Cytokines

Question 1

TNF

Answer 1

• Source: Macrophages, mast cells, T lymphocytes, dendritic cells
• Stimulates expression of endothelial adhesion molecules and secretion of other cytokines
• systemic effects in acute inflammation
• augments neutrophil responses to stimul
• increases microbicidal activity of macrophages (increased NO production)
• promotes lipid and protein mobilization and suppresses appetite –> cachexia

Question 2

IL-1

Answer 2

• Source: Macrophages, endothelial cells, some epithelial cells, dendritic cells
• Similar to TNF
• greater role in fever; acute inflammation
• Activates fibroblasts to synthesize collagen
• stimulates proliferation of synovial and mesenchymal cells
• stimulates T_H17 responses –> induce acute inflammation

Question 3

IL-6

Answer 3

• Macrophages, other
• Systemic effects
• Acute phase response (acute inflammation)

Question 4

Chemokines

Answer 4

• Macrophages, endothelial cells, T lymphocytes, mast cells, other cells
• Acute inflammation
• Recruitment of leukocytes to sites of inflammation; migration of cells in normal tissues

Question 5

IL-17

Answer 5

• T lymphocytes
• Recruitment of neutrophils and monocytes in both acute and chronic inflammation

Question 6

IL-12

Answer 6

• Dendritic cells, macrophages
• Increased production of IFN-gamma
• Chronic inflammatory response

Question 7

IFN-gamma

Answer 7

• T lymphocytes, NK cells
• Activation of macrophages (increased microbial and tumor cell killing)
• Chronic inflammation

Question 8

Promote leukocyte adhesion to endothelium and migration through vessels

Answer 8

TNF and IL-1

Question 9

IL-17

Answer 9

• Produced mainly by a subpopulation of T lymphocytes
• Induces chemokine secretion and neutrophil recruitment
• Important in adaptive immunity
• “Cold Abcesses” lack warmth and redness typical of acute inflammatory responses

Question 10

Endothelial activation

Answer 10

TNF and IL-1

Question 11

Effects of TNF and IL-1

Answer 11

1. Endothelial Activation
   
   • increased expression of endothelial adhesion molecules
     
     • E- and P- selectins
     • leukocyte integrin ligands
   • increased production of inflammatory mediators
     
     • other cytokines and chemokines
     • growth factors
     • eicosanoids
   • increased procoagulant activity of the endothelium
2. Leukocyte Activation
   
   • stimulation of function and responses of neutrophils, macrophages
   • activates fibroblasts (IL-1) to synthesize collagen
   • stimulates proliferation of synovial and mesenchymal cells
3. Systemic Acute-phase Response
   
   • fever
   • sepsis
   • energy balance (promotes lipid and protein mobilization and suppresses appetite)

Question 12

Systemic protective effects

Answer 12

• TNF, IL-1, IL-6
  
  • Brain —-> fever
  • Bone marrow —-> leukocyte production
• IL-1, IL-6
  
  • Liver —–> acute phase proteins produced

Question 13

Systemic pathologic effects

Answer 13

• TNF
  
  • Heart —-> decrased cardiac output
  • Endothelium —-> increased permeability
• TNF, IL-1
  
  • Insulin resistance

Question 14

Chemokines

Answer 14

• Family of small proteins that act primarily as chemoattractants for specific leukocytes
• categories based on arrangement of 4 conserved cysteine residues

1. C-X-C
2. C-C
3. C
4. CX₃C

Question 15

C-X-C chemokines

Answer 15

• Chemokines with one amino acid residue separating the first two cysteine residues
• Work primarily on neutrophils
• Ex: IL-8

Question 16

IL-8

Answer 16

• Source: activated macrophages, endothelial cells, other cells
• Effects: causes activation and chemotaxis of neutrophils with limited activity on monocytes and eosinophils
• Induced by: microbial products, IL-1, TNF

Question 17

C-C chemokines

Answer 17

• First 2 cysteine residues are adjacent
• ex: monocyte chemoattractant protein(MCP-1), eotaxin, RANTES
• effects: attract monocytes, eosinophils, basophils, lymphocytes
• NOT as potent for neutrophils

Question 18

Eotaxin

Answer 18

Selectively recruits eosinophils

Question 19

C chemokines

Answer 19

• Lack the first and 3rd of the conserved cysteines
• Ex: lymphotactin
• Relatively specific for lymphocytes

Question 20

CX₃C chemokines

Answer 20

• 3 amino acids between the 2 cysteines
• ex: fractalkine (only)
• Fractalkine
  
  • cell surface-bound protein induced on endothelial cells by inflammatory cytokines
    
    • promotes strong adhesion of monocytes and T cells to the endothelium
  • proteolysis of the membrane bound protein produces soluble form
    
    • potent chemoattractant for monocytes and T cells

Question 21

Inflammatory chemokines

Answer 21

• Produced in response to microbes and other stimuli
• Increase leukocyte integrin affinity
• Promote chemotaxis

Question 22

Homeostatic chemokines

Answer 22

• Produced constitutively in tissues
• Affect/organize various regional cell types (ex: B and T lymphs in spleen and l.n.)