Cytokines I Flashcards
Exam 2
What is the definition of a cytokine?
Cytokines are small proteins (50 to 180 residues) crucial for controlling growth and activity of immune-system cells and blood cells to execute inflammation responses. Over 100 human genes encode cytokines.
Cytokines have major biological roles in immunity, regulating inflammation and hematopoiesis (formation of blood cells)
* Immune cell proliferation and differentiation; pro-inflammatory and anti-inflammatory
* Cell migration
* Chemoattractant/chemotaxis
* Cell-cell communication during an immune response
* Cytotoxicity
* Cytokines affect nearly every biological process (embryonic development, disease pathogenesis, immunity, cognitive function, degeneration in aging)
Cytokines have been developed into protein therapeutics.
* Interferon alpha- multiple sclerosis, hepatitis C
* Interleukin 2- cancer
* Erythropoietin- anemia
What cellular effects result from the production of cytokines?
- Pleiotropic: same cytokine can have different target cells and receptors, with different biological outcomes (IL-4 binds B cells, mast cells)
- Similarly, different cytokines produce similar effects, i.e. they are redundant. IL-2, IL-4, and IL-5 are released by activated effector T cells and all stimulate B cells to proliferate.
- Cascade effect: cytokines can stimulate the production of other cytokines
What about the selectivity between cytokines and cytokine receptors in unusual?
Characteristics of cytokine activity demonstrate that the selectivity between cytokines and cytokine receptors is unusual. These include the redundancy of cytokines, the pleiotropic nature of cytokines, the interplay of cellular effects of cytokines, and the recognition of multiple cytokines by single receptors.
What are the several types of cytokines, and their general structure and function?
Cytokine types
* No unified cytokine classification into types, they are grouped in different ways. Original nomenclature is based on function, cell secretion or target of action. More recent classification considers structure similarity. Some functional types are listed here with examples in parenthesis.
* Interleukin: originally “inter” “leukocyte” but now other cell types known (IL-1, 1Ra, 18, 33, IL-17)
* Colony-stimulating factor (CSF): hematopoietic stem cell signaling to develop into specific blood cell types (IL-2 thru 7, 12, 13, 15, 21, 23, GM-CSF, G-CSF)
* Chemokines: direct immune cells to places in the body (CCL19, RANTES)
* Tumor necrosis factor: regulate inflammation (TNF-alpha)
* Interferons: signals defense against viruses (IFN-alpha, IL-10, 19, 20)
Detailed Response:
- Interleukins- secreted by one leukocyte and acting on other leukocytes in an inflammatory response (inter=between blood cells), regulate growth/differentiation of hematopoietic cells, some have 4-helix bundle structure
- Chemokines- chemotactic activity as in cell migration, cell migration during development, immune response, inflammation, and cancer, some interleukins are chemokines (CXCL8 produced by macrophages or IL-8), have less than 100 residues, can be monomeric or homodimeric, chemokine receptors are GPCRs.
- Tumor Necrosis Factor (TNF-alpha): released by macrophages during acute inflammation upon infection, leading to necrosis and apoptosis, exists as a transmembrane form, mTNF-alpha, and a soluble form, sTNF-alpha, that results from enzymatic cleavage, mTNF-alpha is on moncytes and macrophages, and binds to TWO TNF receptors on tissue cells (juxtacrine) sTNF-alpha binds selectively to one TNF receptor, ribbon structure ~17 kDa monomer forms beta-pleated sandwich, and associates to form a bell-shaped trimer.
- Interferons (IFN-alpha)- regulate signaling among cells infected with viruses or bacterial pathogens, so they “interfere” with viral replication. Also, in regulation of immune response. They activate immune cells such as macrophages and NK cells; upregulate antigen presentation; underlie feelings like fever; muscle pain; flu-like symptoms. There are 3 types, I, II, III, based on receptors they bind. E.g. type I IFNs bind to IFN-alpha receptor (IFNAR)- overall helical in structure.
Study images on your own time
What are the several types of cytokine receptors and their general structure?
Cytokine receptor types: based on common structural features are…
* Ig superfamily
* interferon receptors
* TNF receptors
* chemokine receptors
* TGF receptor
* hematopoietin receptors
Detailed Response:
Immunoglobulin family (Ig)
* ubiquitously present throughout several cells and tissues of the vertebrate body
* have the Ig domain of immunoglobulins
* Ex. IL-1 and IL-18
Hemopoetic Growth Factor (type 1) family
* certain conserved motifs in their extracellular domain.
* Ex. IL-2 receptor for which deficiency is directly responsible for the disease Severe Combined Immunodeficiency (X-SCID).
* Ex. IL-6 receptor
Interferon (type 2 family
* members are receptors for IFN Beta and Gamma
Tumor necrosis factors (TNF) family
* members share a cysteine-rich extracellular binding domain
* In addition to TNF cytokines, binds several other non-cytokine ligands like CD40, CD27, and CD30.
G protein-coupled receptors
* Bind chemokines
Interleukin-17 receptor family:
* little structural similarity with any other cytokine receptor family
* members are IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE
* IL-17 cytokines induce proinflammatory responses and allergic responses and are being investigated for treating rheumatoid arthritis, psoriasis and inflammatory bowel disease
* Signaling pathways from these receptors are not well defined
Note: Certain cytokine receptors show cross-reactivity with multiple different cytokines. To illustrate, the figure shows 3 receptors from the class I cytokine receptor family (gamma chain, gp140, and Beta chain), each with multiple cytokine ligands.
There are a wide variety of receptors, some with multiple chains. Receptors are actived by cytokine binding. Becoming popular with research, especially chemokines.
How are chemokines recognized by their GPCR receptors?
- Chemokines are the subset of cytokines that *direct migration of leukocytes to regions of infected tissue. *
- Human chemokine family= 46 proteins
- Chemokines act as chemoattractant to guide cell migration for various functions
- Immune surveillance (constitutively expressed)
- To promote angiogenesis and tissue differentiation during development
- Proinflammatory (release is stimulated by other cytokines)
Chemokine/chemokine receptor structure: vMIP-II/CXCR4
* Chemokine ribbon/receptor cutaway surface
* Chemokine receptor is solid surface/receptor ribbon
* cMIP is a viral chemokine antagonist from herpesvirus, though to bind like the endogenous chemokine CXCL12
* Complex has extensive binding surface comprising GPCR external loops and extending into transmembrane helical region .
How are cytokines related to immunology?
- First messengers produced and released from various (sender) cells throughout the body: macrophage, B cells, effector T cells, mast cells, endothelial, fibroblasts, and others
- Target cells: macrophages, B cells, effector T cells, tumor cells, plasma cells
- Cell-cell communications can be autocrine (same), paracrine (nearby) or endocrine (distant) signaling.
- Too many cytokines leads to cytokine storms, which damage tissues and can be life threatening.
What are diseases involving cytokines?
- Autoimmune diseases
- Metabolic disorders
- Cancer
- Sepsis
Describe the cytokine network example.
The network of cytokine targeted immune cells demonstrates the pleiotropic nature and cascade effect of cytokine signaling.
* Certain cytokines like IL-1 stimulate many cell types (pleiotropic)
* Some cytokines trigger expression of other cytokines (cascade effect)
* Some, including IL-1, INFs and TNFalpha, stimulate a broad inflammatory response in response to infection or injury.
How do cytokine receptors differ intracellularly and extracellularly?
Extracellular Domains
- Type I cytokine receptors
- Figure of extracellular domains:
- Receptor–> 2 chains, IFNAR1 and IFNAR2
- In complex with cytokine, IFNalpha
- Multiple interactions of different protein chains may be the cause for cross-reactivity.
Intracellular Domains
- Intracellular domains (ICD) of type I cytokine receptors are remarkably atypical
- Long disordered region: large number of residues (up to 600) without apparent structural order and no kinase activity
- Yet, complex intracellular signals are transduced via these ICDs, presumably by binding effector proteins (gray)
