, GM-CSF, prostaglandin E (PGE)
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increases cell proliferation
increases the levels of melanocyte stimulating hormone
receptor on melanocytes and enhances melanocyte
production of melanin
regulator for lymphocyte, macrophage, and natural
killer cell function
fibroblasts are stimulated to produce more collagen and
to release additional cytokines
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Autocrine and Paracrine Effects
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Modulation of the growth and differentiation
of skin cells may involve a direct effect of a
toxic compound on the cellular genome or an
interaction with a receptor with subsequent
alteration of gene expression
A potential outcome of interaction of these
agents with cells is an alteration in the normal
autocrine and paracrine regulatory loops that
exist in the skin
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para-phenylenediamine, or PPD
Allergic Contact Dermatitis
Type IV hypersensitivity = delayed-type hypersensitivity
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Epidermis harbors dendritic cells
(Langerhan’s) with antigen-presenting
capacity and cells belonging to the T-cell
lineage
Epidermis functions as a source as well as a
target for several cytokines, which play a
crucial role in the pathogenesis of
inflammatory and immunologically mediated
skin diseases
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Allergic Contact Dermatitis
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Qualitative and quantitative similarities in the
cytokine response between chemicals with
sensitizing (immune specific) and irritant
(inflammatory) properties and chemicals with
irritant properties
Qualitative and quantitative differences in
cellular response between immune specific
and non-specific inflammatory responses
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Allergic Contact Dermatitis
immune specific
non-specific
 TH1(), DC()
 monocytes/macrophages()
 mast cells()
 PMN(),
 monocytes(),
 macrophages()
 mast cells()
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systemic versus local response
dose and dose rate
cytotoxic T lymphocytes and DNA damage
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Allergic Contact Dermatitis
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Phase 1
– sensitization and activation
– cognitive phase (5-7 days)
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Phase 2
– elicitation
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inflammation
resolution
– neutralization, removal, and elimination of the hapten
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Skin and the Skin Associated Immune System:
Delayed-type Hypersensitivity (Type-IV Allergic Contact Dermatitis)
Two-Phase Response – 1. Sensitization and Activation
2. Elicitation: a) inflammation and
b) resolution
Cell Types / Cytokines
Keratinocytes:
IL-1, IL-3, IL-6, TNF,
GM-CSF, TGF, TGF,
MIP-1, MIP-2, chemokines
Langerhan’s Cells (APC)
MHCII restricted, TNFR+, IL-6R+,
B7
FL
NO2 1-fluoro-2,4-dinitrobenzene
*HCC – hapten carrier complex
1
Cytokine
2
Macrophage
NO2
HCC*
Keratinocyte
3
Capillary
Cytokines
Lymphocytes, intraepidermal
MHCII restricted, CD4+, TH1
memory cell or MHCI, CD8+,
TH2 memory cell - Perivascular
Mast Cell
4
Lymphatic
DISSEMINATION
1. Haptenic bearing site
2. Systemic
Afferent
Macrophages (resident)
TNF, -IFN, IL-1, IL-6,
chemokines
Local Draining Lymphnode
Naive T-cells
(CD4+ TH1, CD8+ TH2)
IL-2, IL-4, TGF
1. SENSITIZATION
HEV
ENDS COGNITIVE PHASE
APC
Arterial
LDLN
TH1
Venous
Efferent
5
IL-2
APC + TH1
TH1 MEMORY CELLS
CD4+
6
ACTIVATION and CLONAL EXPANSION
of TH1CELLS that are Hapten Specific
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Skin and the Skin Associated Immune System:
Delayed-type Hypersensitivity (Type-IV Allergic Contact Dermatitis)
2. ELICITATION
Two-Phase Response – 1. Additional presentation of hapten
2. Rapid proinflammatory response to remove hapten
FL
-IFN
NO2
-IFN
1
Cytotoxic T-Lymphocyte
7
5
Activation of
TH1 cells
Macrophage,
activated
CD4+ TH1 Cells
3
NO2
4
HCC*
Keratinocyte
2
Monocyte
RECRUITMENT
and
ACTIVATION
IL-2
Lymphatic
Mast Cells
6
Mast Cell
Mast Cell
Afferent
HEV
ANGIOGENESIS
IL-2
DISSEMINATION
1. Haptenic bearing site
2. Systemic
Arterial
APC + TH1 CELLS
LDLN
Venous
TH1 MEMORY CELLS
(inactive)
Efferent
1. Ends with resolution (elimination of hapten)
2. Sustained exposure may result in wound response
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Allergic Contact Dermatitis
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Sustained exposure and dysregulation of the
response may result in a wound response and
continued inflammation and attempts at
fibrosis (granulomatous reaction)
Sensitizing and irritant properties of a
chemical may show qualitative and
quantitative differences in response to the
dose and dose rate of exposure
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Allergic Contact Dermatitis
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Low level exposures to a sensitizing chemical
may induce an inflammatory response out of
proportion the dose required by an irritant
chemical to produce the same level of
inflammatory response
Overall, the increased burden of inflammation
may increase the induction of reactive oxygen
species and systemic disease
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