chemokines (GPCR) and cytokines (Jak/Stat) Flashcards
List the kinetics of the inflammatory response to microbial infection
1) Exudation
2) Neutrophils
3) Apoptosis
4) Mono Nuclear Cells (macrophages, DC)
List the secretions that acccompany the Kinetics of the inflammatory response to microbial infection
1) at 30 minutes
- Histamine
- Serotonin
- Bradykinin
- Complement
2) 1hr-3hr-6hr
PGs
LTs
3) 24HR
TNF
IL-1Beta
LX
4) 24 hr- 48hr
MCP1 or CCL2
IL6
5) 48hr cyPGs BAX p53 TGF-Beta1 TRANSFORMING GROWTH FACTOR BETA-1
Platelets secrete WHAT molecule that the intestines also secrete.
SEROTONIN
T/F Platelets express MHCI despite not have a nucleus.
True
T/F RBC do NOT express MHCI because it doesn’t have a nucleus
True
Anti-inflammatory mediators examples?
Lipoxins (LXs)
CyPGs (cyclopentenone PG)
Lipoxins and CyPGs are WHAT mediators and attenuate WHAT and Promote WHAT from the inflammatory site
CyPGs and LX are ANTI-INFLAMMATORY, that ATTENUTATE CELL MIGRATION and promote APOPTOSIS and CLEARANCE of LEUKOCYTES from inflammatory sites
Which is the umbrella term? Cytokines or Chemokines
Cytokines are more general
Chemokines are CHEMOattractant CYTOKINEs
Chemokines are a type of cytokines
Chemokines are a type of cytokines T/F
True
CCL21 are highly expressed in lymph nodes at attract what receptors?
CCR7 Receptors found on APC and naive T cells
During healthy homeostasis, CCL21 attracts and retain what cells in the Lymph NOde
NAIVE T cells in the LYMPH NODE (due to theri CCR7)
During INNATE immune response, CCL2 (MCP-1) attracts WHAT and WHAT to sites of injury and infection?
MONOCYTES and MACROPHAGES
CCL2 (MCP-1) is different from CCL21 by?
CCL2 attracts MONOcytes and MACROphages to sites of INJURY and INFECTION
CCL21 is expressed in LYMPH NODES and attract APC cells and NAIVE T cells
CCL2 is also known as
MCP-1
MCP-1 is also known as
CCL2
What chemokine attracts Monocyte and Macrophages to site of injury and infection?
CCL2 or MCP-1
What chemokine attracts APC to Lymph Nodes via their CCR7?
CCL21
During homeostasis at the LYMPH NODE, WHAT chemokine is expressed to retain WHAT kind of cells
CCL21 is expressed at LN to RETAIN NAIVE T Cell
Understand the since CHEMOkines interact with GPCR the same chemokine can produce (same/different) effect on cells with different GPCRs.
DIFFERENT
the same chemokine can bind to Gs at one cell and a Gi at a different cell, SAME chemokine different effect at different receptors
T/F Chemokines are SMALL 8-10kd, SOLUBLE and thus can DIFFUSE AWAY from site of secretion.
True
Chemokines also efficently bind to…?
Extracellular Matrix
What is the benefit of Chemokines efficently binding to the ECM?
it can TETHER cells that expressing CHEMOKINE RECEPTORS to the ECM presenting CHemokine
For Chemokines and Cytokines, which has Jak/Stat and which has GPCR
Chemokines/PG - GPCR
Cytokines - JAK/STAT
Describe the cysteine residues of Alpha chemokines
Alpha Chemokines or CXC chemokines have an a.a between the FIRST and THIRD conserved CYTSTEIN RESIDUES
Alpha Chemokines are also known as
CXC chemokines
Nomenclature CXCL8
CXC chemokines are also known as
Alpha Chemokines
CXC chemokines or Alpha Chemokines are targeted more to WHAT cells than to other immune cells.
CXC chemokines or Alpha chemokines are targeted more to NEUTROPHILS than to other immune cells
Nomenclature CXCL8
Beta Chemokines are also known as
CC chemokines
nomeclature CCL4
CC chemokines are also known as
Beta Chemokines
Nomenclature CCL4
Describe the cytstein residues of Beta Chemokines
The first two conserved CYSTEINE residues are adjacent with no a.a. in b/w
CC chemokines or Beta Chemokines tend to NOT be a WHAT for WHAT CELL: NAME OF MOLECULE that specifically recruits WHAT IMMUNE CELL
CC chemokines tend NOTbe a CHEMOATTRACTANT to NEUTROPHILS:
EOTAXIN recruits EOSINOPHILS
What chemokine targets Neutrophils more than other immune cell
Alpha or CXC chemokine
nomeclature CXCL8
C chemokines aka
Gamma Chemokine
Gamma Chemokine
aka C chemokine
Describe the cystein residues of Gamma Chemokines
C chemokine or gama chemokine LACK the FIRST and THIRD cysteines.
CHEMOATTRACTANT for SPECIFIC LYMPHOCYTES subsets
NOMENCLATURE XCL1
CXXXC Chemokines only member is
CX3CL1 and cleaved FROM THE CELL SURFACE
A chemokine that is attracted to specific LYMPHOCYTE subsets.
Gamma Chemokine, C chemokine, XCL1
What type of chemokine is CXCL10
Alpha Chemokine, CXC chemokine, has an a,a b/w FIRST and THIRD CYSTEINE Residues
What type of chemokine: EOTAXIN specifically recruits EOSINOPHILS
Beta Chemokine, CC chemokine
has adjacent first and 2nd cystein residues
What type of chemokine is cleaved from the cell surface
CXXC chemokine, CX3CL1
What type of chemokine is not a chemoattractant for NEUTROPHILS?
Beta chemokine or CC chemokine
What type of chemokine is XCL1?
Gamma or C chemokine that lacks the first and 3rd cystein residue
What type of chemokine is CCL5?
Beta chemokine, CC chemokine with adjacent first and second cysteine residue
PAMPS and DAMPS induce the expression of specific WHAT that in turn recruit specific immune cells to injury/infection site and also RECRUITS CYTOKINES?
CHEMOKINE
CHEMOKINES RECRUIT SPECIFIC IMMUNE CELLS & CYTOKINES
T/F can chemokines RECRUIT CYTOKINES?
Yes
Chemokines in response to PAMP/DAMP recruit specific immune cells and cytokines to site of infection/injury
CCL2 is expressed to the site of WHAT and presented on WHAT recruits what CELL that has CCLR2?
CCL2 is tethered to the surface of DAMAGED ENDOTHELIA and presented on ECM
monocyte with the CCL2R is recruited there
The (monocyte/ECM) has the CCR2 receptor and the (monocyte/ECM) has the CCL2?
The MONOCYTE has the CCR2 RECEPTOR and the ECM has CCL2.
macrophage full of phagocytosed debri
FOAM CELL
ADAPTIVE immune response is coordinated by regulating both the WHAT and the WHAT?
Regulating both THE EXPRESSION of the CHEMOKINE and the EXPRESSION of the CHEMOKINE RECEPTOR
ADAPTIVE IMMUNITy
What chemokine is expressed at high levels at the Lymph Node
CCL21
Which Cells are home to and are localized w/in the LYMPH NODE?
Naive T cells with their corresponding CCR7 Receptors
After encountering PAMPs and DAMPS, WHAT CELLS leave the tissues, carrying antigen and expressing CCR7 to the LN?
DENDRITIC CELLS
Foam Cells
MACROPHAGE full of phagocytosed debri
Dendritic Cells carrying antigen and expressing CCR7 are drawn to the LN because?
The high amounts of CCL21 expressed at LYMPH Nodes
What cells present antigen to what cells their antigen?
DENDRITIC CELLS (ACTIVATED/MATURE) present their antigen to NAIVE T CELL AT LYMPH NODE
without CCR7 receptor; they can no longer see CCL21.
Activated Effector T cells
These cells down-regulate their CCR7 and leave LN because they aren’t retained in LN by CCL21 anymore
Activated Effector T cells
Why is there NOT a break out chemokine based therapies?
Chemokines participate in a WIDE VARIETY of FUNCTIONs from development, normal function, to tissue defense/reapir. It’s hard to target disease specific processes
Chemokine Antagonist are studied as potential therapies for WHAT, WHAT, and WHAT?
Chemokine Antagonist for:
1) chronic inflammatory disease
2) autoimmune disorders
3) LYMPHOMAS
Activated Effector T cells down regulated WHAT and leave WHERE because they are no longer retained by WHAT?
Activated effector T Cells DOWN REGULATE CCR7 and LEAVE LN bc they aren’t retained by CCL21 anymore
CT tissues of any organ
Stromal Cells
cells that perform the biological function of their organ
Parenchymal Cells
Cells that wrap around endothelial cells
Pericytes
Stuff that are relased by activated immune cells and STRESSED stromal cells.
Cytokines are SOLUBLE and small 25kD
Cytokine has both what and what actions?
Cytokines has both AUTOCRINE and PARACRINE action
Regulating adjacent cells
Paracrine
regulating self behavior
Autocrine
these stuff can even act SYSTEMICALLY
Cytokines
examples
TNF
IL-6
IL-1
on LIVER’s production of chemical mediators of inflammation
- fibrinogen
- crp protein
- sap protein
- SP-A/SP-D
- MBL
Exists as a monomer
IL-4 a cytokine
Exists as a trimer
TNF a cytokine
Stuff that primary acts as chemoattractants for specific leukocyte subsets
Chemokines
this stuff during early innate immune response to damage attracts monocytes and macrophages to sites of injury and infection
CCL2
this recruits APC cells to LN to present antigen to naive T cells
CCL21
TNF, IL-6, IL-1
Examples of systemic cytokines
Cytokine are NOT GPCRs T/F
True
These receptors are activated by DIMERIZATION.
Cytokine Receptors
IL-4
exist as a monomer
TNF
exist as a trimer
How are cytokine action mediated?
JAK/STAT linked receptors
Cytokine receptor’s cytoplasmic domain bind WHAT
Janus Kinases (JAKs)
After cytokine binds what happens to the receptor
the receptor dimierizes
When cytoplasmic JAKs are brought together they
1) phosphrylate each other
2) phophrylate the cytoplasmic part of the receptor
WHAT transcriptional factors bind to which part of the receptors and what happens to them?
STATs bind to the PHOSPHRYLATED RECEPTORS and are PHOSPHRYLATED by JAKs
Phosphrylated Stats form what and translocate where to initiate what?
Phosphrlylated stats dimerize and translocate to the nucleus to initiate new gene transcription
…phsophrylate themselves and cytoplasmic protion of the cytokine receptor
JAKs
….bind to phosphrylated regions of cytoplasmic protion of the cytokine receptor
STATs
….dimerizes the WHAT bringing together the JAKS
CYTOKINE binding dimerizes the CYTOKINE RECEPTOR and brings JAKS together to phosphrylate one another and also the cytoplasmic portion of the receptors
What must occur before STATs can translocate to nucleus and initiate gene transcription
STATs have to bind to the cytoplasmic phsophrylated part of the cytokine receptor to by phosphrylated by the JAKs and dimierize before translocating
What must occur before STATs are able to bind to the cytoplasmic portion of the cytokine receptor?
JAKs have to posphrylate themselves and the cytopalsmic protions of the cytokine receptor
Activates NK cells, which induces the differentiation of CD4 T cells into Th1 cells
IL-12 cytokine
….lymphocyte activation, increased Ab production
IL-6 cytokine
….activates vascular endothelium, lymphocytes, local tissue destruction, increasses access of effector cells
IL-1Beta
….activates vascular endothelium, increases vascular permeability, leads to increased entry of IgG and compelment, and cells to tissues and increased fluid drainage to lymph nodes
TNF-alpha
….cause FEVER and induces ACUTE PHASE PROTEIN PRODUCTION
IL-6
…..causes FEVER and MOBILIZES METABOLITES, SHOCK!!!!!
TNF-alpha
….causes FEVER and PRODUCTION of IL-6
IL-1beta
IL-12
Activates NK cells, which induces the differentiation of CD4 T cells into Th1 cells
TNF-alpha
….activates vascular endothelium, increases vascular permeability, leads to increased entry of IgG and compelment, and cells to tissues and increased fluid drainage to lymph nodes
…..causes FEVER and MOBILIZES METABOLITES, SHOCK!!!!!
IL-1Beta
….activates vascular endothelium, lymphocytes, local tissue destruction, increasses access of effector cells
….causes FEVER and PRODUCTION of IL-6
IL-6 cytokine
….lymphocyte activation, increased Ab production
….cause FEVER and induces ACUTE PHASE PROTEIN PRODUCTION
Actions of cytokines, list global, local, and final net effects.
Global
behavioral responses like anorexia, lethargy, slow-wave sleep, decreased social/exploratory behaviro
&
Systemic immune respones
Local
Regulating different lymphocytes, APC, and innate
Final Net effects
- based on RATIO and CONCENTRATIONS of specific cytokines present
Systemic effects of cytokines
Fever,
production of IL-6 which leads to lymphocyte activation, increased ab production
Mobilization of metabolites
Shock
Sickness behavior is associated with
Cytokines IL-1beta IL-6 TNF alpha secreted by MACROPHAGES act on BRAIN to induce sickness behavior
What produces IL-1beta, IL-6, TNF-alpha
Macrophage
Which anatomy does IL-1Beta, IL-6, and TNF alpha act on to produce sickness behavior
Brain
Which MHC class is presented on all cells and with the exception also platelets
MHC I
Which MHC class is presented only on APC cells
MHC II
What are APC cells?
dendritic cells, macrophages, and B cells
Cytokines produced by APC cells determine the final effector function of
Antigen-activated T cell
Different cytokines are produced by stage and type of infection/tissue damage thus you can use cytokine type to find out
the STAGE of the disease and the PATHOGEN SPECIFIC IMMUNE RESPONSES
can amplify innate immune responses
cytokines
The effector function of Antigen-activated T cells is determined by
Cytokines PRODUCED BY APC cells
Biologics like MAB can block cytokine actions
Anti-TNF therapies
Anti-TNF therapies have been life-changing for
Rheumatoid Arthritis and Psoriasis
Side effects on Anti-TNF therapies
TNF is required for NORMAL pathogen defense
- immunoDEFICIENT
- TNF required to promote proliferation of myeliating cells and remyelination in disease like ms and guillian-barre syndrome
- INCREASE demyelination and NERVE DAMAGE in pt with CNS disease
…helps determine stage and pathogen specific immune responses
cytokine
What determines the final effector function of antigen-activated T cell?
Cytokines produced by APCs
Sickness behavior promotes a conservation of resources with generation of toxic environment for invading pathogen T/F
True
….required for normal pathogen defense and required in brain to promote proliferation of myelinating cells and remyelination
TNF
Why aren’t anti-TNF used as first line therapy
- demyelination and nerve damage in pt with CNS disease
- immuno deficient since need TNF normally to fight off pathogens
Pericytes
cells that wrap around endothelial cells
Parachyemal Cells
cells that perform the organ’s function
Stromal Cell
CT of any organ
