Lec. 6 - Cytokines

Exam 1

What are cytokines? What can they cause?

Small proteins that regulate the innate and adaptive immune system by binding to target cell receptors.

• Can cause gene expression, differentiation, regulation

Cytokines can take 3 actions to “communicate”. What are they? Define them.

1. Paracrine: Cytokines interact with nearby cells

2. Autocrine: Cytokines interact with the cell that released them

3. Endocrine: Cytokines go through the bloodstream to interact with distant cells

Cytokines can be pleiotropic. What does this mean? Give an example of a pleiotropic cytokine.

A singular cytokine can have many different affects.

• ex.: TGF-b → can inhibit macrophage activation & proliferation, can suppress inflammation & block IFN-g

Cytokines can also be redundant. What does this mean? Give 2 examples of redundant cytokines?

Different cytokines have the same effect

• ex.: TNF-a & IL-6 → chemokine production

Cytokines can have synergy. What does this mean?

Cytokines can enhance their effect when released together (ex. A + B = large response / Only A or B = small response)

Cytokines can be antagonistic. What does this mean?

When cytokines counteract each other. (A + B = reduced response / Only A or B = regular response)

Dendritic cells and macrophages release cytokines after recognizing PAMPs (in the innate system). What type of cytokine signaling (communication) do they send and what do they cause in response?

Paracrine: leads to local inflammation (remember, effects nearby cells)

Endocrine: leads to fever, acute phase reactants (APRs), and hematopoiesis

What are the 6 cytokines that are part of the innate immune system?

1. IL-1 family

2. IL-6

3. Chemokines

4. IFN alpha & beta

5. TNF alpha & beta

6. TGF beta

What activates IL-1 (interleukin) cytokines?

When cells come in contact or are killed by microbial components (ex. LPS, bacteria/viral nucleic acids)

What are the 3 types of IL-1 innate cytokines that are usually released and what do they cause?

1. IL-1a: released from dead cells, activates inflammation & recruits immune cells

2. IL-1b: Activates inflammation (released by mono & macro) & recruits immune cells (phagocytes), causes fever

3. IL-1RA: Is a receptor antagonist that blocks binding of IL-1a&b → anti-inflammatory

What are IL-6 cytokines released by? (these are innate cytokines)

Monocytes, macrophages & non-immune cells

IL-6 cytokines can be considered what kind of cytokine (as in, can the cytokines do a lot or a little)? What all does this cytokine activate?

• Pleiotropic

  • Stimulates liver → acute phase reactants (APRs)

  • Stimulates bone marrow → granulocytes

  • Activates T & B cells

  • Makes B cells → plasma cells

Chemokines are a type of innate cytokine. What do they influence?

• Cell motility & migration (movement)

Recruits WBC & guides into tissue via CAMs (modulating adhesion) → allows for diapedesis/extravasation

IFN a & b are innate cytokines. What cells produce IFN-a and IFN-b?

IFN-a: produced by DCs & macrophages

IFN-b: produced by virus-infected cells

What do the cytokines IFN a & b do?

• Interferes w/ viral replication

• Recruits NK cells

• Increases MHC I expression → helps cytotoxic T cells get into the system

TNF a & b are innate cytokines. What are they released by and upon contact with what? What does this cytokine do?

• Macrophages → upon contact w/ LPS

Cytokine activates:

• Inflammation

• CAM expression on endo cells (slows down Neutros so they can enter tissue)

• Cause tumor cell death

TGF-b is an innate cytokine. What does it do? What kind of cytokine is it (as in, can it do many things or not)?

• Anti-inflammatory & anti-proliferative (prevents WBC production)

Pleiotropic:

• Inhibits activation & proliferation of macro & B cells

• anti-inflammatory for mature T cells

• regulates cell growth/diff, apoptosis, migration

What are the cytokines of the adaptive immune system? Which cells produce these?

• IL-2 & IFN-g → Th1 cells

• IL-4 & IL-10 → Th2 cells

• IL-10 & TGF-b → T-reg cells

• IL-17 → Th17 cells

What do Th1 cells guide the adaptive immune response towards?

cell-mediated immunity

IL-2 & IFN-g are adaptive immune cytokines produced by Th1. What do they do?

• IL-2: Differentiates T & B cells → causes B cells to release IgG1 & 3 (opsonins)

  • Enhances NK’s

• IFN-g: increases expression of MHC I & II

  • activates macros, Th1 cells, CD8+ (cytotoxic), & NK cells

What do Th2 cells guide the adaptive immune response towards?

antibody-mediated immunity

IL-4 & IL-10 are adaptive immune cytokines produced by Th2. What do they do?

• IL-4: allows Th2 proliferation (suppresses Th1)

  • Activates other IL’s to differentiate eos’ & produce Ab’s

• IL-10: antagonizes IFN-g (suppresses Th1) → anti-inflammatory

  • Prevents IL-12 expression (IL-12 promotes diff. of Th1)

What do Th17 cells help defend against in the adaptive immune system?

Bacterial & fungal infections in mucosa

IL-17 is an adaptive immune cytokines produced by Th17. What does it do?

• IL-17: inflammatory → promotes neutrophil recruitment

  • secretes anti-microb peptides (kills bacteria)

When people have an inflammatory or autoimmune disease, what cell is likely to be dysregulated? Why?

Th17 cells b/c they promote inflammation due to their cytokine

What do Treg cells help the adaptive immune establish?

Peripheral tolerance (protects from self-activation) & can protect tumor cells

IL-10 & TGF-B are adaptive immune cytokines produced by Th2. What do they do?

• IL-10: anti-inflammatory (meaning it downregulates stuff)

• TGF-B: anti-inflammatory

CSF (colony stimulating factor) help proliferate & differentiate WBCs. Which cytokine helps the myeloid progenitor cell survive?

IL-3

What is anti-cytokine therapy? Provide an example of a therapy.

• Therapy using humanized monoclonal ab’s that are used to stop chronic inflammation by disrupting interactions between cytokines & their receptors

  • ex. ixekizumab blocks IL-17 in psoriasis

What are the 3 ways cytokines are tested in a clinical setting? Briefly explain them.

1. Multiplexed ELISAs: monoclonal Ab’s used to detect different kinds of cytokines

2. Microbead assays: Beads w/ different fluorescent wavelengths combines with a second Ab → detects up to 100 different cytokines

3. ELIspot: quantify the # T cells that secrete specific cytokines in response to Ag (creates a halo on plate if receptor bound cytokine)