Inflammation, cytokines, chemokines

what causes inflammation

initiated by pro-inflammatory factors, including cytokines and chemokines produced by activated innate immune cells

characteristics of inflammation

• increased vascular diameter > increased blood flow - heat and redness

• expression of cell-adhesion molecules lining the blood vessels to promote leukocyte migration to the tissue - extravasation

• increased vascular permeability > accumulation of fluids and proteins in the tissue - pain and swelling

• clotting at the site to prevent the spread of the pathogen

leukocyte migration to site of infection - steps

• selectin induced leukocyte rolling along the endothelium

• adhesion molecules arrests leukocyte rolling

• leukocyte extravasion via more adhesive proteins migrates leukocytes into the tissues

• migration of leukocytes along a matrix associated concentration gradient of chemokines

soluble mediators of inflammation

• lipid mediators secreted by macrophages and granulocytes (prostaglandins, leukotrienes, platelet activation factor PAF)

• that is followed by cytokines and chemokines

• C5a and others act as chemoattractants for neutrophils and monocytes. also increases vascular permiability

• kinin system of plasma proteases triggered by tissue damage to generate polypeptides that regulate blood pressure, coagulation, and pain eg bradykinin

• sterile injury can also induce neutrophil recruitment and activation of kinin and coagulation systems

cytokines

• small proteins, also called interleukin (IL) followed by a number

• affect the cells that release them (autocrine), affect adjacent cells (paracrine), or affect distant cells (endocrine)

• can also recruit other stuff to help them

4 structural families of cytokines

1. IL-1 family: 11 members including IL-α, IL-β, and IL-18

2. hematopoietin superfamily: include non immune system growth and differentiation factors, and interleukins with roles in adaptive and non-adaptive immunity

3. interferons: antiviral proteins produced in response to viral infections. Three known classes: type I, II, and III

4. tumor necrosis factor (TNF) family: 17 members and many are transmembrane proetins, which can also be secreted in some circumstances

Chemokines

• type of chemoattractant cytokines that induce Chemotaxis (movement of nearby responsive cells toward the source of the chemokine)

• more than 50 known chemokines. some also function in lymphocyte development and angiogenesis

• All chemokines are related in amino acid sequences, use G-protein-coupled receptors

Hematopoietic cytokine family receptors

Associated with the JAK family of tyrosine kinases → activate STAT transcription factors

STATS form dimers that translocate into the nucleus to initiate gene transcription

IL-6 in the liver

Production of acute-phase proteins

C-reactive protein

• an acute-phase protein

• CRP binds to phosphocholine portion of certain bacterial and fungal cell-wall lipo polysaccharide

• CRP binds to bacteria and acts as an opsonin to induce phagocytosis of the bacterium

• activates compliment cascade → binds to Cq1

Mannose-binding lectin

• MBL binds to mannose residues on microbial surfaces and activatethe lectin patway of compliment activation

• acts as opsonin that is recognized by monocytes

surface proteins (SP-A and sp-D)

produced by the liver and a variety of epithelia and act as opsonins

Interferons

• IFN are antiviral proteins induced by viral infection

• Direct antiviral activity

• also contribute to immune cell activation

Three classes of IFNs

1. Type I : Have antiviral activity. Includes IFN-α, IFΝ-β (almost all cells produce these), IFN-κ, IFN-ε, IFN-ω

2. Type II : No antiviral activity. Moderates other immune cells. only member is IFN-γ

3. Type lll: encoded by 3 IFN-λ genes

and I RF9 path wayIFIN-I induce a state of resistance to viral replication in all cells by binding to the interfereon α receptor (IFNAR) and inducing expression of interferon stimulated genes via the JAk/STAT and I RF9 path way

Interfereon stimulated genes

ISGs include oligoadenylate synthase, dsRNA -dependent protein kinase, etc

different proteins affect different pathways

Tumor necrotic factor α

TNF α functions as a membrane bound cytokine in the local containment of infection by:

• Inducing expression of adhesion molecules for leukocyte extravasion

• Inducing expression of proteins which trigger blood clotting in local small vessels

• if septic, release of TNF α is catastrophic

Releasing TNFα by macrophages in the liver, spleen, and other tissues cause: 

• vaso dilation → loss of blood pressure

• vascular permeability → loss of blood volume & shock (septic shock)

• Disseminated intravascular coagulation → vital organ failure

• septic shock has