tnf alpha pathway Flashcards
what are the main categories in the TNF superfamily?
morphogenesis, apoptosis, proliferation
what are the main medical uses of TNF alpha?
anti tumour agent able to shrink tumours in mice and target for treatment of diseases like rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriasis
how can tnf alpha be delivered as an anti-tumour agent
administered to soft tissue sarcomas and melanomas in the extremities by in limb perfusion
what kind of molecule is TNF?
cytokine involved in the immune response
why can tnf alpha not be used for treatment systemically?
it cannot be injected into the bloodstream as it is pro-inflammatory
how high is tnf alpha expression in quiescent cells under normal conditions and why?
barely expressed as there is no challenge so no need for the powerful pro inflammatory cytokine
what transcription factors are involved in transcription of tnf alpha?
NFKb, NFAT, CREB
what is the result of chronic tnf output?
diseases like rheumatoid arthritis and psoriasis
how does the transmembrane form of tnf alpha transmit messages?
cell to cell communication
how does the soluble form of tnf alpha transmit messages
it is released from the cell into the bloodstream
how is sTNF formed?
cleavage of transmembrane tnf by tnf converting enzyme (TACE)
what are the characteristics of the tnfr1 receptor?
it is always expressed and is found on nearly every cell type, characterised by a death domain due to its ability to cause apoptosis. irreversibly binds soluble tnf and can also bind transmembrane tnf
how high is tnf alpha expression in quiescent cells under stress like bacteria, viruses, irradiation?
higher expression
what are the characteristics of tnfr2 receptor?
it is highly regulated and is mainly found in immune cells, though can also be found in other cells eg cardiac muscle. it binds soluble tnf in a reversible manner and is thought to only be fully activated by transmembrane tnf alpha
how are soluble tnfrs formed?
the extracellular domains of tnfr1 and tnfr2 can be cleaved proteolytically by matrix metalloproteinase enzymes such as TACE
what is the function of soluble tnfrs?
to be an endogenous inhibitor of tnf as it binds to it, preventing it from binding to membrane bound tnfr and transducing a signal, dampening down inflammation
what disease is linked to cleavage resistant tnfr1 mutations?
dominantly inherited autoinflammatory syndromes - tnfr1 associated periodic syndromes
how does the affinity of soluble tnfr compare to transmembrane tnfr?
ow affinity due to the membrane receptors cooperativity enhancing their binding strength
what is the role of tnf alpha in maintaining health?
lack of tnf or tnfr shows impaired wound healing, host defence against pathogens, activation of immune cells, cell proliferation and survival and appropriate apoptosis
what is the impact of an absence of tnf alpha in mice?
high susceptibility to infectious agents
what is the impact of an absence of tnfr1 in mice?
resistance to low levels of endotoxin and increased susceptibility to infection
what is the impact of an absence of tnfr2 in mice?
increased sensitivity to pathogens, reduced antigen induced t cell apoptosis
what human diseases can be caused by mutations in tnf alpha, tnfr1 and tnfr2?
tnf alpha - cerebral infarction, tnfr1 - tnfr1 associated periodic syndrome and crohn’s disease, tnfr2 - crohn’s disease
