Signal transduction via the NF‐κB pathway: a targeted treatment modality for infection, inflammation and repair

Abstract

Activation of transcription factors plays a pivotal role in many signal transduction pathways. Of particular interest is NF-kappaB, which is present in the cytoplasm in an inactive form, where it can be activated in response to many different stress conditions such as infection, inflammation, heat shock etc. It has also been associated with apoptosis and tissue repair. Modulation of signal transduction events that mediate activation of NF-kappaB seems to have a great potential in not only treating many disease conditions, but also in tissue repair. The present review article is an attempt to put together many different conditions where the NF-kappaB activation pathway appears to be crucial in transducing signals under stress conditions, and to explore the possibility of its modulation as a targeted treatment modality.

Albaconol, a Plant-Derived Small Molecule, Inhibits Macrophage Function by Suppressing NF-κB Activation and Enhancing SOCS1 Expression

“…One of these common pathways is known to be NF-κB, as it controls the expression of proinflammatory genes such as cytokines, adhesion molecules and cytotoxic molecule-generating enzymes including iNOS and COX-2 (23,24). So, many researchers are trying to develop potent inhibitors of NF-κB as a novel anti-inflammatory drug.…”

Chronic Lymphocytic Leukemia: A Paradigm of Innate Immune Cross-Tolerance

“…In particular, TLR4 has been described as the primary LPS sensor. Its activation leads NF-kB translocation into the nucleus and, subsequently, the transcription of inflammatory genes, such as TNFa, IL1b, IL6, and IL12 (40)(41)(42)(43). Defects in TLR4 signaling have been observed at the level of the receptor, adaptors (MyD88 and TRIF) (44,45), signaling molecules, and transcription factors.…”

Prohibitin Inhibits Tumor Necrosis Factor alpha–induced Nuclear Factor-kappa B Nuclear Translocation via the Novel Mechanism of Decreasing Importin α3 Expression

“…As shown in Figure 3A, cells treated with TNF-␣ showed a 45% decrease in promoter activity compared with vehicle-treated cells transfected with full-length promoter (Ϫ1054), indicating that TNF-␣ decreases PHB promoter activation. Because NF-B is a major downstream signaling molecule of TNF-␣ (Ali and Mann, 2004), cells were pretreated with various doses of PDTC, an NF-B inhibitor, for 30 min followed by treatment with TNF-␣ for 6 h. The TNF-␣-induced decrease in PHB promoter activity was dependent on the dose of PDTC used and was completely abolished in cells pretreated with 100 M PDTC ( Figure 3A). These results suggest that the TNF-␣-induced decrease in PHB promoter activity is dependent on NF-B.…”

“…A major signaling pathway activated by TNF-␣ is the nuclear factor-kappa B (NF-B) pathway, which plays a central role in inflammatory responses and also regulates transcription of multiple cytokines including interleukin (IL)-2, IL-6, IL-8, TNF-␣, and ICAM-1 (Ali and Mann, 2004), and is required for regulation of apoptosis and proliferation of intestinal epithelia (Steinbrecher et al, 2008). In most cells, the predominant form of NF-B is comprised of a heterodimer of p50 (NF-B1) and p65 (Rel-A) that is sequestered in the cytosol complexed to inhibitory I B proteins, preferentially I B-␣.…”