Download Cytokines In Health and Disease General Properties of Cytokines

Cytokines In Health and Disease
General Properties of Cytokines
- Produced by nearly all cells of innate and adaptive immunity
- Non-antigen specific, low molecular weight glycoproteins
- Rapidly synthesized in response to a stimulus
 Not usually stored with the cell
 Typically have short half-lives
- Serve as chemical messengers of the immune system
 Cells are regulated by the quantity and type of cytokine to which they are exposed
 Cells are regulated by the expression or down-regulation of cytokine receptors
- Action is over short and long ranges (can result in systemic effects)
- Exert effects by binding to specific receptors on the target cell surface
 When cytokines are induced, cytokine-producing cells secrete cytokine proteins that bind to receptors
on target cells. This binding triggers signal transduction pathways and gene expression in target cells
that leads to the activation, proliferation, and/or differentiation of the target cells
- Are pleiotropic, meaning one cytokine can affect the activity of many different target cell types
 Play a crucial role in amplification of the immune system
- Have functional redundancy, meaning that more than one cytokine can act on a single cellular target
- Rarely act alone in vivo
 Synergistic effects – combined effect of two cytokines is greater than sum of their individual effects
 Antagonistic effects – one cytokine can inhibit the biological activity of another cytokine
- Act via several different mechanisms
 Autocrine – cytokine acts locally on the same cell that secreted it
 Paracrine – cytokine acts on other cells
 Endocrine – cytokine acts systemically
- Interleukins (ILs)
 Regulate interactions primarily between leukocytes (can regulate other cells)
 IL-2, IL-3, IL-4…(named according to their discovery)
- Interferons (IFNs)
 Type I interferons (IFN-α, IFN-β)
o Interfere with viral replication within host cells
 Type II interferons (IFN-γ)
o Activate macrophages to increase killing of microbes within phagosomes or phagolysosomes
- Tumor necrosis factors (TNFs)
 Derived from macrophages (TNF-α) and T cells (TNF-β)
 Cause apoptosis of tumor cells
 Induce inflammation
- Colony-stimulating factors (CSFs)
 Most named for the cell type they stimulate to grow
o Macrophage-CSF (M-CSF), granulocyte-CSF (G-CSF)
 Promote expansion and differentiation of bone-marrow progenitor cells
 Essential for maturation of granulocytes, monocytes, dendritic cells, lymphocytes
o M-CSF stimulated production of monocytes from bone marrow
 Essential for the differentiation of tissue macrophages
o M-CSF simulates differentiation of monocytes into macrophages once in tissue
- Chemokines
 Affect leukocyte movement by attracting leukocytes (neutrophils, monocytes, lymphocytes)
o Monocyte chemotactic protein-1 (MCP-1)
Cytokines in Innate Immunity
Cytokine-mediated innate immunity against extracellular bacteria
- Primary mechanisms utilized are complement activation, phagocytosis, and the inflammatory response
- Cytokines plays a major role in activating phagocytes and recruiting leukocytes during inflammation
- Macrophages respond to extracellular bacteria by phagocytosis and producing TNF-α, IL-1, and chemokines
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TNF-α and IL-1 act on vascular endothelium at the site of infection to induce expression of adhesion
molecules and stimulate secretion of chemokines
o Chemokines recruit neutrophils and monocytes for attachment
 IL-8 preferentially recruits neutrophils to site of infection
 MCP-1 produce by macrophages recruits monocytes
o Adhesion molecules promote attachment of blood neutrophils and monocytes to endothelium
 TNF-α and IL-1 are endogenous pyrogens that act on the hypothalamus to induce fever
o Stimulated hypothalamic cells increase synthesis of prostaglandin E2 (PGE2), a compound
that leads to the increase of body temperature
 PGE2 inhibitors (aspirin) reduce fever by blocking action of TNF-α and IL-1
o LPS is an exogenous pyrogen that induces fever indirectly by acting on endogenous pyrogens
o Fever aids host defense because most pathogens grow less efficiently at raised temperatures
o Prolonged production of TNF-α leads to cachexia, the wasting of muscle and fat cells
Cytokine-mediated innate immunity against intracellular bacteria
- Principally mediated by NK cells and phagocytes
- Macrophages and dendritic cells respond to intracellular bacteria by secreting IL-12
 IL-12 induces local production of IFNγ from NK cells at the site of infection
o IL-12 is also the chief mediator of early innate immune response to intracellular microbes
 IFNγ activates macrophages to destroy phagocytosed bacteria within the phagosome or phagolysosome
Cytokine-mediated innate immunity against viruses
- Two primary mechanisms against viruses
 Inhibition of infection by type I IFNs (IFNα and IFNβ)
o IFNα and IFNβ are secreted by virus-infected cells and APCs (chiefly dendritic cells)
o Cause infected cells to synthesize enzymes that interfere with viral transcription and replication
 A cell that has responded to IFNα and IFNβ and is resistant to viral infection is said to
be in an “antiviral state”
 NK cell-mediated killing of virus-infected cells
o APCs respond to viruses by producing IL-15 and IL-12
 IL-15 stimulates the proliferation of NK cells
 IL-12 enhances the cytotoxic function of NK cells
Cytokines in Adaptive Immunity
- Adaptive immune response is mounted if innate immunity fails to eliminate a pathogen
- Host must induce an appropriate set of adaptive effector functions
 IgE is essential in eliminating helminthic parasites while Tc cells are required to destroy viruses
- Following antigen encounter, naïve Th cells differentiate into Th1, Th2, or Th17 functional subsets
 Cytokines secreted by APCs during the innate immune response determine differentiation of Th cells
- Th1 cells
 Primarily a pathway of cell-mediated immunity
o Primarily activates macrophages, NK cells, and CD8+ T cells (CTLs)
 Cytokine IL-12 made in response to antigen and exposed to naïve Th cells during antigen presentation
 IL-12 induces naïve Th cells to differentiate towards the Th1 subset
o Newly-differentiated Th1 cells produce IFNγ, IL-2, and TNF-β
o IFNγ
 Promotes differentiation of proliferating Th cells towards Th1 cells
 Inhibits differentiation of Th2 and Th17 cells
 Activates macrophages to kill ingested microbes in phagolysosomes
 Acts on B cell to promote isotype class switching to those IgG subclasses that bind to
Fcγ receptors on phagocytes and activate complement
o IL-2
 Initially induces T cell proliferation of all activated T cells
 Later induces proliferation and differentiation of Th1 cells (not Th2 or Th17)
 Induces proliferation of NK cells, B cells, and activated effector CTLs
o TNF-β activates endothelial cells and neutrophils (is a mediator of acute inflammation)
Cytokines in CTL responses
o Requirement of Th cells for CTL responses varies with the type of antigen exposure
o When innate immune response is very strong against a virus
 IL-12 and type I IFNs are most important for CTL response
 After naïve T cell receives first two signals necessary for activation, a third signal from
IL-12 (or type I IFNs) is required for further proliferation of CTLs
 Effector CTLs acquire expression of perforin, granzymes and possibly CD95L
 Effector CTLs secrete IFNγ, LT, and TNFα
 If microbe induces strong IL-12 and/or type I IFN responses, Th1 is not required
o When innate immune response is weak against a virus
 If a microbe induces low-level production of cytokines IL-12 and type I IFNs, CD8+ T
cells fail to develop into effector CTLs
- Th cells may be required for inducing a CTL response
 Th1 cells can interact with APCs to up-regulate the production of these cytokines
 Th1 cells may provide a direct signal to CD8+ T cells to develop into effector CTLs
o Regardless of innate immune response strength, the absence of Th cells (thus, cytokine IL-2)
results in the inability to generate CD8+ memory cells and, thus, a secondary immune response
Th2 cells
 Primarily a pathway of humoral immunity
o Primarily induce antibody production (does not activate macrophages, NK cells, or CTLs)
 Basophils take up antigens (allergens, helminths) and produce cytokine IL-4 during antigen
presentation to Th cells
o IL-4 drives differentiation of Th cells towards the Th2 subset
 Th2 cells produce IL-4, IL-5, and IL-13
o IL-4
 Promotes differentiation of proliferating Th cells towards Th2
 Inhibits differentiation of Th1 and Th17 cells
 Stimulated B cell antibody heavy chain class switching to the IgE isotype
 Induces B cell isotype switching to those IgG subclasses that are efficient neutralizers
but weak opsonizers (weak complement and Fcγ binders)
 Suppresses IFNγ-mediated activation of macrophages
o IL-5
 Stimulated proliferation of B cells
 Activates and stimulates growth and differentiation of eosinophils (kill helminths)
o IL-13
 Stimulated mucous production by goblet cells
 Promotes elimination of helminths
 Stimulated B cell antibody heavy chain class switching to IgE isotype
Th17 cells
 Primarily a pathway of neutrophil-mediated immunity
 Dendritic cells produce TGFβ and IL-6 in response to specific antigens
o TGFβ and IL-6 drives differentiation of Th cells towards Th17 subset
o IL-23 produced by APCs is required to stabilize the differentiated Th17 cells
 Th17 cells produce IL-17
o IL-17 acts on a variety of cell types, inducing expression of pro-inflammatory cytokines
 TNFα induces fever and the expression of adhesion molecules and chemokines
 IL-1 induces fever and the expression of adhesion molecules and chemokines
 IL-8 recruits neutrophils to site of infection
 G-CSF stimulates production and differentiation of granulocytes from bone marrow
 GM-CSF stimulates production and differentiation of granulocytes and macrophages
o IL-17 is important for neutrophil recruitment (helps control early stages of infection)
 Especially important for control of extracellular bacterial and fungal infections
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o IL-17 receptor deficient mice are highly susceptible to infection by extracellular pathogens
 Th17 cells also play a role in autoimmunity
Regulatory T cells (Tregs)
- Suppress or control adaptive immune responses
- Whether naïve or activated, express high levels of CD25 (IL-2 receptor)
 IL-2 is responsible for proliferation of Th1, CTL, NK, and B cells (cell-mediated immunity)
- Produce immunosuppressive cytokines TGFβ and IL-10
 Inhibit functions of macrophages, dendritic cells, lymphocytes (suppresses inflammatory response)
 TGFβ acts on B cells in germinal centers to induce isotype switching to IgA
- Maintain tolerance against self antigens
- Maintain pregnancy
Cytokines in Disease
- Cytokines are only beneficial when produced at concentrations optimal for inducing innate and adaptive
immune responses
- Overproduction of cytokines can result in life-threatening complications
 LPS-mediated bacterial septic (endotoxic) shock
o Gram negative bacterial cell walls contain LPS (endotoxin)
o LPS is a potent stimulator of TNFα production by macrophages
o Severe gram negative bacterial sepsis (infection of the blood stream or body tissues) causes
overproduction of TNFα and IL-1 by macrophages
 Large quantities of these cytokines enter the blood stream and act as an endocrine
hormone, causing systemic clinical and pathologic abnormalities
o Septic shock is characterized by cardiovascular collapse, disseminated intravascular
coagulation (DIC), and hypoglycemia
 Condition of severe hemodynamic and metabolic disturbance
 Systemic actions of TNFα and IL-1 that lead to shock
o High levels of TNFα cause alternation of the pro-coagulant-anticoagulant balance, with
increased expression of pro-coagulant protein tissue factor and decreased expression of
anticoagulant factors (thrombomodulin, endothelial protein C receptor)
 Results in DIC
 Thrombosis can lead to organ failure
o TNFα-induced overproduction of nitrous oxide (NO) by vascular smooth muscle causes
vascular relaxation, hyporeactivity, and vasodilation
 Leads to reduction of organ perfusion, inhibition of myocardial contractility, and
eventually heart failure
o Excess TNFα in the blood stream causes systemic inflammatory response syndrome (SIRS)
 TNFα activates neutrophils and promoted their migration to tissues
 Activated neutrophils release lytic enzymes that can damage endothelial cells and
cause widespread inflammation
 The escape of fluid from blood to the interstitial space can cause reduced blood flow to
organs, potentially causing organ dysfunction and/or organ failure
- Reduced blood flow to and fluid accumulation in the liver can impair liver
function, resulting in decreased gluconeogenesis (hypoglycemia)
- Leakage of fluid into the lungs greatly reduces ability to transfer oxygen into
the blood stream, leading to acute respiratory distress syndrome (ARDS)
 Superantigen-mediated toxic shock
o A variety of microbes and viruses produce toxins (called superantigens) whose unique
properties allow them to induce toxic shock. They can activate T cell irrespective of antigen
specificity, stimulating enormous quantities (2-20%) of T cells. This results in overproduction
of cytokines, a pathological condition that ultimately leads to systemic toxicity