Neutrophils transcription factors

Neutrophil-Specific Granule Deficiency. In this rare disorder, secondary or specific granules in neutrophils are absent. The defect may arise from a mutation that leads to the loss of function of the transcription factor CCAAT/enhancer binding protein e (C/EBPe), which is needed for neutrophil response to inflammation (91). Specific granule deficiency affecfs fhe migration of neutrophils. 

It is possible to measure the formation of various radicals such as reactive oxygen species in cells. Reactive oxygen species (ROS) activate the nuclear factor of activated T cell transcription factor (NFAT), which is associated with its dephosphorylation, nuclear translocation, and increased affinity for DNA binding. Vanadium activation of nuclear factor of activated T cells (NFAT) was found to correlate with formation of the ROS H202 and was dependent upon the activity of calcium channels [39], In activated human neutrophiles, vanadium(II), (III), and (IV) increased hydroxyl radical formation and attenuation of myeloperoxidase activity, whereas V(V) did not show these effects. Similar results were seen in a cell-free system [40], Increased lipid peroxidation in liver but not in kidneys was found in normal rats treated with vanadate [41]. 

The failure of antioxidant mechanisms to correct redox disequilibrium could lead to the escalation of oxidative to tier 2. Tier 2 cellular responses are characterized by the activation of cellular signaling pathway such as stress-activated kinases (p38 MAP kinase and JNK) along with activation and nuclear translocation of transcription factors NF-kB and STAT-1. NF-KB-induced transcriptional activation leads to the production of a number of pro-inflammatory cytokines, including the neutrophil chemoattractant IL-8. STAT-1 activation stimulates the increased production of CXC-motif chemokines that function in lymphocyte recruitment and activation. Therefore, tier 2 oxidative responses result in an inflammatory response in the lung. 

The molecular mechanism of the NO pro-inflammatory activity is also multifaceted NO regulates the inflammatory responses by cell-specific inhibition of the transcription factor NF-kB, IL-ip, interferon-y (IFNy). At sites of inflammation, increased free radical activity is associated with the activation of the neutrophil NADPH-oxidase and/or the uncoupling of a variety of redox systems, leading to a substantial increase in ROS. Free radicals thus produced, have the capacity to mediate tissue destruction, either alone or in concert with proteases [53]. 

Enzyme-catalyzed reactions Electron transport in mitochondria Signal transduction and gene expression Activation of nuclear transcription factors Oxidative damage to molecules, cells, and tissues Antimicrobial action of neutrophils and macrophages Aging and disease... 

In addition to the STAT and NF-kB families, other transcription factors have been reported to be expressed in neutrophils, and others still are likely to be present. These will be briefly covered in this section. 

McDonald PP, Bovolenta C, Cassatella MA Activation of distinct transcription factors in neutrophils by bacterial LPS, interferon-7, GM-CSF and the necessity to overcome the action of endogenous proteases. Biochemistry 1998 37 13165-13173. 

McDonald PP, Cassatella MA Activation of transcription factor NF-kB by phagocytic stimuli in human neutrophils. FEBS Lett 1997 412 583-586. 

Sugita N, Kimura A, Matsuki Y, Yamamoto T, Yoshie H, Hara K Activation of transcription factors and IL-8 expression in neutrophils stimulated with lipopolysaccharide from Porphyromonas gingivalis. Inflammation 1998 22 253-267. 

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