Relationship Between NFKB and NO

One of the major sites of action of NFKB is the activation of iNOS. In 1993, it was shown that the murine gene coding iNOS contained two putative NFKB

TNF-a

TNF-a receptor I

Survival pathway

Death pathway

IkB kinase complex

Caspase activation

IkB kinase complex

Caspase activation

P50 P65 Ikb

Figure 10.4 Life and death decisions in cells. Cellular stimulation with tumour necrosis factor-a (TNFa) simultaneously activates survival and death signalling pathways. Reprinted with permission from Nature (from Pomerantz and Baltimore, 2000). Copyright (2000) Macmillan Magazines Limited. p50 and p65 are subunits of NFKB

Figure 10.4 Life and death decisions in cells. Cellular stimulation with tumour necrosis factor-a (TNFa) simultaneously activates survival and death signalling pathways. Reprinted with permission from Nature (from Pomerantz and Baltimore, 2000). Copyright (2000) Macmillan Magazines Limited. p50 and p65 are subunits of NFKB

binding sites, one of which, NF-KBd, is necessary to confer inducibility by bacterial lipopolysaccharide (Xie etal., 1993). Stimulation of RAW 264.7 macrophages with LPS showed NFKB/Rel activation (p50-p50 and p50-p60) and binding to both NFKB sites in the mouse iNOS promoter (Goldring et al., 1995). Therefore activation of NFKB should lead to the transcription of iNOS. The regulatory cross-talk between iron metabolism and NO in macrophages is further highlighted by the transcriptional regulation of the iNOS gene by iron. Hence in macrophages the regulation of iron metabolism and NO is tightly connected. Recent studies in our laboratories have shown that alveolar macrophages, isolated from iron loaded rats decrease NO release after an LPS/IFNg challenge (Legssyer et al., 2001), possibly reflecting two pathways: (i) the presence of iron acting as a catalyst in NFKB activation via production of hydroxyl radicals from Fenton chemistry, and (ii) a decrease in iNOS transcription and translation due to its regulatory loop between iron metabolism and the NO/NOS pathway of iron metabolism (Weiss et al., 1994).

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