Term
|
Definition
- Help develop cellular and humoral responses: IL-4 antibody; IL-2 T cell growth factor
- Inductiono of inflammation: IL-1
- Wound healing
- Regulation of hematopoiesis
- Induction of cytokine secretion is antigen specific, effects are not
- Activated T cells secrete cytokines, naive T cell do not
|
|
|
Term
| Functional Groups of Cytokines |
|
Definition
- TNF-alpha (tumor necrosis factor)
- IFN-alpha (interferon)
- IL-2 (interleukin)
- IL-4
- IL-5
- TGF-beta (transforming growth factor)
- IFN-gamma
|
|
|
Term
| TNFalpha blockade used in clinic |
|
Definition
- Enbrel - chimeric TNF-receptor/IgG constant region - Rheumatoid arthritis
- Remicade - Monoclonal antibody against TNFalpha receptor - Rheumatoid arthritis, Crohns
- Humira - Monoclonal antibody against TNFalpha receptor - Rheumatoid arthritis, Crohns
- Approved for: psoriasis, Crohns, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, ulcerative colitis -life saving drugs
|
|
|
Term
| Viral mimics of cytokines and cytokine receptors |
|
Definition
- Leporipoxvirus (a myxoma virus)
- Soluble IFN-gamma receptor
- Several poxviruses
- Soluble IFN-gamma receptor
|
|
|
Term
| Cytokine Receptor Families |
|
Definition
- 5 families grouped together due to similar structures
- Immunoglobulin superfamily receptors
- Class I cytokine receptors
- Class II cytokine receptors
- TNF receptors
- Chemokine receptors
|
|
|
Term
| Immunoglobulin superfamily receptors |
|
Definition
- Three repeats of S-S on bubble
- Ligands - (IL-1)
|
|
|
Term
| Class I cytokine receptors (hematopoietin) |
|
Definition
- Two conserved cysteines (top), two WSXWS (bottom)
- Ligands
|
|
|
Term
| Class II Cytokine Receptors |
|
Definition
- Structure: two CC on top of two CC
- Ligands
- IFN-alpha
- IFN-beta
- IFN-gamma
- IL-10
|
|
|
Term
|
Definition
- Structure: 4 units stacked on top of each other composed of (C1/C3/C2)(C1/C3/C2)......
- Ligands
|
|
|
Term
|
Definition
- Structure: imbedded in membrane with G protein
- Ligands
- IL-8
- RANTES
- MIP-1
- PF4
- MCAF
- NAP-2
|
|
|
Term
|
Definition
- Can be made of multiple subunits: redundancy in composition of receptors made up of diff. subunits
- Certain subfamilies have subunits in common
- Some induce the upregulation of an additional receptor subunit chain leading to the formation of high affinity receptors: IL-2; IL-15
|
|
|
Term
| GM-CSF receptor subfamily (common beta subunits) |
|
Definition
|
|
Term
| IL-6 Receptor subfamily (common gp130 subunit) |
|
Definition
|
|
Term
| IL-2 Receptor subfamily (common gamma subunit) |
|
Definition
- IL-2
- IL-15
- IL-7
- IL-9
- IL-4
|
|
|
Term
| Low and High Affinity Receptors |
|
Definition
- Low-Affinity Receptors (alpha alone)
- IL-3 to alpha
- IL-5 to alpha
- GM-CSF to alpha
- High-Affinity Receptors (alpha and beta)
- IL-3 to alpha and beta
- IL-5 to alpha and beta
- GM-CSF to alpha and beta
|
|
|
Term
| Differences in outcomes results from availability of cytokine and competition for beta subunits |
|
Definition
- Ex. IL-3 out competes GM-CSF for beta subunits which bind to the alpha subunits which are bound to IL-3
|
|
|
Term
| General Overview of Signal Transduction |
|
Definition
- Begins with ligation of a (cell surface) receptor
- Activation of protein kinases (adds phosphate)/ inhibition of phosphatases
- Docking of adaptor molecules to (phosphorylated) cytoplasmic domains of the receptor or ass. polypep.
- Signal amplification by adaptor molecules
- Activation of transcription factors
- Induction of gene expression
|
|
|
Term
| What happens when a cytokine binds a receptor? |
|
Definition
- Receptor is composed of diff. subunits, which vary in ability to transduce signals and bind cytokine
- Diff. inactive protein tyrosine kinases are associate with diff. subunits of the receptor (Janus Kinase Fam)
- Cytokine binding causes asso. of the receptor subunits and JAKs on the diff. subunits activate each other when in close proximity
- Activated JAKs create a docking site for transcription factors STATs by phosphorylating specific tyrosine residues on cytokine receptor sub.
- After JAKs phosphorylate STATs, the STATs dimerize and translocate to the nucleus to induce gene expression
|
|
|
Term
|
Definition
- Cytokine
- Dimerization of receptor
- Activation of JAK family tyrosine kinases, phosphorylation of receptor
- Tyrosine phosphorylation of STAT by JAK kinase
- Dimerization of STAT
- Specific gene transcription
|
|
|
Term
| Negative feedback loop after JAK/STAT activation leading to reducing signaling by blocking catalytic acitivity of JAK |
|
Definition
- IL-3 (gp130) JAK - phosphorylated
- STAT3 activation
- Acute Phase Proteins & SOCS-1
- SOCS-1: Inhibition
|
|
|
Term
|
Definition
- Mammalian JAK family has four members: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2)
- Mutation in TYK2 gene has been associated with hyperimmunoglobulin E syndrome
- Several mammalian STAT (signal transduces and activators of transcription) family members: STAT1, STAT2, STAT3, STAT4, STAT5 (A & B) and STAT6
|
|
|
Term
|
Definition
- Latent cytoplasmic transcription factors that req. phosphorylation for nuclear retention
- Unphosphorylated STAT proteins shuttles between cytosol and nucleus waiting for activation signal
- Once activated transcription factors reach the nucleus it binds to consensus DNA-recognition motif in the promoter region of cytokine inducible genes and activates transcription of these genes
|
|
|
Term
| STAT and JAK interaction with selected cytokine receptors during signal transduction |
|
Definition
- IFN-gamma - JAK1/2 -STAT1
- IFN-alpha/beta -JAK1 TYK2 - STAT 2
- IL-2 - JAK1 and JAK3 - STAT5
- IL-3 - JAK2 - STAT5
- IL-4 - JAK1 and JAK3 - STAT6
- IL-6 - JAK1 - STAT3
- IL-10 - JAK1 and TYK2 - STAT3
- IL-12 - JAK2 and TYK2 - STAT4
|
|
|
Term
| Recycling Signaling Components |
|
Definition
- Extracellular binding of cytokines induces activation of intracellular JAKs that phosphorylates a specific tyrosine residue in STAT protein promoting dimerization of STAT monomers via SH2 domain.
- Phosphorylated dimer is actively transported -nucleus
- Active STAT dimer binds to cytokine inducible promoter regions of genes containing gamma activated site GAS motif and activate transcription of genes
- STAT protein can be dephosphorylated by nuclear phosphatates which leads to inactivation of STAT and the transcription factor becomes transported out of nucleus
|
|
|
Term
| Clinical Therapeutic based on JAK/STAT signaling |
|
Definition
- Lestaurtinib
- JAK2, for acute myelogenous leukemia (AML)
- Tofacitinib
- JAK3 for psoriasis and rheumatoid arthritis
- Ruxolitinib
- JAK1/2 for psoriasis, myelofibrosis, rheumatoid
- CYT387
- JAK2 for myeloproliferative disorders
|
|
|
