Inflammatory Stress Flashcards
What is inflammation
A localized response to injury or infection that leads to the activation of immune-system cells and their recruitment to the affected sites
What are two main integral components of the host’s defense system
Innate immunity and adaptive immunity
What is inflammations associated with
The release of pro-inflammatory factors from immune cells
What are the signs of inflmations
Heat Redness swelling and pain
What is innate immunity
Nonspecific defense mechanisms that come into play immediately or within hours of a pathogen or damage apperance in the body
What do innate immune cells recognize
Pathogen invasion or cell damage with intracellular or surface receptors including Toll-like receptors
What are innate immune cells in tissues
Macrophages and dendtric cells
What are circulation innate immune cells
leukocytes monocytes and neutrophills
What do these receptors detect
Directly or indirectly pathogen associated molecular patterns (PAMPS)
What are PAMPs
microbial nucleic acids, lipoprotiens and carbodhydrates or pathogen-associated molecular patterns
What are Damps
Damage-associated molecular
patterns (DAMPs) released from injured cells
What do these cells do
All these cells as well as fibroblasts and mast cells screte mutiple molecules (mediators) which mediate different aspects of the inflmmatory response
What do dendtric cells do
Recognize and ingest pathogens and coordiante the activity of many different types of immune cells by relasing pro-inflammatory cytokines and chemokines to recruit them to site of infection of immediate protection and by serving as antigen-presenting cells to adaptive immune cells
What do neutrophills and macrophages do
Recruited to sites of inflammation are directly involved in killing invading pathogens; accumulation of dead leucocytes including neutrophils eventually leads to the presence of pus at the site of the infection
What do the majority of innate immune cells express
Cell-surface receptors which recognize and are activated by broad classes of microbial molecules deemed PAMPS and TLR
What can we use to measure and detect inflmmation
Pro-inflammatory molecules
What are the 3 most common cytokines
Tumor necrosis factor TNF-a
interleukins IL-1B
IL-6
all markers of inflammatory stress
What plays an essential role in conjunction with most common pro-inflammatory cytokines
nuclear factor kB
What was discovered in the adult fly
Toll signaling induces the expression of several host-defense mechanisms including antimicrobial peptise which is critical for defense agianst gram positve bacteria and fungal pathogens
What are homologs of Toll where were they found and how many are there
Toll like receptors found in other animals associated with resistance to viral bacterial and fungal infection best characterized cell surface recports that interact with PAMP and DAMP 13 TLRs
What are the three domains of TLR
Extracellular domain- leucine rich repeats forms a sickled shaped and is involved in ligand recognition binds to microbial lipopolysaccharides, cell wall and nucleic acids
Cytoplasmic domain - contains specific subdomains TIRs which are responsible for the recuitment of six adapter protiens cytoplasmic tail binds MyD88- TIR TIR interacations
Transmembrane domain
What is the second domain of MyD88
Death domain which is responsible for recruiting IRAK4 and IRAK 2 they also have DD domains these domains can bind to each other through DD interactations MyD88-DD/DD-IRAK
This occurs as a result of TLR activation this then phosphorylates downstream signalling molecules leading to release of active transcrpition factor NF-kb and trasncription of pro-inflammatory genes
What are the two categories of microbial ligands
pathogen derived cell wall components (lipids, protiens, glycans) and pathogen derivednucleic acids
What do the TLR 1, 2 ,4 ,5 ,6
Cell surface receptors and serve a sensors for microbed present and they recognize specefic components of pathogen eneveloope/cell wall
What do TLR3,7,8,9,13 do
Located intracellulary in the membrane of endosomes they detect RNA and DNA components of degraded pathogens that have been taken into cells by phagocytosis
What activates the dimers of TLRS
Various ligands, lipoteichoic acid and diacyl and triacyl lipoproteins
Where is Nf-kB found
Promoter region of the inflammatory response genes: inflammatory cytokines, chemokines, COX-2, cytochrome p450 and HSP90, adhesion
What is COX-2
Inflammatory response gene thought to be responsible for much of the increased prostaglandind production at inflammatory sites target of many anti-inflammatory drugs
What is prostaglandins
Hormone like compounds which have important effects on local blood flow and perception of pain ADVIL inhibits COX enzymes
What is the COX-2 gene highly dependent on
NF-Kb activation
What are three famileies that central for NF-kb signaling
- Nf-kb/Rel family of transcription factors 2. IkB inhibitor protiens
- I-kB protein kinases (IKK)
what is NF-kb REL family composed of
Five related transcription factors RElA/p65 RElB c-rel NFkb1 p50/p105 and NF-kB2 p52/p100
What are the similarties of the transcription factors in the NF-kb/Rel family
Share a N terminal DNA binding domain and the dimerization domain RHD can form homodimers and hetrodimers that regulate the expression of genese influencing a broad range of biological processes
What can NF-kB dimers bind to
Variety of releated target DNA sequences called kB sites to modulate gene expression
What do RelB c-REL and p65 contain
C-terminal transcription activation domainds TAD which enable co-activator recruitment and target gene expression
What do p50 p52 lack
TAD and only activate transcription by forming heterodimers with p65 c-REl or RelB or by recruiting other TAD contaning protiens
What can p50, p52 do
Repress transcription on binding to DNA
What is the inihibtiory ikB family composed of
8 protiens two of them are non processed
What does the IKK complex family connsist of
conssit of two catalyticallly active kinases IKK1 and IKK2 and NEMO
What are the components of Canonical NF-kB components
- Transcription factor which is a hetro dimer RELA(p65)/p50 (NF-kB1)
- Sensor which is IKbA an inhibitor of NF-kB
- Transducer which trimeric IKK complex composed of two catalytic subunits and one regulatory subunit
What is the canonical NF-kb signaling pathway in resting cells
NF-kb is inactive in complex with I-KB and the acatviation
What are the 6 steps of canonical NF-kB signaling pathway
- Many agents can stimulate trimeric I-kB kinase activation by phospphoylation IKKb subunit. The phosphorylation of IKB is driven by protien kinase TAK1
- The I-kb kinase B subunit phosphorylates the inhibitos 1-kBa, which then binds an E3 ubiquitin ligase
- E3 ubiqutin ligase induces polyubiquitination of I-kbA
4.Uqbiunitated I-kbA degraded - Removal of I-kBa unmasks nuclear loclaization signals in both subunits of NF-kB causing them to translocate into the nucleus
- NF-kb acitvates transcption of numerous target genes including genes encoding various inflammatory cytokines and the gene encoding I-kBa which acts to terminate signaling
How can you measure NF-kB activation
Western blotting and immunofluroescene for detecting p65
What was pulmonary arterty endothelial cells treated with
lipopolysaccharide which is a cell wal component of Gram negative bacteria
What were the results of spatio temporal changes
There is a time dependent movement of p65 from cytoplasm to nucleus over 2h
second fluorscence immunostaning shows taht p65 from cytoplasm to nucleus over 1h however over 4-24 hours the staning returns back to the cytoplasm
What does the stain returning back to the cytoplasm mean
The negative feedback is working due to acummulation of newly synthesized I-kBA which is required to maintain the balance and avoid overactivation of NF-kb
What are the noncanonical components of NF-kb
- transcrption factor hetrodimer RELB/p52
- Sensor which is NF-kb2 p100
Transducer which is IKKa kinase and one catlytic subunit
What is the difference between the non canonical and the canonical pathway
Non canonlical pathway relies on phospholatyion of induced p100 processing into p52 triggered by TNFR
Dependent on NIK kinase and IKKA but not on the trimeric IKK complex and TGF-b acitvated kinase 1 TAK!
Slow and persistent
What does NF-kb non-canonical releate to
Lymphoid oragnogensis, -cell survival and maturation, dendtric cell activation and bone metabolism
What does deregulated non-canonical NF-kb signaling associated with
Lymphoid maliganices
