April 2005 Ark International Training Seminars Cytokine :
Hormone interrelationship R A Holding DO Slide 2 April 2005 Ark
International Training Seminars Cell communication - The basis of
life For the smooth operation of all physiological processes in the
organism, all of the approximately 60 trillion cells of the body
need to be able to communicate. For the smooth operation of all
physiological processes in the organism, all of the approximately
60 trillion cells of the body need to be able to communicate. This
complex communication occurs via two chemical substances:- This
complex communication occurs via two chemical substances:-
CytokinesCytokines Cell surface molecules.Cell surface molecules.
Slide 3 April 2005 Ark International Training Seminars Cell
communication - The basis of life This communication occurs as a:
This communication occurs as a: direct communication:direct
communication: adhesion molecules (cell-to-cell contact) adhesion
molecules (cell-to-cell contact) indirect communication:indirect
communication: cytokines (messenger substances) bound to specific
receptor sites. cytokines (messenger substances) bound to specific
receptor sites. These types of communication take place
concomitantly and may also have an influence on one another. These
types of communication take place concomitantly and may also have
an influence on one another. Slide 4 April 2005 Ark International
Training Seminars Immune and endocrine system reciprocity The cells
of immune and neuroendocrine systems share signal molecules and
receptors The cells of immune and neuroendocrine systems share
signal molecules and receptors Both hormones and neuropeptides
alter function of the immune system Both hormones and neuropeptides
alter function of the immune system Immune system is innervated by
noradrenergic sympathetic nerve cells that have direct contact with
lymphocytes and macrophages Immune system is innervated by
noradrenergic sympathetic nerve cells that have direct contact with
lymphocytes and macrophages In turn, the immune system-derived
cytokines influence the function of both neural and endocrine
systems In turn, the immune system-derived cytokines influence the
function of both neural and endocrine systems Slide 5 April 2005
Ark International Training Seminars Stress, physiology &
function Slide 6 April 2005 Ark International Training Seminars
Overview of inflammation: Local inflammatory response Local
inflammatory response Macrophages and monocytes initiate acute
phase response (APR)Macrophages and monocytes initiate acute phase
response (APR) The APR initiates 1 st phase of inflammatory
cytokinesThe APR initiates 1 st phase of inflammatory cytokines
IL-1 IL-1 TNF- TNF- They activate the 2 nd phase of cytokines that
augment the shift in balance necessary for the inflammatory
responseThey activate the 2 nd phase of cytokines that augment the
shift in balance necessary for the inflammatory response IL-12
IL-12 INF- INF- GM-CSF (Granulocyte-Macrophage Colony Stimulating
Factor) GM-CSF (Granulocyte-Macrophage Colony Stimulating Factor)
Fibroblast growth factor Fibroblast growth factor Slide 7 April
2005 Ark International Training Seminars Hormonal stimulation of
pro-inflammatory cytokines Slide 8 April 2005 Ark International
Training Seminars Control of the immune reaction The specific
control of the sequence of the activating and the suppressive steps
in the of the immune response is mediated by the immune cells
through the release of both pro- inflammatory and anti-inflammatory
cytokines. The specific control of the sequence of the activating
and the suppressive steps in the of the immune response is mediated
by the immune cells through the release of both pro- inflammatory
and anti-inflammatory cytokines. The ratio of Th1
(pro-inflammatory) and Th2 (anti- inflammatory) cells and their
cytokines is clinically important. The ratio of Th1
(pro-inflammatory) and Th2 (anti- inflammatory) cells and their
cytokines is clinically important. They balance each other by
inhibiting each other and stimulating their own responseThey
balance each other by inhibiting each other and stimulating their
own response Slide 9 April 2005 Ark International Training Seminars
Pro-inflammatory Th1 cells and their cytokines Th1 cells are
pro-inflammatory and are a response to intracellular organisms such
as viruses, bacteria and some parasites Th1 cells are
pro-inflammatory and are a response to intracellular organisms such
as viruses, bacteria and some parasites Inhibition of Th1 leads to
failure to respond to infection and to kill cancer cells Inhibition
of Th1 leads to failure to respond to infection and to kill cancer
cells Chronic stimulation of Th1 leads to autoimmune disease and
chronic inflammation Chronic stimulation of Th1 leads to autoimmune
disease and chronic inflammation Th1 dominant diseases include: Th1
dominant diseases include: Hashmotos diseaseHashmotos disease Type
1 diabetesType 1 diabetes Multiple SclerosisMultiple Sclerosis
Crohns diseaseCrohns disease SarcoidosisSarcoidosis These
activating cytokines are: TNF, IL-1, IL-2, IL-6, IL- 12, IFN-,
IFN-, TGF. These activating cytokines are: TNF, IL-1, IL-2, IL-6,
IL- 12, IFN-, IFN-, TGF. Slide 10 April 2005 Ark International
Training Seminars Anti-inflammatory Th2 cells and their cytokines
Th2 cells are anti-inflammatory and are a response to helminth
parasites and allergens Th2 cells are anti-inflammatory and are a
response to helminth parasites and allergens Chronic stimulation of
Th2 leads to chronic allergic response and failure to respond to
infection and cancer cells Chronic stimulation of Th2 leads to
chronic allergic response and failure to respond to infection and
cancer cells Th2 dominant diseases include: Th2 dominant diseases
include: Allergies / atopyAllergies / atopy
InflammationInflammation The Th2 or anti-inflammatory or
suppressing cytokines are: IL-4, IL-5, IL-10, and to some extent
IL-13 The Th2 or anti-inflammatory or suppressing cytokines are:
IL-4, IL-5, IL-10, and to some extent IL-13 Slide 11 April 2005 Ark
International Training Seminars Inflammatory triggers Slide 12
April 2005 Ark International Training Seminars Control of the
immune reaction The defensive posture can be: The defensive posture
can be: excessive in partexcessive in part extreme antigen
exposition extreme antigen exposition over-stimulation
over-stimulation lacking counter regulation lacking counter
regulation inhibited in partinhibited in part over-expression of
immune complexes, cytokines and/or adhesion molecules).
over-expression of immune complexes, cytokines and/or adhesion
molecules). The over and under expression will impedes the immune
functions or causes such systemic side effects as, for example, the
wasting syndrome seen in HIV infections. The over and under
expression will impedes the immune functions or causes such
systemic side effects as, for example, the wasting syndrome seen in
HIV infections. The immune system then recognises endogenous
structures as being foreign (cross-reactions, insufficient
tolerance). The immune system then recognises endogenous structures
as being foreign (cross-reactions, insufficient tolerance). This is
considered to be the cause of autoimmune diseases. The immune
system can react excessively to harmless substances (insufficient
tolerance) with the subsequent development of allergies.This is
considered to be the cause of autoimmune diseases. The immune
system can react excessively to harmless substances (insufficient
tolerance) with the subsequent development of allergies. Slide 13
April 2005 Ark International Training Seminars Types of cytokines
The immune cells secrete numerous soluble and, in part, highly
specialised mediators which, in a series of complex interactions,
guarantee for the viability, development, differentiation,
proliferation and activity in the organism. The immune cells
secrete numerous soluble and, in part, highly specialised mediators
which, in a series of complex interactions, guarantee for the
viability, development, differentiation, proliferation and activity
in the organism. These cytokines are soluble glycoproteins that
function as intercellular signalling molecules. These cytokines are
soluble glycoproteins that function as intercellular signalling
molecules. The other three intercellular signalling molecules are
neurotransmitters, endocrine hormones and autacoidsThe other three
intercellular signalling molecules are neurotransmitters, endocrine
hormones and autacoids Slide 14 April 2005 Ark International
Training Seminars Cytokines Cytokines have an effect on all cells
(not only on the immune cells). Cytokines have an effect on all
cells (not only on the immune cells). Cytokines maintain a rigidly
controlled communication network between the individual cell types
including those of the nervous system. Cytokines maintain a rigidly
controlled communication network between the individual cell types
including those of the nervous system. Cytokines are released in
the course of normal cell functions, especially in response to
particular stimulus: e.g. antigens, immune complexes, complement,
enzymes, other cytokines. Cytokines are released in the course of
normal cell functions, especially in response to particular
stimulus: e.g. antigens, immune complexes, complement, enzymes,
other cytokines. Slide 15 April 2005 Ark International Training
Seminars Control of the immune reaction In contrast to the
reactions seen with many hormones, those attributed to cytokines
usually only involve local, short-distance signals. In contrast to
the reactions seen with many hormones, those attributed to
cytokines usually only involve local, short-distance signals.
Normally, their release is usually only necessary for a definite
purpose, at a defined time and at a locally-limited site. Normally,
their release is usually only necessary for a definite purpose, at
a defined time and at a locally-limited site. Slide 16 April 2005
Ark International Training Seminars Slide 17 April 2005 Ark
International Training Seminars Cellular inflammation: triggers
Cell type Trigger B-lymphocyte ACTH, -endorphins, growth hormone,
IGF-1 T-lymphocytes ACTH, -endorphins, growth hormone, IGF-1,
prolactin, TSH Mast cells, eosinophils, neutrophils Kinins,
vasoactive intestinal peptide, somatostatin Slide 18 April 2005 Ark
International Training Seminars Cellular inflammation: triggers
Cell type Trigger Platelets Serotonin, PAF, neuropeptide-Y
Splenocytes LH, FSH, CRH, prolactin Thymocytes CRH, LHRH, AVP,
oxytocin Macrophages ACTH, -endorphins, growth hormone, substance P
Slide 19 April 2005 Ark International Training Seminars Cellular
inflammation: neuroendocrine regulation CytokineEffect TNF type
(TNF-, TNF-, IL-1) type 1 APR type 1 APR CRP CRP serum amyloid
protein serum amyloid protein type 2 APR type 2 APR IL-6 type
(IL-6, IL-11) type 2 APR type 2 APR fibrinogen fibrinogen
Corticosteroids APR APR Synergy with most cytokines Angiostatic
Insulin cytokine effects cytokine effects FGF, TGF- cytokine
effects cytokine effects Slide 20 April 2005 Ark International
Training Seminars TNF type cytokines TNF-, TNF-, IL-1) TNF-, TNF-,
IL-1) They have the effect of increasing type 1 acute phase
reactants (APR), increasing CRP and serum amyloid protein and
decreasing type 2 APRThey have the effect of increasing type 1
acute phase reactants (APR), increasing CRP and serum amyloid
protein and decreasing type 2 APR i.e. they assist in the
pro-inflammatory responsei.e. they assist in the pro-inflammatory
response They increase ACTHThey increase ACTH They have a variable
effect on prolactin except for IL-6 that increases prolactinThey
have a variable effect on prolactin except for IL-6 that increases
prolactin They lower the production of growth hormone, TSH and
LHThey lower the production of growth hormone, TSH and LH Slide 21
April 2005 Ark International Training Seminars Hormonal effects on
inflammation Corticosteroids increase acute phase reactants (APR),
support the action of most cytokines and are angiostatic
Corticosteroids increase acute phase reactants (APR), support the
action of most cytokines and are angiostatic IL-1, IL-1, TNF-, IL-2
and IL-6 increases ACTH production IL-1, IL-1, TNF-, IL-2 and IL-6
increases ACTH production Insulin decreases the action of most
cytokines Insulin decreases the action of most cytokines FGF and
TGF-decrease theaction of most cytokines FGF and TGF-decrease
theaction of most cytokines Slide 22 April 2005 Ark International
Training Seminars Cytokine & effects on hormones
cytokineACTHprolactin Growth hormone TSHLHFSH IL-1 ?? ??? TNF- IL-2
IL-6 INF- ? TGF- ? PDGF ?? Slide 23 April 2005 Ark International
Training Seminars Overview of inflammation Slide 24 April 2005 Ark
International Training Seminars Most common stimuli for cytokine
expression Stress Stress PsychologicalPsychological
AllergiesAllergies Chemical toxicityChemical toxicity Toxic metal
exposureToxic metal exposure Glycosylated proteinGlycosylated
protein Chronic subclinical infectionChronic subclinical infection
DysbiosisDysbiosis Radiation / electromagneticRadiation /
electromagnetic TraumaTrauma Low oestrogen Low oestrogen Slide 25
April 2005 Ark International Training Seminars General activity of
cytokines Cytokines involved in acute inflammation Cytokines
involved in acute inflammation TNF-, IL-1, IL-6, IL-8, IL-11TNF-,
IL-1, IL-6, IL-8, IL-11 And other chemokines, G-CSF, and GM-CSFAnd
other chemokines, G-CSF, and GM-CSF Cytokines involved in chronic
inflammation Cytokines involved in chronic inflammation They can be
subdivided into: -They can be subdivided into: - Cytokines
mediating humoral responses Cytokines mediating humoral responses
IL-4, IL-5, IL-6, IL-7, and IL-13IL-4, IL-5, IL-6, IL-7, and IL-13
Cytokines mediating cellular responses Cytokines mediating cellular
responses IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12,
interferon (IFN), transforming growth factor- (TGF), and tumour
necrosis factor- and (TNF).IL-1, IL-2, IL-3, IL-4, IL-7, IL-9,
IL-10, IL-12, interferon (IFN), transforming growth factor- (TGF),
and tumour necrosis factor- and (TNF). Slide 26 April 2005 Ark
International Training Seminars Humeral versus cellular immunity
Dominance of the humoral immunity IL-4, IL-5, IL-6, IL-7, and
IL-13Increased production of IL-4, IL-5, IL-6, IL-7, and IL-13
IL-1, IL-2, IL-3, IL-4, IL-7, IL- 9, IL-10, IL-12, IFN, TGF-, and
TNF- and .Decreased production of IL-1, IL-2, IL-3, IL-4, IL-7, IL-
9, IL-10, IL-12, IFN, TGF-, and TNF- and . Check for parasites and
mycobacterium. Dominance of cellular immunity IL-1, IL-2, IL-3,
IL-4, IL-7, IL-9, IL-10, IL-12, IFN, TGF-, and TNF- and .Increased
production of IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12,
IFN, TGF-, and TNF- and . IL-4, IL-5, IL-6, IL-7, and
IL-13Decreased production of IL-4, IL-5, IL-6, IL-7, and IL-13
Check for viruses and bacteria. Slide 27 April 2005 Ark
International Training Seminars Pro-inflammatory or activating
cytokines TNF-,TNF-, IL-1,IL-1, IL-2,IL-2, IL-6,IL-6, IL-12,IL-12,
IFN-,IFN-, TGF.TGF. Slide 28 April 2005 Ark International Training
Seminars IL-1 comes mainly from macrophages and monocytes. IL-1
comes mainly from macrophages and monocytes. IL-1 is induced by
micro-organisms, microbial products, antigens, inflammatory agents,
plant lectins, lymphokines and certain chemicals IL-1 is induced by
micro-organisms, microbial products, antigens, inflammatory agents,
plant lectins, lymphokines and certain chemicals IL-1 activates the
process known as the acute phase response. IL-1 activates the
process known as the acute phase response. This response is
characterised by production of a variety of hepatic proteins (e.g.,
C-reactive protein, serum amyloid A, fibrinogen, complement, alpha
1-antitrypsin)This response is characterised by production of a
variety of hepatic proteins (e.g., C-reactive protein, serum
amyloid A, fibrinogen, complement, alpha 1-antitrypsin)
Pro-inflammatory cytokines Slide 29 April 2005 Ark International
Training Seminars IL-1 activates adhesion molecules on vascular
endothelium. (VCAM) activates adhesion molecules on vascular
endothelium. (VCAM) stimulates the production of IL-8 that
activates neutrophils. stimulates the production of IL-8 that
activates neutrophils. elicits the release of histamine from mast
cells at the site of inflammation causing increased capillary
permeability and vasodilatation. elicits the release of histamine
from mast cells at the site of inflammation causing increased
capillary permeability and vasodilatation. a potent mitogen for
astroglial cells and induces astrocytes to synthesise NGF. a potent
mitogen for astroglial cells and induces astrocytes to synthesise
NGF. interferes powerfully with the hypothalamic-hypophyseal-
gonadal axis (HHGA). interferes powerfully with the
hypothalamic-hypophyseal- gonadal axis (HHGA). At the CNS level,At
the CNS level, decrease plasma LH levels (Luteinising hormone), a
phenomenon attributed to the inhibition of hypothalamic secretion
of LHRH and LHRH gene expression. decrease plasma LH levels
(Luteinising hormone), a phenomenon attributed to the inhibition of
hypothalamic secretion of LHRH and LHRH gene expression. Slide 30
April 2005 Ark International Training Seminars Effect of IL-1 &
TNF- on cartilage Slide 31 April 2005 Ark International Training
Seminars IL-2 Generated by T lymphocytes after stimulation by
antigen or mitogen Generated by T lymphocytes after stimulation by
antigen or mitogen Pro-inflammatory cytokine that plays a critical
role in regulating both cellular and humoral chronic inflammatory
responses. Pro-inflammatory cytokine that plays a critical role in
regulating both cellular and humoral chronic inflammatory
responses. Largely responsible for immunologic memory. Largely
responsible for immunologic memory. The immune system forms a
long-term "memory" from antigen exposure so that any future contact
will stimulate an immediate defence against that particular
antigen.The immune system forms a long-term "memory" from antigen
exposure so that any future contact will stimulate an immediate
defence against that particular antigen. Slide 32 April 2005 Ark
International Training Seminars IL-2 Influence the maturation and
differentiation of lymphocytes in the thymus and bone marrow.
Influence the maturation and differentiation of lymphocytes in the
thymus and bone marrow. There are two major classes of lymphocytes:
There are two major classes of lymphocytes: B lymphocytes (B cells)
derived from the bone marrowB lymphocytes (B cells) derived from
the bone marrow B cells express antibody molecules on their
surface, and when stimulated by antigen, each B cell becomes a
plasma cell that secretes antibodies specific for that antigen. B
cells express antibody molecules on their surface, and when
stimulated by antigen, each B cell becomes a plasma cell that
secretes antibodies specific for that antigen. T-lymphocytes (T
cells)T-lymphocytes (T cells) Slide 33 April 2005 Ark International
Training Seminars IL-2 T-lymphocytes (T cells) derived from bone
marrow but matured by the thymus.T-lymphocytes (T cells) derived
from bone marrow but matured by the thymus. T cells also express
what appear to be antibody molecules on their surfaces, but unlike
B cells, these molecules cannot be secreted T cells also express
what appear to be antibody molecules on their surfaces, but unlike
B cells, these molecules cannot be secreted T cells react to
antigen stimulation by secreting other types of molecules; T cells
react to antigen stimulation by secreting other types of molecules;
cytotoxic ("killer") T cells secrete molecules that kill infected
or abnormal cells on contact,cytotoxic ("killer") T cells secrete
molecules that kill infected or abnormal cells on contact, "helper"
T cells secrete a variety of cytokines involved in the immune
response."helper" T cells secrete a variety of cytokines involved
in the immune response. Thus, a foreign antigen stimulates both B
cells and T cells, and the resulting immune response is specific
for that antigen alone.Thus, a foreign antigen stimulates both B
cells and T cells, and the resulting immune response is specific
for that antigen alone. Slide 34 April 2005 Ark International
Training Seminars IL-2 After an antigen binds receptors on an
individual T cell, the antigen stimulates the T cell to secrete
IL-2 and to make IL-2 receptors. After an antigen binds receptors
on an individual T cell, the antigen stimulates the T cell to
secrete IL-2 and to make IL-2 receptors. The T lymphocyte has two
receptor sites; The T lymphocyte has two receptor sites; the first
site readily binds IL-2,the first site readily binds IL-2, the
second site attaches more slowly to the IL-2 molecule.the second
site attaches more slowly to the IL-2 molecule. It is the
interaction at the second site, however, that activates the T cell,
causing it to undergo complex changes in morphology, metabolism,
expression of surface receptors, and the production of cytokines It
is the interaction at the second site, however, that activates the
T cell, causing it to undergo complex changes in morphology,
metabolism, expression of surface receptors, and the production of
cytokines Slide 35 April 2005 Ark International Training Seminars
IL-2 Stimulates the proliferation of B cells, helping them to
secrete antibodies Stimulates the proliferation of B cells, helping
them to secrete antibodies IL-2 stimulates production of Natural
Killer T cells IL-2 stimulates production of Natural Killer T cells
They represent the first line of defence against intracellular
pathogens because of their immediate responsiveness to IL-2.They
represent the first line of defence against intracellular pathogens
because of their immediate responsiveness to IL-2. In synergy with
IL-1.In synergy with IL-1. Il-2 has been found to be low in
persistent microbial infections and cancer and there is a
considerable body of research into the immuno-stimulatory effect of
IL-2. Il-2 has been found to be low in persistent microbial
infections and cancer and there is a considerable body of research
into the immuno-stimulatory effect of IL-2. Slide 36 April 2005 Ark
International Training Seminars IL-2 lymphokine secretion
lymphokine secretion In turn IFN-, lymphotoxin, IL-4, IL-3, IL-5,
GM-CSF {macrophage colony stimulating factor})In turn IFN-,
lymphotoxin, IL-4, IL-3, IL-5, GM-CSF {macrophage colony
stimulating factor}) Enhanced expression of MHC (Major
Histocompatability Complex) class II proteins Enhanced expression
of MHC (Major Histocompatability Complex) class II proteins
Stimulates fibroblasts to secrete extracellular matrix Stimulates
fibroblasts to secrete extracellular matrix Slide 37
