Cytokine Receptor Signaling

Question 1

Cytokines

Answer 1

Small secreted proteins with immune modulatory functions

Question 2

Functions of Cytokines

Answer 2

• Important to fend of specific pathognes and maintain tissue homeostasis
• Control cellular proliferation, activation, and differantation
• Recruitment of cells into sites of injury
• Must be tightly regulates to avoid immunodeficiencies or inflammatory disease

Question 3

Key players in cell communication

Answer 3

1. Stimulus: The distinct inout that promotes cytokine expression and/or secretion
2. Cytokine-producing cell: cells that first encounter the sti,uls to synthesize and release cytokines
3. Target cell: Cells that are capable of sensing and responding to a secreted cytokine
4. Biological Activity: The distinct functions regulated by a cytokine

Question 4

Cytokines can elicit functions locally and distally

Answer 4

Cytokines can exert regulatory functions on the cells that secrete them (autocrine), other nearby cells (paracrine), or be released into the bloodstream to exert function on distant cells (endocrine).

Question 5

Pleiotropy

Answer 5

One cytokine can have multiple biological functions on one or more cells

Question 6

Redundacy

Answer 6

Two or more cytokines can have a similar function on one or more cell types

Question 7

Synergy

Answer 7

When two or more cytokines can cooperate to promote a given biological outcome

Question 8

Antagonism

Answer 8

Signal integration between two cytokines where one inhibits the immunomodulatory function of the other

Question 9

Molecular factors that contribute to the duration of cytokine signaling

Answer 9

Receptor expression at the cell surface
Ligand: receptor interactions
Molecules that regulate signal transduction
* Feed-foward: Positive regulation/amplification of the signaling cascade
* Feed-back: Negative regulation/termination of the signaling cascade

Host Genetics and interactions with pathogens

Question 10

Receptor expression at the cell surface

Answer 10

Cytokine and their receptors are classified based on strcutural similarities

Question 11

Ligand confromation directs receptor interaction

Ligand: receptor interactions

Answer 11

• Tumor necrosis factor (TNF) - Receptor have a cysteine ritch domain
• Ligands for trimers
• Soluble TNF (sTNF) and membrane-bound TNF (mTNF) bind to TNFR1
• mTNF can bind TNFR2
• Binding of TNF to TNFR1 or TNFR2 elicits distinct intracellular events.

Question 12

Ligand:
Receptor affinity dictates signaling outcomes

Ligand: receptor interactions

Answer 12

• The receptor family characterized by SEF?IL-17R (SEFIR) region in cytoplasmic tail
• IL-17 A-F are monomers
• IL17 receptor subunits: IL17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE
• IL17 binds to the IL17R as dimers
• Affinity: IL-17 homodimers&raquo_space; IL17F homodimers&raquo_space;> IL-17:Il-17F heterodimers

Question 13

Sharing kinases and transcription factors:
Type I and II cytokine receptors

Ligand: receptor interactions

Answer 13

• Four janus Kinases which distinctly engage receptors
• STATs: differentially expressed across cell types and can from unique transcriptional complexes.

Question 14

Type I and II Receptors
JAK/STAT signaling

Ligand: receptor interactions

Answer 14

Phosphorylation event shape JAK/STAT signaling
Motifs in receptors and JAKs dictate the ability to interact:
* proximity of motif to membrane
* sequence specificty

STATs are recruited to receptor STAT-binding sites

Question 15

Type I Receptors
The common gamma chain family of cytokines

Ligand: receptor interactions

Answer 15

Question 16

Functional redundancy:
The Interferon (IFN) Receptors

Ligand: receptor interactions

Answer 16

Interferons: “intefere” with viral replication
Response to type I and II IFNs is ubiquitous across cells
Response to type III IFNs is restrcited to a few cell types
The IFNLR1 subunit is restrcited to a few cell types:
* Epithelial cells
* Human hepatocytes
* Neutrophils and a few other lymphocytes

Question 17

SOCS proteins prevent excessive inflammation

Molecules that regulate signal transduction

Answer 17

Type I and II cytokine receptors induce suppressor of cytokine signaling (SOCS) protein family
SOCS exert negative feedback by inhibiting JAK kinase activity
Other target genes downstream of the receptor can promote positve feedback to receptor signaling

Question 18

Decoy receptors can inhibit cytokine signaling

Molecules that regulate signal transduction

Answer 18

IL-1 receptors form heterodimers
* IL-1, IL-33, and IL-36 bind their specific receptors: IL-1R1, ST1, and IL-36R

These use IL-1RAcP, as a common subunit
Formation of the myddosome:
Signaling complex that induces recruitment of MyD88, IRAK, TRAF6 –> NF-kB and mitgen-activated protein kinases (MAPK)

Question 19

Inborn erros in immunity

Host Genetics and Interactions with pathogens

Answer 19

Genetic mutation on a receptor that makes them failed their interaction
Loss-of-function mutations:
* Loss of immune cell development and/or functionality
* Susceptibility to pathogen invasion

Gain-of-function mutations:
* Increased inflammation
* Proliferative diseases

Question 20

Dysregulation of cytokine signaling drives disease

Answer 20

Question 21

Therapeutic targeting of cytokine receptors

Answer 21

Biologics: Protein-based therapeutics
Agonists: Substance that can initiate receptor responses
Antagonists: Substance that can inhibit receptor responses
Orthosteric inhibition: Targeting the TNF: receptor binding sites
Allosteric inhibition: Targeting sites that are disticnt from receptor: ligand interaction sites.

Question 22

Cytokine signaling in a nutshell

Conclusion

Answer 22