Cytokine Receptor Signaling Flashcards
Cytokines
Small secreted proteins with immune modulatory functions
Functions of Cytokines
- 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
Key players in cell communication
- Stimulus: The distinct inout that promotes cytokine expression and/or secretion
- Cytokine-producing cell: cells that first encounter the sti,uls to synthesize and release cytokines
- Target cell: Cells that are capable of sensing and responding to a secreted cytokine
- Biological Activity: The distinct functions regulated by a cytokine
Cytokines can elicit functions locally and distally
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).
Pleiotropy
One cytokine can have multiple biological functions on one or more cells
Redundacy
Two or more cytokines can have a similar function on one or more cell types
Synergy
When two or more cytokines can cooperate to promote a given biological outcome
Antagonism
Signal integration between two cytokines where one inhibits the immunomodulatory function of the other
Molecular factors that contribute to the duration of cytokine signaling
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
Receptor expression at the cell surface
Cytokine and their receptors are classified based on strcutural similarities
Ligand confromation directs receptor interaction
Ligand: receptor interactions
- 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.
Ligand:
Receptor affinity dictates signaling outcomes
Ligand: receptor interactions
- 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»_space; IL17F homodimers»_space;> IL-17:Il-17F heterodimers
Sharing kinases and transcription factors:
Type I and II cytokine receptors
Ligand: receptor interactions
- Four janus Kinases which distinctly engage receptors
- STATs: differentially expressed across cell types and can from unique transcriptional complexes.
Type I and II Receptors
JAK/STAT signaling
Ligand: receptor interactions
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
Type I Receptors
The common gamma chain family of cytokines
Ligand: receptor interactions
Functional redundancy:
The Interferon (IFN) Receptors
Ligand: receptor interactions
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
SOCS proteins prevent excessive inflammation
Molecules that regulate signal transduction
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
Decoy receptors can inhibit cytokine signaling
Molecules that regulate signal transduction
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)
Inborn erros in immunity
Host Genetics and Interactions with pathogens
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
Dysregulation of cytokine signaling drives disease
Therapeutic targeting of cytokine receptors
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.
Cytokine signaling in a nutshell
Conclusion
