No abstract is provided for this article.
It is not known whether one or both of the interleukin 1 (IL1) receptors mediates the induction of the DNAbinding protein NF-KB.Nuclear extracts of the murine lines EL4.NOB.1 and 70213, which bear the type I (80 kDa) and type I1 (67 kDa) IL1 receptor, respectively, were analyzed by an electrophoretic mobility shift assay.A 265-base pair sequence of the human serum amyloid A gene or a synthetic oligonucleotide each containing the NF-KB site were used as the DNA probes.IL1 induction of NF-KB was rapid (optimal at 15-30 min) and transient in both cell types.The IL1 receptor antagonist (ILlra), which binds strongly to the type I receptor, inhibited the NF-KB response in both cell lines.ILlra did not bind to the type I1 receptor on 70213 cells as judged by competition for binding with ''61-ILla.When 1261-ILlra binding to 702/3 cells was measured, a small number (10/cell) of high affinity sites (& = 6 % 10"' M) were detected.These were likely to have been type I receptor because an antibody to this inhibited the NF-KB induction in 70213 cells (as well as EL4).Potential signal transduction mechanisms involving protein kinase C or oxygen radicals were studied.Phorbol 12-myristate 13-acetate induced NF-KB with a similar time course to IL1 in 70213 but only after 4 h in EL4.IL1 was unaffected by a protein kinase C inhibitor (staurosporine).HzOz did not mimic IL1, and IL1 was not inhibited by an antioxidant.The type I receptor mediates the induction of NF-KB in response to IL1 via a signaling mechanism that still remains to be identified.The central role of IL1' in mediating multiple immunological and inflammatory events has been documented extensively (Dinarello, 1991).IL1 binds independently to two dis-
No abstract is provided for this article.
Immune cells divide rapidly when mounting an immune response against a pathogen, for example, or when initiating a wound-healing response. To accommodate the increased energy requirements to mount the immune response, these cells may employ metabolic pathways similar to those engaged by cancer cells—pathways such as aerobic glycolysis. This correlation presents the intriguing possibility that understanding immune cell metabolism will provide new and actionable insights into the behavior of tumor cells. In this webinar, our expert speakers will explore how this phenomenon is being studied and describe how it could enable the development of new strategies in the fight against cancer. View the Webinar
Nuclear factor-κB (NFκB) is a transcription factor with a pivotal role in inducing genes involved in physiological processes as well as in the response to injury and infection. A model has been proposed whereby the diverse agents that activate NFκB do so by increasing oxidative stress within the cell. Activation of NFκB involves the phosphorylation and subsequent degradation of an inhibitory protein, IκB, and recently many of the proximal kinases and adaptor molecules involved in this process have been elucidated. Additionally, we now understand in detail the NFκB activation pathway from cell membrane to nucleus for interleukin-1 (IL-1) and tumour necrosis factor (TNF). This review revisits the evidence for the oxidative stress model in light of these recent findings, and finds little in the new information to rationalise or justify a central role for oxidative stress in NFκB activation. We demonstrate that much of the evidence for the involvement of oxidative stress is either specific to a stimulus in a particular cell line or open to reinterpretation. In particular, the activation of NFκB by hydrogen peroxide is cell-specific and distinct from physiological activators such as IL-1 and TNF, while inhibition by antioxidants, also found to be cell- and stimulus-specific, can involve diverse and unexpected targets which may be distinct from redox modulation. We conclude that in most cases the role of oxidative stress in NFκB activation is at best facilitatory rather than causal, if a role exists at all. In addition, other evidence suggests a role for lipid peroxides in pathways where such a role exists. In future, when a role for oxidative stress in a pathway is postulated, the challenge will be to show which particular kinases or adaptor molecules, if any, are redox-modulated.
No abstract is provided for this article.
The interleukin 1 toll-like receptor superfamily is an expanding family of receptors, functioning as a rapid defense response to infection and injury, and possibly having other roles in human disease.
The family of Toll-like receptors have garnered much interest because of their ability to detect bacterial and viral molecules and to activate the innate immune response. In his Perspective, O9Neill introduces a trio of papers ( Zhang et al., Heil et al., and Diebold et al.) that provide new information about how Toll-like receptors activate innate immunity.
