Cytokines of innate immunity (Heck) Flashcards
Examples of Type I Cytokine Receptors
Hematopoietin R
Jak-STAT
Type II Cytokine R
Jak-STAT
IL-1 Family R types
TLR, receptor for IL-1 and IL-18
What are the cytokine R
Type I, Type II, IL-1 Family, TNF, and GPCRs
Categories of cytokines
Mediators and regulators of innate immunity, mediators and regulators of adaptive immunity, mediators of hematopoiesis
The role of TNFa in the acute inflammatory response to gram negative bacteria
Stimulates recruitment of neutrophils and monocytes to infection site and activates them by:
Induces vascular cells to express selectin,
induces vascular cells and macrophages to secrete chemokines,
stimulates mononuclear phagocytes to produce IL-1
stimulates microbicidal action of neutrophils and macrophages
What are the systemic effects caused by moderate quantities of TNF
fever, secretion of acute phase proteins and the production of leukocytes
What are the systemic effects caused by too much TNFa
Septic Shock, thrombus formation, hypoglycemia
What does IL-6 initiate the production of, and from where
hepatocytes start to sythesize serum amyloid protein, C reactive protein, fibrinogen, mannose binding lectin and SP-A and SP-D
which proteins act as an opsonin and activate complement
C reactive protein when binds to phophorylcholine and Mannan-binding lectin when it binds to mannose residues on bacterial surfaces
what 2 processes work in adjunct to cause decreased viral and bacterial replication, and increased antigen presenting
Increased body temp from hypothalamus
Protein and energy mobilization to allow increased body temp in response from TNFalpha (and IL-6 and IL-1)
How is C reactive protein used clinically
measured to monitor inflammatory response
How does TNFa cause septic shock
endotoxin shock. In high quantities, it inhibits myocardial contractility and sm mm tone. Stimulates tissue factor for coagulation and inhibits the inhibitor thrombomodulin.
low blood glucose due to overuse of muscles and underproduction by liver
What produces TNFalpha
Activated mononuclear phagocytes, antigen-stimulated T cells, NK cells and Mast cells.
What activates release of TNFalpha
TLR activation by LPS (gram-)
INFgamma by T cells and NK cells
PAMP recognition
Two pathways of TNF type R
Gene Expression of inflammatory mediators using MAPK or NFkB
Apoptotic- extrinsic pathway
role of IL-1
similar to TNF. mediates local inflammation and induces expression of Integrin Ligands on endothelial cells so extravasation of leukocytes can happen
What produces IL-1
Mononuclear phagocytes
Neutrophils
Epithelial cells
Endothelial cells
What activates the release of IL-1
TLR activation by PAMPs or LPS
What are the systemic activities of IL-1
Induces fever, acute phase proteins and neutrophil/platelet production
Does not induce apoptosis
Can’t cause apoptosis by itself
Induces production of IL6
Systemic activities of IL-6
Fever and production of acute phase proteins
What are chemokines and what are their general role
Chemotactic cytokines that have a roll in the cell trafficking during inflammation
What cells produce chemokines
Leukocytes, Endothelial Cells, Epitehlial cells, Fibroblasts, lympoid organs
What activates the production of chemokines
TLR signaling
TNF or IL-1 signaling
What does R activation from chemokines do?
modulates the cytoskelteon and integrin affinity. chemokines stimulate T cell integrins to transform from low affinity to high affinity state for ligand binding and cause clustering so tight adhesion for Tcell to APC cell
What 2 cells do chemokines act on systemically
Endothelial Cells and Leukocytes
How do chemokines work on endothelial cells
Chemokines can diffuse through endothelium and bind heparin sulfate on proteoglycans in lumen to be displayed to leukocytes. This increases extravasation and promotes angiogensis after tissue injury
How do chemokines work on leukocytes
Alternating polymerization and depolymerization of actin
What is the role of IL-12
Mediator of early innate immune response
What produces IL-12
Activated dendritic cells
Activated macrophages
(In response to microbe)
What activates the production of IL-12
TLR activation
LPS
Intracellular bacteria (Liseria) and viruses
APCs stimulating T cells(CD40)
What are the 4 general systemic activities of IL-12
stimulates NK and both types of T cells to make IFN gamma
causes gram - sepsis
T helper differentiation(CD4+)
Induces Cytotoxic functions of NK and Cytotoxic T cells (CD8+)
What is the result of IL-12 stimulating IFN gamma production
IFN stimulates macrophages to kill engulfed bacteria.
How does IL-12 contribute to grame - sepsis
LArge amounts of IL-12 induce IFN gamma which with LPS induces TNF–> septic shock
What is the role of Type I interferons
Interfere with viral inception, involved in early innate immune response and intracell microbes
What produces Type I interferons a and b
IFN-a in Immune cells(dendritic and mononuclear phagocytes)
IFN-b in systemic cells like Fibroblasts
What activates Type I IFNs
Viral nucleic acids and mononuclear phagocytesCD40
What is the local result of R activation with Type I IFNs
Induces proteins which inhibit viral replication machinery- paracrine activity to protect neighbors
Increases MHC I expression to increase the CTL (CD8+) mediated killing
(prevent spreading of virus)
What are the systemic activities of IFNs
sequester lymphocytes in lymph nodes to enhance antigen dependent activation
What is the role of IL-10
Inhibit innate immune response in macrophages and dendritic cells
How does IL-10 inhibit innate response
Limit production of IL-12 thereby IFN gamma and also inhibits the expression of MHC II
What produces IL-10
Activated macrophages, Regulatory T cells (CD25+) and non-lymphoid cells like keratinocytes
What are the innate responders to Extracellular bacteria
TNF, IL-1 and chemokines to promote extravasation and the main responder are neutrophils
What are the innate responders to intracellular bacteria
IL-12 and INF gamma to promote phagocytosis and stimulate adaptive responses
Main responder is macrophages
What are the innate responders to Viruses
Type I INFs and IL-12 to inhibit replication
Activate NK and enhance cytotoxic activity
Main responder are NK cells
What do IL-15 and IL-18 do
15 causes NK and T proliferation
18 causes NK and T cells to produce IFN-gamma
Septic shock symptoms
Hyper or hypothermia, Tachycardia, hypotension, tachypnea, acute hyperventilation with respiratory alkalosis, mental status changes (obtundation) and a patient hx suggestive of new infection
What is measured to Dx septic shock
TNF and IL6 circulating
What test do we measure IFN gamma in blood
latent TB
When a patient rejects a transplant what cytokine is detected
IL-2R
Give exmaples of cytokines used for Tx
IFN-a for chronic hepatitis and hematologic cancers
IFN-b for multiple sclerosis
IL-12 in clinical trials to boost immunes response
GM-CSF to recover from chemotherapy and BM transplant
EPO to treat anemia and chronic renal failure
What cytokines do we block clinically
Basiliximab to prevent IL-2 from binding R to inhibit transplant rejection
anti TNF and IL1 ab to treat rheumatoid arthritis and inflammatory bowel disease
