What does tumour necrosis factor excess do to the immune system long term?
Members of the tumour necrosis factor (TNF)/TNF-receptor (TNF-R) superfamily coordinate the immune response at multiple levels. For example, TNF, LTalpha, LTbeta and RANKL provide signals required for lymphoid neogenesis, CD27, OX-40, 4-1BB and CD30 deliver costimulatory signals to augment immune responses, while pro-apoptotic members such as TNF, CD95L and TRAIL may contribute to the termination of the response. Biological identity of individual family members has been revealed through studies of gain of function or gene deficient mutants. Most notable are the development of spontaneous inflammatory polyarthritis in human TNF-globin transgenic mice, the auto-inflammatory syndromes resulting from mutations in the 55-kDa TNF-R, and, in particular, the obligatory role for the RANKL/RANK axis in osteoclastogenesis and bone remodelling. A growing appreciation of the molecular basis of signalling pathways transduced by TNF-R has provided a framework for better understanding the biology of this expanding family. For while the rapid and robust activation of NF-kappaB and MAPK pathways is typical of acute TNF-R engagement, the molecular basis of sustained receptor signalling remains a mystery, in spite of its relevance to chronic inflammatory and immune responses. Focusing on T cells, this report describes some of the molecular footprints of sustained TNF-R engagement and illustrates how these may influence immune function. A common theme arising is that prolonged TNF stimulation alters signalling thresholds over time. The authors propose that one major outcome of long term exposure to TNF is a state of localised IL-2 deficiency at sites of inflammation. The implications of this deficiency are discussed.
Clark
J
J
Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College, 1 Aspenlea Road, Hammersmith, London W6 8LH, UK.
Vagenas
P
P
Panesar
M
M
Cope
A P
AP
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007107:Immune System / Q000503:physiopathology*; D007249:Inflammation / Q000276:immunology; D007376:Interleukin-2 / Q000172:deficiency; D051379:Mice; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D007376:Interleukin-2; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha