What are cytokines? What cells produce cytokines?
What signals cytokinen production?
Cytokines are soluble factors produced by different immune cell types that mediate immune responses. They are principal mediators of communication between cells of the immune response. Cytokines interact with specific receptors that lead to responses by the receiving cells.
As mentioned in the innate immunity lecture notes interaction of PAMPS to PRRS on macrophages lead to signal transduction, which ultimately leads to expression of cytokine genes. This is true of any innate cell type with a PRR, which is associated with
signal transduction (e.g., Toll-like receptors on dendritic cells or mast cells). Cytokine expression also occurs when antigen engages antigen specific receptors on T and B lymphocytes.
What is the response of IL-2 acting through autocrine signaling on T-cells? Explain the difference in response when IL-2 binds to receptors on naive T-cells vs activated T-cells.
Naive T-cells possess low affinity IL-2 receptors with only beta and gamma chains. Activated T-cells express high affininity IL-2 receptors with alpha, beta, and gamma chains. Activated T-cells release IL-2 which in turn binds to IL-2 receptors on the same cells and induces T-cell proliferation.
What are the effects of paracrine signaling of IFN-γ binding to receptors on macrophages? What cells release this cytokine?
TH1 cells release IFN-γ which binds to IFN-γ receptors on macrophages. This stimulates the degradation of intravesicular bacteria within the macrophage.
attached is slide 11 of PP
Explain the effects of mutual activation between NK cells and macrophages.
What cytokines are released from each cell?
IL-12 binds to receptor on NK cells and signals for them to make IFN gamma which binds to IFN gamma receptors on macrophages. This sends a strong signal to the macrophage to degrade mycobacteria--> need strong signals to kill mycobacteria.
Via what mechanism (autocrine, paracrine, endocrine) do IL-1, IL-6, and TNF-α signal?
What are their effects?
IL-1, IL-6, and TNF-α act through endocrine signaling
attached is slide 14 of pp
What acute phase proteins does IL-6 induce synthesis of? Where in the body are these proteins synthesized? What are the effects of these proteins?
What secretes IL-6?
One of the key effects of endocrine effects of cytokines is the effect of IL-6 on the liver. IL-6 induces hepatocytes to synthesize Acute-phase Proteins. Acute phase proteins consist of 1) fibrinogen (forms clots at site of inflammation to contain the pathogen) and 2) mannose binding lectin which activates complement (more to come in the Complement lecture coming up in this block) and induces phagocytosis of bacteria by acting as an opsonin.
One important protein made by hepatocytes exposed to IL-6 is (3) C-reactive protein which interacts with phosphocholine on dead and dying cells and some bacteria. C-reactive proteins act as a opsonin and as an activator of complement.
IL-6 is secreted by macrophages.
What cell type mostly secretes interleukins?
Give examples of the effects of tumor necrosis factor (TNF) cytokines.
What are the effects of interferons?
What kind of molecule are colony stimulating factors (CSFs)? What are their functions?
What cells secrete transforming growth factor beta (TGF-β)? What are their effects?
Interleukin (IL) are a group of cytokines (secreted proteins and signaling molecules) that initially observed to be expressed by white blood cells (leukocytes) Latin inter ‘between, among. Are expressed by other cells as well but mainly by leukocytes. Note that they can also act in an autocrine fashion
Tumor necrosis factors (TNF) refer to a group of cytokines that can cause cell death of some tumor cell lines upon interaction with its receptors. They are known to have a wide variety of biological effects in inflammatory responses. These include but not limited
to activation of endothelial cells, increases vascular permeability and induces fever.
Interferons are initially named for their ability to "interfere" with virus replication. They
are now know to have a wide variety of biological effects on the immune system
Colony-stimulating factors (CSFs) are secreted glycoproteins that bind to receptor proteins on the surfaces of hematopoietic stem cells, thereby activating intracellular signaling pathways that can cause the cells to proliferate and differentiate into specific kind of blood cells. They also induce macrophages and DCs to secrete cytokines
Transforming growth factor beta (TGF-β) is a secreted protein that controls proliferation, cellular differentiation, and other functions in most cells. It has a negative
impact on immune responses and is produced by a group of T-cells known as T-regulatory
State what cells produce the following cytokines and the activity of the cytokines:
IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α
attached is slide 18 of course notes
What is chromosome are the genes for Type 1 interferons (IFN-α and β) located? Type II interferons (IFN-γ)?
What prouduces each of these interferons?
What induces production of these interferons?
What are the functions of Type I and Type II interferons?
attached is slide 20 of PP
State what cells produce and the functions of the following cytokines:
attached is slide 19 of PP
Most interleukin receptors have how many separate proteins combining to form one receptor?
What is the common protein present in 6 different interleukin receptors?
Receptors typically have two to three separate proteins making up the receptors (combinations of α, β, γ). In some instances specific chains are shared among many receptors. One of the most common is a gamma chain shared with six different interleukin receptors.
What are the most common signaling molecules/pathway associated with cytokine receptors?
Following receptor engagement, downstream signaling molecules are activated. The most common signaling molecules associated with cytokine receptors are the Janus Kinase (JAK)/ Signal Transducer and Activator of Transcription (STAT) molecules.
Explain how the JAK/STAT pathway is activated and what the downstream affects are.
- JAK is associated with the cytoplasmic tails of the receptor chains and only become activated when cytokine brings together at least two of the receptorchains.
- JAK activates one another and leads to the phosphorylation of tyrosine residues (autophosphorylation) within the JAK molecules.
- The phosphorylated residues recruit STAT molecules.
- JAK activates the STAT molecules by phosphorylating them.
- The phosphorylated STAT molecules interact with one another (form a dimer) and are now able to enter the nucleus where they interact with specific promoter sites within genes.
- Activated STAT begins to initiate transcription of specific genes within the cell (more cytokines, for example)
attached is slide 22 of PP
What may cause severe combined immunodeficiency (SCID)?
What immune cells are affected by SCID?
What is the prognosis of SCID? How is it treated?
Cytokine receptors are extremely important in development, differentiation and function of lymphocytes. Without the common gamma chain of interleukin receptors cells of the adaptive and innate immune response do not develop or function properly.
One of the causes of severe combined immunodeficiency syndrome (SCID) is lack of common gamma chain (will also be in Primary Immunodeficiencies Lecture). This primary immunodeficiency is congenital.
- The lack of the common gamma chain leads to the inability to develop T-cells and NK cells.
- B-cell responses are also severally compromised (see lecture notes on AntibodySynthesis).
- Children with this congenital defect obtain severe infections from pathogenic microbes and have a very short life expectancy if not given a bone marrow transplant.
- Another cause of SCID is lack of the IL-7 receptor, which is critical in the development of T-cells.
What intracelluar signaling pathway do interferons activate when binding to their receptors? How is it different for Type I vs Type II interferons?
Interferon receptors are similar to the interleukin receptors in that they utilize a JAK/STAT pathway to induce transcription of genes with cells expressing interferon receptors.
Type I: Inteferon response factor 9 binds to the STAT dimer. This transcription factor binds ISRE (interferon response element)
Type II: STAT dimer binds to GAS on the DNA
see slide 25 of PP
Type I interferons are critical for expression of genes involved in antiviral response. These antiviral responses are so inhibitory to virus’ ability to propagate, that
the viruses have evolved counter measure to knock out interferon responses.
What are chemokines?
What kind of receptors do chemokines possess? What follows after activation of chemokine receptors?
Chemokines are cytokines, which are utilized to bring immune cells to sites of infection/inflammation. The receptors that are engaged by chemokines are typically
tetra-spanning receptors that associate with membrane associated G-proteins. The binding of chemokines activates the G-proteins so that it acts as a signal-transducing molecule that induces gene expression leading to increased migration of cell to sites of
What are the pro-inflammatory cytokines? What cells secrete them?
What are their actions?
• IL-1β and TNF-α
– Neutrophil activation
– Endothelial cell activation-expression of ICAM-1 to increase diapedesis
– Acute phase proteins, acts at thalamus to increase body temp, protein and energy mobilization to generate increased body temp, neutrophil mobilization
– Neutrophil recruitment
– NK cell activation-induces IFN-γ and TNFα production
Activation of what receptors by what molecules leads to production of prostaglandins and leukotrienes?
Explain what enzymes are needed to generate prostaglandins and leukotrienes. What is the precursor to these molecules? How is it generated?
In addition to cytokine secretion engagement of PRRs by PAMPs leads to is the production of
inflammatory lipid products. This includes Prostaglandins and Leukotrienes. Both lipid
products are a direct result of Phospholipase A2 (PLA2) when PRRs are triggered. PLA2 cleaves plasma membrane lipids into Arachadonic acid (AA). AA is further processed by cyclooxyegenases (COX-1, COX-2) to form prostaglandins (PG) or Lipoxygenase to form
Name the specific molecules generated from COX-1 and COX-2 action on arachidonic acid.
Prostaglandins: PGE2, PGD2
Name the specific molecules generated from lipoxygenase action on arachidonic acid. Name what molecules are further derived from this product and the enzymes involved.
attached is slide 33 of PP
Name the prostaglandins and leukotrienes that cause the following effects:
vasodilation/increased capillary permeability
Note that lipid mediators are not as stable as cytokines and tend to have more local effects (exception is PGE2 which induces fever).