Cytokines.ppt

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CYTOKINES

• M.Prasad Naidu
• MSc Medical Biochemistry,
• Ph.D.Research Scholar

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CYTOKINES

• Cytokines are small secreted proteins which
  mediate and regulate immunity, inflammation, and
  hematopoiesis. They are produced in response to
  an immune stimulus.
• Cytokine is the general term for a large group
  of molecules involved in signaling between cells
  during immune responses. All cytokines are
  proteins, some with sugar molecules attached
  (glycoproteines).
• They are synthesized and released by white
  blood cells and tissue macrophages.

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• They are proteins, peptides or glycoproteins in
  nature.
• Cytokines stimulate or suppress the functional
  activity of lymphocytes, monocytes,
  neutrophils, fibroblast and endothelial cells.
• They modulate the function of other cell types.
  Long known to be involved in cellular immune
  response, these products have additional effects
  that play important roles in both acute and
  chronic inflammation.
• 200 different human cytokines was have been
  identified

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• TERMS AND DEFINITIONS
• Cytokines generated by mononuclear phagocytes are
  often called Monokines and those by activated
  lymphocytes are reffered to as Lymphokines.
• Additionally, both monocytes and macrophages
  produce cytokines such as CSFs, which stimulate
  the growth of immature leukocytes in the bone
  marrow.

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• GENERAL PROPERTIES
• Cytokines are produced during immune and
  inflammatory responses and secretion of these
  mediators is transient and closely regulated.
• Cytokine effects are often redundant and these
  proteins can influence the synthesis or action of
  other cytokines.
• Cytokines mediate their effects by binding to
  specific receptors on target cells and the
  expression of cytokine receptors can be regulated
  by a variety of exogenous and endogenous signals.

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• Cytokines induce their effects in two ways
• 1) they act on the same cell that produces them
  (autocrine effect)
• e.g IL-2 produced by activated T cells
  promotes T- cell growth
• 2) they affect other cells in their vicinity
  (paracrine effect)
• e.g IL-7 produced by marrow stromal cells
  promotes the differentiation of B- cell
  progenitors in the marrow
• Many classic growth factors act as cytokines and
  conversely many cytokines have growth promoting
  properties.

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• The main sets of cytokines are
• Interleukins
• Interferons
• Tumour necrosis factors
• Growth factors
• Colony stimulating factors
• Chemokines

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INTERFERONS (IFNs)

• Interferons (IFNs) are proteins made and released
  by helper CD4 T lymphocytes, as well as through
  monocytes, macrophages, and endothelial cells in
  response to the presence of pathogens such as
  viruses, bacteria or parasites or tumor cells.
• IFNs belong to the large class of glycoproteins
  known as cytokines. Although they are named after
  their ability to "interfere" with viral
  replication within host cells

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• They are produced very early in infection and are
  the first line of resistance to a great many
  viruses
• These are particularly important in limiting the
  spread of certain viral infections. One group of
  interferons (IFNa and IFNß) is produced by cells
  which have become virally infected

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• Types of interferon
• Based on the type of receptor human interferons
  have been classified into two major types.
• Interferon type I
• All type I IFNs bind to a specific cell surface
  receptor complex known as the IFN-a receptor. The
  type I interferons present in humans are IFN-a,
  IFN-ß and IFN-?.
• Interferon type II
• In humans this is IFN-?

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• FUNCTIONS
• they activate immune cells, such as natural
  killer cells and macrophages
• they increase recognition of infection or tumor
  cells by up-regulating antigen presentation to T
  lymphocytes and
• they increase the ability of uninfected host
  cells to resist new infection by virus. Certain
  host symptoms, such as aching muscles and fever,
  are related to the production of IFNs during
  infection.

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INTERLEUKINS (ILs)

• These are a large group of cytokines produced
  mainly by T cells, although some are also
  produced by mononuclear phagocytes (or) by tissue
  cells.
• The interleukins were first described as signals
  for communication between white blood cells
  (leuk- from leukocytes).
• Currently, it is well-known that these molecules
  are produced and used as signalling molecules in
  many cells of the body, in addition to immune
  cells.

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• They have a variety of functions, but most of
  them are involved in directing there cells to
  divide and differentiate
• Interleukins represent a broad family of
  cytokines that are made by hematopoietic cells
  and act primarily on leukocytes
• There are currently 35 well-known interleukins,
  however, there are many more to be found and
  characterized.

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TUMOUR NECROSIS FACTORS (TNF)

• Tumor necrosis factors (or the TNF-family) refers
  to a
• group of cytokines family that can cause cell
  death.
• TNF acts via the TNF Receptor (TNF-R) and is part
  of the extrinsic pathway for triggering
  apoptosis.
• TNF interacts with tumor cells to trigger
  cytolysis or cell death.

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• Types
• Tumor necrosis factor-alpha (TNF-a) is the most
  well-known member of this class, and sometimes
  referred to when the term "tumor necrosis factor"
  is used.
• Tumor necrosis factor-beta (TNF-ß), also known as
  lymphotoxin is a cytokine that is induced by
  interleukin 10

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COLONY STIMULATING FACTORS
(CSFs)

• Colony-stimulating factors (CSFs) are secreted
  glycoproteins which bind to receptor proteins on
  the surfaces of hemopoietic stem cells and
  thereby activate intracellular signaling pathways
  which can cause the cells to proliferate and
  differentiate into a specific kind of blood cell
• These are primarily involved in directing the
  division and differentiation of bone marrow stem
  cells, and the precursors of blood leucocytes

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• TYPES
• CSF1 - macrophage colony-stimulating factor
• CSF2 - Granulocyte macrophage colony-stimulating
  factors (also called GM-CSF and sargramostim)
• CSF3 - Granulocyte colony-stimulating factors
  (also called G-CSF and filgrastim)

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GROWTH FACTROS (GF)

• A growth factor is a naturally occurring
  substance capable of stimulating cellular growth,
  proliferation and cellular differentiation.
• Growth factors typically act as signaling
  molecules between cells and they are important
  for regulating a variety of cellular processes.
• e.g
• Epidermal growth factor (EGF)
• Fibroblast growth factor (FGF)
• Granulocyte-colony stimulating factor (G-CSF)
• Nerve growth factor (NGF)

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• CHEMOKINES
• This large group of chemotactic cytokines direct
  movement of cells around the body, from the blood
  stream into tissues and to the appropriate
  location within each tissue.
• Some of the chemokines also activate cells to
  carry out particular functions.
• Chemokines are cytokines that share the ability
  to stimulate leukocyte movement (chemokinesis)
  and directed movement (chemotaxis) and are
  particularly important in inflammation.

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CYTOKINE RECEPTORS

• Cytokine receptors fall into four families
• 1) Type I receptors
• 2) Type II receptors
• 3) Type III receptors
• 4) Type IV receptors

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• TYPE I RECEPTORS
• The largest family of cytokine receptors is Type
  I receptor superfamily. It is characterized by
  an extracellular region of structural homology
  approximately 200 amino acids long.
• Receptors for cytokines such as IL-2, IL-3, IL-4,
  IL-5, IL-6, IL-7, IL-9, IL-12, G-CSF and GM-CSF
  belong to this family.

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• TYPE II RECEPTORS
• The Type II family of related cytokine receptors
  can be considered part of the immunoglobulin
  superfamily and contains receptors for all IFN
  types as well as IL-10 and M-CSF
• TYPE III RECEPTORS
• TNF family cytokines bind to Type III cytokine
  receptors which all have multiple cysteine-rich
  repeats of about 40 amino acids in the
  extracellular domain.

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• TYPE IV
• Receptors for IL-1a and ß are representative of
  the Type IV cytokine receptor family.
• Regardless of these subtypes, cytokine
  receptors have several common characteristics.
  They usually consist of two or more subunits, and
  receptors for different cytokines may even share
  common subunits.

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MECHANISMS OF CELL ACTIVATION

• The binding of a cytokine to its appropriate
  receptor sets off a cascade that leads to
  induction or inhibition of transcription of a
  number of cytokine regulated genes.
• This occurs via a chain of protein-protein
  recognition events leading to binding of diverse
  trancription factors to DNA .
• Cytokines initiate intracellular signals through
  ligand-induced aggregation of receptor
  components.
• Cytokine binding can cause hetero or
  homo-dimerization of receptors or trimerization
  depend on particular family.

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Rheumatoid Arthritis

• RA is a chronic systemic inflammatory disorder
  that may affect many tissues and organs but
  principally attacks the joints.
• An auto immune reaction in which T cells play the
  pivotal role is widely held to be responsible for
  the chronic destructive nature of RA.
• Once an inflammatory synovitis has been initiated
  by an exogenous agent.

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• T- cells, mainly CD4 memory cells appear within
  the affected joints early early in the
  development of RA
• Soon the endothelial cells of synovial
  capillaries are activated with the expression of
  ICAM-1
• Leading to further attachment and transmigration
  of other inflammatory cells
• This sequence is further enhanced by release of
  IL-1, TNF-a and IFN-?
• Activated CD4 cells simultaneously activate
  monocytes, macrophages and promote the release of
  monokines and activated B cells with antibody
  production in affected joints

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• TNF- a and have induces resorption of cartilage
  and bone bystimulating release of collagenases
  from synovial cells.
• Up regulates expression of adhesion molecules
  (ICAM-1) which inhibits synthesis of
  proteoglycans in cartilage
• Stimulates fibroblasts via platelet derived
  growth factor.

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MULTIPLE MYELOMA

• Multiple myeloma is a plasma cell cancer that
  originates
• in the bone marrow and is characterized by
  involvement of
• the skeleton at multiple sites.
• The proliferation and differentiation of myeloma
  cells seem to be dependent on several cytokines
  most notably IL-6
• Serum levels of this cytokine are increased in
  patients with active disease.

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• IL-6 seems to be produced by tumorous plasma
  cells themselves as well as by fibroblasts and
  macrophages in the surrounding stroma.
• In addition to causing the growth of myeloma
  cells, cytokines also mediate bone destruction by
  acting as osteoclast activating factors.
• (TNF-ß, IL-1, IL-6 and M-CSF)

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CYTOKINE THERAPY
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• Non specific stimulation or inhibition of
  particular
• components of the immune system may sometimes
  be of
• benefit.
• The best results have been obtained with
  cytokines and among these interferon-a (IFN- a)
  is the most widely used mainly for its antiviral
  properties.
• The most striking clinical effect of a cytokine
  has been that of G-CSF in restoring bone marrow
  function after anti cancer therapy.

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• Interferon beta-1a and interferon beta-1b are
  used to treat and control multiple sclerosis, an
  autoimmune disorder.
• Interferon therapy is used (in combination with
  chemotherapy and radiation) as a treatment for
  many cancers. This treatment is most effective
  for treating hematological malignancy leukemia
  and lymphomas including hairy cell leukemia,
  chronic myeloid leukemia, nodular lymphoma,
  cutaneous T-cell lymphoma.
• Both hepatitis B and hepatitis C are treated with
  IFN-a, often in combination with other antiviral
  drugs

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• Administered intranasally in very low doses,
  interferon is extensively used in Eastern Europe
  and Russia as a method to prevent and treat viral
  respiratory diseases such as cold and flu.
• IFN therapy causes immunosuppression, in
  particular through neutropenia and can result in
  some infections manifesting in unusual ways.
• The discovery that the ß chemokines RANTES, MIP
  (macrophage inflammatory proteins) suppress
  HIV-1.

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CYTOKINE INHIBITORS

• Cytokine inhibitors can be used for severe or
  chronic inflammatory conditions.
• Various ways of inhibiting TNF and IL-1 have
  proved valuable in rheumatoid arthritis and more
  controversially in septic shock and severe
  malaria.
• e.g
• Cyclosporin A Pentamidine.

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