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 TNF- R1 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, caspase- 8 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

Figure 1. Regulation of T H 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 T H 1 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 T H 1 development. Toll-like receptors: critical proteins linking innate and acquired immunity

The IL-1R–TLR signaling pathway. Molecular components involved in IL-1R and TLR4 signaling are shown. Activated IL- 1R1 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

Signaling to chromatin through histone modifications Mitogen (EGF) stimulation (Rsk-2)