Lecture 5: Inflammatory Mediators II Flashcards
What is the chief source of cytokines and chemokines in inflammation? (in charge after first 24-48 hrs)
Macrophages and monocytes
lymphocytes use them to communicate during immune processes
Cytokines and chemokines organize and maintain… (4)
- cell migration and phagocytosis
- chronic inflammatory reactions
- healing and regeneration
- immune responses
How is production of pro-inflammatory cytokines induced?
Nuclear signaling; NFk-B transcription pathway
What are interleukins?
Nonspecific nomenclature for cytokines
- monokine from monocyte, lymphokine from lymphocyte
- chemokines are a type of cytokine
Where do IL-1, TNF, and IL-6 come from?
Activated macrophages in inflammation
What do IL-1, TNF, and IL-6 do?
- Mediate cellular phases
- Mediate systemic responses
- Mediate immune responses
- Mediate healing and regeneration
Overlapping; differences not at important as similarities
IL-1, TNF, and IL-6 generally act ______, but can _________
locally; reach sufficient levels to act systemically
Local effects of IL-1, TNF, and IL-6:
- Activation of endothelial cells (increased vascular permeability)
- Induction of adhesion molecules on ECs, neutrophils, monocytes
- Induction of synthesis of other cytokines and GFs
Systemic effects of IL-1, TNF, and IL-6:
- Induction of fever (endogenous pyrogen)
- Malaise
- Synthesis of acute phase proteins
- Leukocytosis (increase in white count)
- Lymphadenitis
TNF-alpha has similar effect to IL-1 and IL-6, but also ________
activation of apoptotic death domain (TNF-R1, TRADD signaling)
What can monoclonal antibodies to TNF be used to treat?
Chronic inflammatory disorders
- rheumatoid arthritis, Crohn’s, psoriasis
- buuut can wipe out immune response (get JC virus, TB)
What is a side-effect of IL-6?
Local production by osteoblasts will increase osteoclast activity –> bone loss
Inhibitors of IL-6 may have a role in post-menopausal osteoporosis
What are chemokines?
Chemotactic molecules (cytokines); local production to mediate chemotaxis of specific cell types
Describe the structure of chemokines.
70-80 amino acids, two conserved cysteines
- C-C chemokines have two adjacent cysteines
- C-X-C have an amino acid separating them
What is IL-8 (CXCL8)?
C-X-C chemokine chemotactic for neutrophils; bind CSCR-1
*also good for endothelial cell migration - angiogenesis
What synthesizes IL-8?
Macrophages, endothelial cells
What is MCP-1?
Chemotactic for macrophages; from macrophages
Induces histamine release from mast cells
What are RANTES and MIP-1?
Chemotactic for eosinophils (allergic response)
List some inflammatory lymphokines that induce Th1 and Th2 responses.
IL-2,4,5,10,13
etc.
What is IFN-gamma?
Activates macrophages; from T-cells and NK cells
Induce expression of MHC I and II
Inhibit Th2
Enhance leukocyte-endothelial adherence
What are Type I Interferons? (alpha and beta)
Produced by various cells and induce resistance to viral replication in all cells
Increase MHC class I Activate NK cells to kill virus-infected cells
What is IL-12?
Synthesized by macrophages and dendritic cells
Important in all cell-mediated responses; activates T-cells
- INDUCE Th1
- INHIBIT Th2 pathways
What do FGF and TNF-alpha do?
fibroblast growth factor
- Stimulate fibroblasts in healing and regeneration
- Cause fibrosis
List some angiogenic factors.
VEGF, FGF, PDGF (platelet-derived GF)
What are colony-stimulating factors and what do they do?
GM-CSF, G-CSF, M-CSF
Differentiate granulocytes in marrow
Stimulate neutrophils, eosinophils, macrophages
How can septic shock be caused?
Binding of LPS to TLRs (like TLR4) stimulates pro-inflammatory cytokine synthesis
Where does nitric oxide come from in inflammation?
Endothelial cells (local vasodilation) and activated macrophages
This is iNOS
What is nitric oxide synthesized from?
L-arginine (nitric oxide synthase)
- eNOS in endothelium and nNOS in neurons is constitutively expressed
How can NO cause cancer?
In chronic inflammation, where it is expressed for a long period of time, its role as a ROS damages cellular DNA and can cause cancer
- H. pylori, alcoholism, hepatitis
Is NO long-acting?
No! Half-life is seconds long and only local
What does NO do?
Enhance vasodilation, platelet aggregation/adhesion, bactericidal activity, inhibit leukocyte migration
Both positive and negative effects in inflammation
