Transcript Document

TNF superfamily
TNF: produced by macrophages, monocytes,
lymphocytes, fibroblasts upon inflammation,
infection, injury, environmental challenges.
Important for innate and adoptive immunity.
TNF: inflammatory responses to microbial
infections.
LT (lymphotoxin):cellular or hymoral immunity
FASL, TRAIL, TNF: apoptosis
The TNF and TNFR superfamilies
Tumor-necrosis factor (TNF) was discovered as a serum factor
that was able to kill cancer cells in mice. The TNF receptor
(TNFR) led to the discovery of a superfamily of transmembrane
proteins.
There are 18 ligands and 28 receptors many of which are being
targeted for therapeutic purposes.
TNFR signaling is important for the immune response and
FASL and APO2L/TRAIL (TNF Related Apoptosis Inducing
Ligand) induce apoptosis in a p53-independent way.
Members of the TNFR superfamily can be divided in two
groups: one class of receptors called death receptors DR
contains a cytoplasmic death domain (DD), whereas the other
class does not.
Some TNFR members do not signal but act as “decoys” that
compete with receptors for ligands. Some tumor cells
overexpess decoy receptors.
TNF signal transduction
pathway. Engagement of TNF
with its cognate receptor TNFR1 results in the release of
SODD and formation of a
receptor-proximal complex
containing the important
adaptor proteins TRADD,
TRAF2, RIP, and FADD. These
adaptor proteins in turn recruit
additional key pathway-specific
enzymes (for example, caspase8 and IKK ) to the TNF-R1
complex, where they become
activated and initiate
downstream events leading to
apoptosis, NF- B activation,
and JNK activation
Fas L-induced apoptosis by autoproteolytic processing of
casp-8
Cross-talk between:
apoptosis, NFκB and
JNK/AP-1
TNF: positive feed back
Toll-like receptors: critical proteins linking innate and
acquired immunity
Figure 1. Regulation of TH cell development by TLRs on APCs. Through the
recognition of pathogens or their products, TLRs can induce the production of
cytokines such as IL-12 and IL-18 in APCs. These cytokines function as "instructive"
cytokines and drive naïve T cells to differentiate into TH1 cells. Pathogens are also
captured in multiple ways, including phagocytosis, endocytosis or via TLRs
themselves. Captured pathogens are then processed and presented to T cells as
major histocompatibility complex–antigen. This up-regulation is also triggered by
TLR signaling. TLR-stimulated APCs mainly induce TH1 development.
The IL-1R–TLR
signaling pathway.
Molecular components
involved in IL-1R and
TLR4 signaling are
shown. Activated IL1R1 or TLR4
associates with a
cytoplasmic adaptor
molecule, MyD88,
through the homophilic
interaction between
their TIR domains.
MyD88 also possess
the death domain,
which mediates the
association with a
serine-threonine
kinase, IRAK
Toll Like Receptors
Drosophila: Fungal infections trigger generation of Spatzle
through proteolysis
Spazle = ligand of Toll
Mammalian TLR recognize microbial components (LPS,
CpG DNA) directly
NFκΒ activation by TNFR and TLR receptors.
NFκB
CBP/p300 as co integrators of diverse
signaling pathways
Mitogen (EGF) stimulation
(Rsk-2)
Signaling to chromatin through histone modifications