Shahed Saleh

Shahed Saleh

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SCIENTIFIC TEAM –الفريق العلمي

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مبسم الله الرحمن الرحي

Definition

❖ What are cytokines?

• A 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.

• Cytokine or immunocytokine is a generic name used to describe a

diverse group of soluble proteins and peptides which act as humoral

regulators at nano- to- picomolar concentrations

• Their major functions are to mediate and regulate immune response

and inflammatory reactions.p

so they are low molecular weight polypeptides released from cells to affect other cells and mediate signaling uh between the cells

General properties :

Most cytokines are low molecular weight polypeptides or glycoprotein (8~80 KD),

and most of them are monomer

Natural cytokines are secreted by activated cells such as activated immune

cells, matrix cells and tumor cells

Cytokines

Lecture 10

Date : 29/7/2021

الأسود: كلام الدكتور ✓

السلايدالأزرق: ✓

الأخضر: شرح أو توضيح خارجي ✓


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One kind of cytokines can be produced by different cells. One kind of cells can

secrete different cytokines. Cytokines initiate their actions by binding to specific

membrane receptors on target cells.

▪ so they are released from certain cell and then they initiate their action by binding to the to their receptor on the target cell

Cytokines can act on the cells that produce them (autocrine), on other cells in the immediate vicinity (paracrine), or on cells at a distance (endocrine) after being carried in blood or tissue fluids.

so it's it's released from this cell and then it binds to its equivalent receptor on the same cell that it was released from to have the activation effect and this is called autocrine. on other cells in immediate or other cells in the immediate vicinity within the cell this is called paracrine, so it's released from cell (x) to target cell (y) or neighboring cell while this is paracrine or on cells at distance and this is called endocrine after being carried in blood or tissue fluid.

٣:٣٠عند دقيقة : الرسمةشرح (A)so we have here the inducing stimulus it's going to activate the cytokine gene the cytokine is going to be produced by this cell and then it is going to affect the neighboring cells by binding to the receptor on the neighboring cell this is going to lead to gene activation of the cytokine and this is going to give the end result or the biological effect of the cytokine released. (B)so a autocrine it's released from this cell and then it's bind to receptor in the same cell to activate the cytokine gene paracrine released from this cell to the neighboring cell and endocrine it goes through the circulation to the stem cell to bind to the to its equivalent receptor in the distant cell and activate the cytokine a gene.

Cytokine Names :

•Interleukins - produced exclusively by leukocytes


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• Lymphokines - produced by lymphocytes

• Monokines - produced exclusively by monocytes

• Interferons - involved in antiviral responses

• Colony Stimulating Factors - support the growth of cells in semisolid medias

and has to do with the hematopoietic differentiation

• Chemokines - promote chemotaxis. and they are responsible for attracting the blood cells to the location of infection

Effects of Cytokines:

• Pleiotropism refers to the ability of one cytokine having multiple effects on

diverse cell types.

• Redundancy refers to the property of multiple cytokines having the same or

overlapping functional effects.

• Synergy refers to the property of two or more cytokines having greater than

additive effects.

• Antagonism refers to the ability of one cytokine inhibiting the action of another.

٦:٩دقيقة:شرح الرسمة عند *so here we can see the pleiotropism effect so the activated ct4 helper cell is going to release interleukin 2 which is going to lead to differentiation of both the Ig E and the T helper 2 differentiation . *redundancy as we can see IL-2 and IL-4 have the same role in proliferating the B cell ,so two types of cytokine doing the same work. *synergy , here we can see that interferon gamma and TNF increase expression of class 1 MHC molecules on many cell types so they have more than additive effects.


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*antagonism so the interferon gamma leads to macrophage activation while the interleukin-10 inhibits macrophage activation.

Cytokine General Actions : • Development of cellular and humoral immune responses • Induction of inflammation • Regulation of hematopoiesis • Control of cellular proliferation and differentiation • Induction of wound healing • Chemotaxis

Classification of cytokines • Interleukin, IL • Interferon , IFN • Tumor necrosis factor, TNF • Colony stimulating factor, CSF • Chemokine • Transforming growth factor

1. Interleukin 1 (IL-1) Family: i. typically secreted very early in the immune response by dendritic cells and monocytes or macrophages(ag representing cell). ii. IL-1 secretion is stimulated by recognition of viral, parasitic, or bacterial antigens by innate immune receptors. so once a foreign antigen or foreign pathogen is detected by the innate immune system this is going to activate and lead to the production of interleukin-1 iii. IL-1 family members are generally pro-inflammatory, (what does that mean)? • they induce an increase in the capillary permeability at the site of


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cytokine secretion, • amplification of the level of leukocyte migration into the infected tissues. • IL-1 has systemic (whole body) effects and signals the liver to produce acute phase (CRP) and IL-6 • These proteins further induce multiple protective effects, including the destruction of viral RNA. so the goal of releasing the interleukin-1 is destruction of the viral RNA or the invading pathogen by increasing capillary permeability ,amplification the level of leukocyte migration into the site of infection and signal the level to produce the acute phase reactants such as c reactor protein and interleukin-6. ●generation of a systemic fever response which helps to eliminate many temperature sensitive bacterial strains so it helps in production of fever and this elevation works as protective mechanism because some bacterial strains cannot grow in elevated temperatures. IL-18 stimulate production of the macrophage-activating cytokine IFN-γ by NK cells and T cells. ××Fever Mechanism / homework : The mechanism of fever appears to be a defensive reaction by the body against infectious disease. When bacteria or viruses invade the body and cause tissue injury, one of the immune system’s responses is to produce pyrogens. These chemicals are carried by the blood to the brain, where they disturb the functioning of the hypothalamus, the part of the brain that regulates body temperature. The pyrogens inhibit heat-sensing neurons and excite cold-sensing ones, and the altering of these temperature sensors deceives the hypothalamus into thinking the body is cooler than it actually is. In response, the hypothalamus raises the body’s temperature above the normal range, thereby causing a fever.

https://www.britannica.com/science/infectious-disease

https://www.britannica.com/science/bacteria

https://www.britannica.com/science/virus

https://www.britannica.com/science/immune-system

https://www.britannica.com/science/pyrogen

https://www.britannica.com/science/hypothalamus

https://www.merriam-webster.com/dictionary/inhibit

https://www.britannica.com/science/neuron


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●Innate immune response : IL-1 also activates both T and B cells at the

induction of the adaptive immune response.

• E.X. IL-1α and IL-1β ,IL-18

First we have detection of pathogen by the innate immunity, interleukin one is going to be be released to activate both the b and the cells. شرح الرسمة *** so here we can see the local inflammation on the endothelial level it's going to increase the permeability it's going to lead to a up regulation of the adhesion molecule on the inside of the vessels in order to lead to leukocyte rolling and extravasation also the interleukin-1 and tumor necrosis factor is going to activate the leukocytes and it's going to lead to production of the chemokines to attract the white blood cells to the site of infection we have systemic protective effect in the brain we as we said it induces fever by a mechanism, induced by the TNF interleukin-1 interleukin-6 also it has an effect on the liver interleukin-1 interleukin-6 lead to acute phase proteins C reactive ptn or the CRP. also on the bone marrow it induces leukocytes production by TNF interleukin-1 and interleukin 6. also it might have the interleukins might have systemic pathological effects but not we're not talking here about the interleukin and one family here we're talking about another family to the term necrosis factor family and the these effects include decreasing cardiac function and thrombosis leads to formation of thrombus and it also leads to metabolic abnormalities due to insulin resistance.

×Hematopoietin (Class I) Family we're still talking about the interleukin family we have the hematopoietin family which is classified or called as a class one


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because it was the earliest to be structurally categorized not first to be discovered interferon they were the first to be discovered . • Called Class I because earliest to be structurally characterized (not first to be discovered) • Large family of small cytokine molecules with functional diversity • Not all involved in hematopoietic functions Their cellular origins and target cells are as diverse as their ultimate functions, which range from; • signaling the onset of T- and B-cell proliferation (e.g., IL-2), • to signaling the onset of B-cell differentiation to plasma cells and antibody secretion (e.g., IL-6), • to signaling the differentiation of a T helper cell along one particular differentiation pathway versus another (e.g., IL-4 vs. IL-12) • and finally, to initiating the differentiation of particular leukocyte lineages (e.g., granulocyte monocyte-colony stimulating factors GM-CSF, G-CSF). • E.X. IL-2, IL-4, IL-5, IL-7, IL-9,IL-12, IL-15, IL-21 and GM-CSF

×IL-17 Family (most recently described cytokines

,proinflammatory cytokine cluster) • interleukins 17A, 17B, 17C, 17D, and 17F. Signaling through most members of this family culminates in the generation of inflammation. • IL-17 released by activated T cells and stimulates the production of factors that signal a pro inflammatory state, including IL-6, chemokines CXCL8, and (G-CSF)

2. Interferon (Class II)


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First cytokines to be discovered

○Type I - Secreted by not only macrophages and dendritic cells but

also by virus infected cells: (1) Interferons α,and (2) interferon-β,

○Type II – produced by activate T and NK cells , known as interferon-γ

& cytokines include IL-10.

Interferon-γ is used medically to bias the adaptive immune system toward a cytotoxic response in diseases such as leprosy and toxoplasmosis (intracellular pathogens), in which antibody responses are less effective. what does that mean? If we give interferon gamma that means we stimulate the body to produce more cytotoxic t cells and so these cytotoxic t cells to target cells which are infected by intracellular pathogens to kill these cells and in this case antibody response are less effective because we're talking about intracellular infection. antibody response is good enough when the invading pathogen is still outside the cell once it's intracellular then we need something to induce a strong cytotoxic effect interferon gamma does that and it induces the activation of macrophages with subsequent destruction of any intracellular pathogen and differentiation of cytotoxic T cells. BY

– and inducing the activation of macrophages, with subsequent

destruction of any intracellular pathogens

– and the differentiation of cytotoxic T cells.

• All three INFs(increase the expression of MHC complex proteins on the surface of cells, thus enhancing their antigen-presentation capabilities.) so they increase the ability of all the cells to express major histocompatibility complex in order to present the intracellular pathogen or organism or foreign antigen which is intracellularly into the surface of the cell so that can be recognized the target by the cytotoxic t cell.


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٢٠:٥شرح الرسمة عند دقيقة :

so here we see the mechanism of induction of type 1 interferon by the viruses here we have the virus it's been internalized into the endosome and then the DNA or RNA of the virus binds to , or what we call the PAMP, it binds to the pattern recognition receptor, then it's going to activate a signaling pathway which is going in the nucleus to activate to activate production of interferon alpha and beta.once the interferon is is activated and released from this viral infected cell it's going to bind to the receptor on the uninfected cell and this is going to lead to phosphorylation of translation initiation factor elongation factor to alpha activation of RNA and this is going to lead to inhibition of viral protein synthesis degradation degradation of viral RNA and inhibition of viral gene expression and virion assembly, so the net effect of the interferon gamma is affecting the production of the viral protein and that's how it inhibits the viral replication.

3. Tumor Necrosis Family (TNF)

• Can signal development, activation, or death of certain cells

(homeostasis)

• Which induce apoptosis, or programmed cell death, is a mechanism

of cell death in which the cell dies from within and is fragmented into

membrane-bound vesicles that can be rapidly phagocytosed by

neighboring macrophages.

×Cytokines of the TNF Family;

• There are two members having the same name of the TNF family:

TNF-α and TNF-β. Both of these are secreted as soluble proteins.

• There are two members of the TNF family:

TNF-α and TNF-β


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• TNF-α is a proinflammatory cytokine, produced primarily by activated

macrophages, and lymphocytes, in response to infection,or

inflammation.

• TNF-β is produced by activated lymphocytes and can deliver a variety of signals. On binding to neutrophils, endothelial cells lead to increased expression of MHC and of adhesion molecules. so tnf as we've seen previously plays a role tnf with interleukin one in the cellular in the liquid site extravasation and rolling, where the neutrophils bind to the endothelial cells uh leading to increased expression of MHC and adhesion molecules.

• Fas ligand (FasL), induces apoptosis.and this member as other

members lead to apoptosis induction

4. Colony-Stimulating Factors (CSF)

• Cytokines that stimulate proliferation or differentiation of pluripotent

hematopoietic stem cell and different progenitors.

– Multi-CSF (IL-3)

– Granulocyte macrophage-CSF (GM-CSF)

– Monocyte-CSF (M-CSF)

– Granulocyte-CSF (G-CSF)

– Stem cell factor (SCF)

– Erythropoietin (EPO) which is secreted by the kidney in response to cellular hypoxia and the net result is production of more red blood cells to cope with this hypoxic status.


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٥:٢٦٢شرح دقيقة

metabolic stem cell differentiation pathway and lining specific markers so we can see here the interleukin-3,GM-CSF,M-CS roles in the differentiation of the different steps of the metabolic stem cell ,here we can see the interleukin the scf here we can the interleukin-3 the scf here the GM-CSF , M-CS granular monocyclone stimulating factor, so they play an important role in almost all the steps of differentiation of the hematopoietic cells as we can see in this figure.

5. Chemokines

• Direct the Migration of Leukocytes Through the Body

• Are structurally related family of small cytokines that bind to cell-

surface receptors and induce the movement of leukocytes up toward

the chemokine source.

• This soluble factor-directed cell movement is known as chemotaxis,

and molecules that can elicit such movement are referred to as

chemoattractants

• located on the surfaces of endothelial cells, enables them to bind to

the inner surfaces of blood vessels and directing leukocyte movement.

CXCLgroup: attract neutrophils

•CCL group: attract monocytes and macrophages

(although not neutrophils) to the site of infection.

Figure3-3:here this is just to show the role of the tnf the interleukin one and uh other cytokines in the uh leukocyte extravasation steps that we've talked about previously


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6. Transforming Growth Factor

• Growth-factor are cytokines which stimulate the growth of

their target cells.

➢ Transforming growth factor- (TGF-)

➢ Epithelia growth factor (EGF)

➢ Vascular endothelia cell growth factor (VEGF)

➢ Fibroblastic growth factor (FGF)

CK receptor

Membrane-binding cytokine receptors:

The receptor consists of extra-cellular region,trans-membrane region

and cytoplasmic region.

CK receptors can be grouped into five families according to structure

and function: Ig receptor superfamily

Type Ⅰ CK receptor superfamily

Type Ⅱ CK receptor superfamily

Type Ⅲ CK receptor superfamily

G-protein linked receptor superfamily

Functional Categories

• Mediate/regulate innate immunity


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– TNF, IL-1, IL-12, IFN type1, IL-10

• Mediate/regulate adaptive immunity

– IL-2, IL-4, IFN-γ, TGF-β

• Stimulates hematopoiesis

– IL-3, IL-7,GM -CSF,M-CS, SCF

Specific Interleukins Functions:

▪ IL1: Play role in inflammation

▪ IL2: Growth factor for B and T cells (clonal expansion)

▪ IL3: Haematopoetic growth factor which stimulates colony formation of blood cells. it takes the t helper cell from the t helper 0 , the t helper zero is acted up one with interleukin four, it's going to differentiate into two helper two cell • IL4: Stimulates development of Th2 cells from naïve Th cell.

Stimulates Ig class switch from IgG1 to IgE (allergy)

• IL5: Produced by Th2 cells and aids in the growth and

differentiation of eosinophils

• IL6: acute phase response. Is an acute phase reactant which leads to the production of and the action on liver as well to produce the c-reactive protein as well.

IL10: Suppresses inflammatory responses and Inhibits production of

IFN-γ, IL-2, IL-3, TNFα, GM-CSF

IL-12: is involved in the differentiation of naive T cells into Th1

cells


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Cytokines and Clinical Applications

• Cytokines and cytokines inhibitors can be used in many

clinical applications and treatments.

– Advantages: Known ligands, receptors and mechanisms of

action

– Problems with cytokine therapies: Effective dose levels, short

half-life, can cause unpredictable side effects

Colony stimulating factors (CSFs): hematological disorders

associated with cancer therapy

Erythropoietin (EPO): anemia associated with kidney disease

Interferon α: antiviral therapy (chronic Hepatatis B and C)

IFN- : multiple sclerosis

IFN-g: chronic granulomatous disease (CGD)

IL-2: kidney cancer, melanoma

*Cytokine storm /homework :

What is ?and its relation with the progression of SARS infection

A severe immune reaction in which the body releases too many

cytokines into the blood too quickly. Cytokines play an important role in

normal immune responses, but having a large amount of them

released in the body all at once can be harmful. A cytokine storm can

occur as a result of an infection, autoimmune condition, or other


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disease. It may also occur after treatment with some types of

immunotherapy. Signs and symptoms include high fever, inflammation

(redness and swelling), and severe fatigue and nausea. Sometimes, a

cytokine storm may be severe or life threatening and lead to multiple

organ failure. Also called hypercytokinemia.,so it is involving elevated

levels of circulating cytokines and immune-cell hyperactivation.

high level of cytokines also indicates a poor prognosis in COVID-19. Besides,

excessive infiltration of pro-inflammatory cells, mainly involving

macrophages and T-helper 17 cells, has been found in lung tissues of patients

with COVID-19 by postmortem examination. Recently, increasing studies

indicate that the “cytokine storm” may contribute to the mortality of COVID-

19. Here, we summarize the clinical and pathologic features of the cytokine

storm in COVID-19. Our review shows that SARS-Cov-2 selectively induces a

high level of IL-6 and results in the exhaustion of lymphocytes.

بالتوفيق ..


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Shahed Saleh