Term
| general function of a cytokine |
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Definition
| they are small proteins or glycoproteins that bind specific receptors on target cells. THe receptors trigger the cells to increase proliferation and to increase survival, by preventing programmed cell death (apoptosis) or in some cases, they influence production of daughter cells of a particular lineage |
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Term
| what manners can cytokines act in? |
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Definition
autocrine, paracrine, and endocrine manners.
they can be soluble in blood, bound to ECM, and expressed on surface of bone marrow stromal cells |
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Term
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Definition
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Term
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Definition
| stimulating a nearby cell |
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Term
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Definition
| acting throughout the body |
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Term
| cytokines have been called what other names? (4) |
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Definition
1) growth factors (bc they make cells grow)
2) interleukins (bc they were orignially thought to provide communication between leukocytes but now we know they also talk to non-leukocyte cells)
3) colony stimulating factors (stimulate colony growth in the lab)
4) chemokines (ones that induce cell migration) |
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Term
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Definition
| -produced by interstitial kidney cells (sense oxygen levels in blood)which use transcription factor hypoxia inducible factor (HIF) to regulate this protein's production. |
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Term
| when oxygen levels are _________ HIF acts on EPO promotor to increase EPO production |
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Definition
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Term
| when oxygen levels are ______ HIF is degraded and EPO production is reduced |
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Definition
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Term
| hypoxia can be caused by: |
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Definition
-low hematocrit
-lung disease
-travel to high altitudes |
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Term
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Definition
| this protein acts on RBC precursors to increase their proliferation and decrease their death resulting in an increase in RBC. This takes several days, so if you need to raise your hematocrit rapidly, EPO is not a good way to do it (you need a blood transfusion instead). Production of new RBCs also requires nucleotides for DNA synthesis and iron. |
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Term
| If you need to raise the hematocrit levels quickly in blood, is EPO a good way to do that? |
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Definition
| NO, if you increase EPO levels, it will still take several days to leave an effect; therefore you are better off just giving a blood transfusion for fast way to raise hematocrit. |
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Term
| what happens to animals lacking the gene for EPO or its receptor? |
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Definition
| they die from severe anemia. |
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Term
| why can patients with kidney disease be anemic? |
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Definition
this is because they would have inadequate EPO production because kidney cells would be damaged.
in this case, treatment with EPO can improve their hematocrit |
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Term
| patients receiving chemotherapy that impoars RBC production can be anemic and respond well to ______ treatment |
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Definition
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Term
| There are also _______ receptors on nerve cells |
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Definition
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Term
| Is EPO considered a wonder drug??? |
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Definition
| For a while, it was. Even athletes used it to blood dope illegally to increase their hematocrit levels. However, EPO can cause death from high blood pressure and it sometimes worsens progression of cancer in some cancer patients. Now patients use it sparingly at low doses only if necessary. |
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Term
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Definition
| a cytokine that stimulates platelet (thrombocyte) precursors, the megakaryocytes. It binds the c-MPL tyrosine kinase receptor on target cells nad is produced mainly by liver (and sometimes kidney and muscles). It is taken up by PLTs and destroyed, so levels and effect depend on PLT count. |
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Term
| how is TPO level affected by high PLT count? |
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Definition
| TPO is then taken up by platelets and removed from circulation, so there is less effect. |
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Term
| What other thing does TPO stimulate besides PLT precursors? |
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Definition
| Stem cells (in combination with other cytokines) |
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Term
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Definition
| No. A few patients exposed to it when injected developed auto-antibodies to it, making them become severely thrombocytopenic. However, TPO receptor agonists (peptide and non-peptide) have been developed/approved and are helpful in cancer patients who have gotten chemotherapy or stem cell transplant, patients with autoimmune PLT destruction and hepatitis C |
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Term
| if the liver is being destroyed by hepatitis C, what happens to the levels of TPO in body? |
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Definition
| they decrease bc the liver is being destroyed and that is what makes TPO |
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Term
| GM-CSF (granulocyte-macrophage colony stimulating factor) |
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Definition
| stimulates production of neutrophils, eosinophils, and monocytes (macrophages are tissue monocytes) in combination with other cytokines. |
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Term
| G-CSF (granulocyte colony stimulating factor) |
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Definition
| stimulates neutrophil production and function. |
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Term
| how are G-CSF and GM-CSF similar? |
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Definition
| They are both made by a variety of cells (stromal cells, endothelial cells, and others), they are used to increase granulocyte counts following chemotherapy, and for congenital disorders of decreased granulocyte number and function. They are also used to mobilize stem cells from the bone marrow for stem cell donation. |
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Term
| what are all the different names for stem cell factor? |
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Definition
-Steel factor
-c-kit ligand
-mast cell growth factor |
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Term
| what are many things that stem cell factor (SCF) does? |
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Definition
| it is a ligand for c-kit receptor, a tyrosine kinase receptor, is also a mast cell growth factor, affects melanin production and gametogenesis. it is also produced by bone marrow stromal cells and expressed on surface of these cells (stimulating stem cells that are already in bone marrow, and perhaps helping them stay there) in soluble form. |
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Term
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Definition
involved in
-inflammation
-infection
-tumorigenesis
-hematopoiesis
many are involved in cross-talk, cancer, infection
these are secreted proteins that have sugar group that increases their half life, typically small and can circulate in blood stream or locally in microenvironment, acting to stimulate cell that produces the,, close by, or right next to them (autocrine, paracrine, or endocrine) |
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Term
| official definition of cytokines |
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Definition
1) signaling proteins (or glycoproteins) secreted by various cells
2) typically small, low molecular weight. sugar helps stabilize them (increase their half life)
3) they can act in autocrine, paracrine, or endocrine manner
they have various effects, depending on target cell (increase proliferation, decrease cell death/apoptosis, or affect cell lineage decisions)
5) their effects can be additive, synergistic or antagonistic
6) they comminucate with target cells by binding specific receptors
7) unlike hormones, they are potent at extremely low concentrations
8) unline hormones, they are made by many cell types |
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Term
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Definition
| cell secretes a cytokine that stimulates itself |
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Term
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Definition
| cell secretes a cytokine that stimulates a cell nearby |
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Term
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Definition
| a cell secretes a cytokine that stimulates another cell elsewhere in the body |
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Term
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Definition
they communicate with target cells by binding specific receptors
-200 to 500 receptors/cell
-activate signaling cascades (Janus kinases) |
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Term
| since cytokines are potent at extrememly low concentration, what is the average concentration of them in the blood? |
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Definition
less than 1ng/ml
circulating levels are almost undetectable |
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Term
| Hypoxia inducible factor (HIF) |
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Definition
| when there are low oxygen levels in the body, this binds to promotor region of mRNA of EPO gene and induces transcription of more EPO |
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Term
| when there are high oxygen levels in the blood, this DOES NOT bind to EPO mRNA, thus EPO is not made |
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Definition
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Term
| is just having EPO enough to make more RBC's? |
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Definition
| no, in addition to EPO, you also need enough iron, proteins, etc to make more RBC's |
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Term
| What factors do you need in order to make more RBC's? |
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Definition
| you need EPO, pro-growth factors, anti-death factors to stimulate CFU-E and then you also need iron |
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Term
| Can you ingest EPO orally in order to get more? |
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Definition
| no, because since it is a cytokine/protein, if you ingest it orally then enzymes in your saliva in the mouth will degrade it and it will not be absorbed |
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Term
| what are the 2 main things that TPO stimulates? |
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Definition
| hematopoeitic stem cells and formation of megakaryocytes to eventually make platelets |
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Term
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Definition
| Platelets take up TPO via these receptors and remove if from the circulation |
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Term
| where is G-CSF made? and what does it do? |
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Definition
this is made by fibroblasts, endothelial cells, macrophages (in all organs)
-it increases neutrophil numbers and function |
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Term
| Where is GM-CSF made? and what does it do? |
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Definition
this is made by t cells, endothelial cells, and stromal cells
-this increases neutrophil, eosinophil, and monocyte/macrophage numbers and function
-works by priming-making cells more senesitive to other growth factors |
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Term
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Definition
| making cells more sensitive to other growth factors |
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Term
| Stem cell factor is also known by what other names |
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Definition
-c-kit ligand (binds c-kit receptor)
-mast cell growth factor (stimulates growth of mast cells)
-steel factor (steel locus-affects pigmentation/melanogenesis) and also affects gametogenesis |
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Term
| walk through the stem cell factor process |
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Definition
first the c-kit ligand binds to c-kit receptor and then is able to enter through the bone to signal the fibroblasts to increase in number
stem cell factor (c-kit ligand) is soluble and membrane bound forms exist
-synergizes with other cytokines
-also affects mast cell development, gametogenesis, melanogenesis |
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Term
| where is stem cell factor located? |
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Definition
| it can either be on the surface of the bone or secreted (soluble) an can be on the matrix |
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Term
case 1
Kidney failure whould be most likely to cause reduction of which cytokine and while cell type? |
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Definition
EPO
-you can correct this by giving patient exogenous source of EPO carefully |
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Term
case 2 T or F:
A patient with bleeding from aspirin use should be treated with TPO |
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Definition
False
Aspiring impairs platelet function, TPO woul not help this patient bc TPO increases PLT number, but not their function. |
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Term
case 3 A 49 yr old man received chemotherapy for lymphoma and became neutropenic. You should
A) measure G-CSF level
B) Measure TPO level
C) Measure stem cell factor (c-kit ligand level)
D) None of the above |
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Definition
D) non of the above
this is because you cannot measure levels of cytokines (bc their levels are so low in the blood) and if we were to measure the level of cytokines, thats not really the problem, the problem is that we are killing neutrophil cells due to chemotherapy
you could give them more G-CSF though so they can make their own neutrophils again |
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Term
case 4 T or F
The congenital syndrome cyclic neutropenia could be treated with G-CSF |
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Definition
True!
Cyclic neutropenia- neutrophil count can drop really low, thus if you give them G-CSF then this can stimulate neutrophil production |
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Term
case 5
You are a HLA match with your sibling and want to donate HSCs. How would you prefer to have them harvested?
A) Bone marrow aspiration
B) Peripheral blood leukapheresis
C) Peripheral blood leukapheresis with G-CSF priming |
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Definition
C) Peripheral blood leukapheresis with G-CSF priming
if your donor and recipient share antigens then the body will less likely to thing the marrow is foreign. you can get them from peripheral blood, but you can't JUST do this because they aren;t locked in their home, so you need G-CSF priming to lock them in place
also bone marrow aspiration can collect marrow but not enough for a transplant/donation |
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