Signal Transducers and Activators of Transcription (STATs) are a family of cytoplasmic proteins with roles as signal messengers and transcription factors that participate in normal cellular responses to cytokines and growth factors. Frequently, however, abnormal activity of certain STAT family members, particularly Stat3 and Stat5, is associated with a wide variety of human malignancies, including hematologic, breast, head and neck, and prostate cancers. Application of molecular biology and pharmacology tools in disease-relevant models has confirmed Stat3 as having a causal role in oncogenesis, and provided validation of Stat3 as a target for cancer drug discovery and therapeutic intervention. Furthermore, a constitutively-active mutant form of Stat3 is sufficient to induce oncogenic transformation of cells, which form tumors in vivo. Constitutive activation of Stat3 signaling is accompanied by upregulation of cyclin D1, c-Myc, and Bcl-x, changes consistent with subversion of normal cellular growth and survival control mechanisms. Block of constitutive Stat3 signaling results in growth inhibition and apoptosis of Stat3-positive tumor cells in vitro and in vivo. The observed dependence of certain tumors on constitutive Stat3 signaling for growth and survival has wide implications for cancer therapy, offering the potential for preferential tumor cell killing. This review evaluates constitutive Stat3 activation as a 'cancer-causing' factor, and proposes a number of molecular strategies for targeting Stat3 signaling for therapeutic intervention.

STAT proteins: novel molecular targets for cancer drug discovery.

Summary: Macrolides have diverse biological activities and an ability to modulate inflammation and immunity in eukaryotes without affecting homeostatic immunity. These properties have led to their long-term use in treating neutrophil-dominated inflammation in diffuse panbronchiolitis, bronchiectasis, rhinosinusitis, and cystic fibrosis. These immunomodulatory activities appear to be polymodal, but evidence suggests that many of these effects are due to inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and nuclear factor kappa B (NF-κB) activation. Macrolides accumulate within cells, suggesting that they may associate with receptors or carriers responsible for the regulation of cell cycle and immunity. A concern is that long-term use of macrolides increases the emergence of antimicrobial resistance. Nonantimicrobial macrolides are now in development as potential immunomodulatory therapies.

Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

International Workshop on Equine Chronic Airway Disease Michigan State University 16–18 June 2000

Controversy exists over whether the lower airway inflammation that characterizes cystic fibrosis (CF) is initiated primarily by the genetic defect To determine if inflammation precedes infection, we examined bronchoalveolar lavage (BAL) fluid cytology, cytokines (interleukin (IL)-1beta, IL-4, IL-5, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha), and free neutrophil elastase activity from 70 CF (aged 15-71 months) children detected by newborn screening and 19 (aged 20-48 months) controls with chronic stridor CF subjects were selected and categorized as pristine (13 aged /= 10(5) colony-forming units/ml of pathogenic bacteria in BAL), and uninfected (15 aged > 6 months, asymptomatic, not taking antibiotics at bronchoscopy, and free of pathogens in their BAL) To further resolve if inflammation develops without infection, inflammatory mediators in paired annual BAL samples from 38 CF subjects were measured, and results were grouped according to whether BAL showed persistence (n = 6), acquisition (n = 8), clearance (n = 13), or absence (n = 11) of infection While pristine, uninfected, and control subjects had similar BAL profiles, infected patients showed elevated inflammatory indices, including increased IL-10 (P < 0001) Pristine subjects had the fewest signs of inflammation Analysis of BAL pairs found differences between the four infection groups for changes in neutrophil percentages, IL-8 (P < 0001), and free neutrophil elastase (P = 0009) Infection was associated with elevated inflammatory mediators in BAL fluid In contrast, minimal or reduced signs of inflammation accompanied absence of eradication of infection from BAL fluid We conclude that in CF, infection initiates and sustains airway inflammation

Lower Airway Inflammation in Infants with Cystic Fibrosis Detected by Newborn Screening

To reveal the causal role of airway epithelial NF-kappaB activation in evoking airway inflammation, a transgenic mouse was created expressing a mutant version of the inhibitory protein I-kappaBalpha This I-kappaBalpha superrepressor (I-kappaBalpha(SR)) acts to repress NF-kappaB activation exclusively in airway epithelial cells, under the transcriptional control of the rat CC10 promoter (CC10-I-kappaBalpha(SR)) Compared with transgene-negative littermates, intranasal instillation of LPS did not induce nuclear translocation of NF-kappaB in airway epithelium of CC10-I-kappaBalpha(SR) transgenic mice Consequently, the influx of neutrophils into the airways and secretion of the NF-kappaB-regulated neutrophilic chemokine, macrophage-inflammatory protein-2, and the inflammatory cytokine, TNF-alpha, were markedly reduced in CC10-I-kappaBalpha(SR) mice relative to the transgene-negative mice exposed to LPS Despite an inability to activate NF-kappaB in airway epithelium, resident alveolar macrophages from transgene-positive mice were capable of activating NF-kappaB in a manner indistinguishable from transgene-negative mice These findings demonstrate that airway epithelial cells play a prominent role in orchestrating the airway inflammatory response to LPS and suggest that NF-kappaB signaling in these cells is important for modulating innate immune responses to microbial products

A prominent role for airway epithelial NF-kappa B activation in lipopolysaccharide-induced airway inflammation.

Cystic fibrosis (CF) is characterised by chronic airway inflammation. Pro-inflammatory mediators in the lung are regulated by the transcription factor nuclear factor kappa B (NFκB). We have assessed the effect of adenovirus and liposome-mediated overexpression of the NFκB inhibitor IκBα, as well as liposome-mediated transfection with oligonucleotides resembling NFκB consensus binding sites (decoys) in a cystic fibrosis airway epithelial cell line (CFTE). Electrophoretic mobility shift assays (EMSA) were used to assess NFκB activity and secretion of the pro-inflammatory cytokine interleukin-8 (IL-8) was measured by ELISA. At a MOI of 30, Ad-IκBα significantly decreased IL-8 secretion to 60% and 43% of control unstimulated and TNF-α stimulated cells, respectively. At this MOI, approximately 70% of cells are transduced. EMSA showed an approximately 50% decrease in NFκB activation. Liposome-mediated transfection of IκBα did not reduce IL-8 secretion, probably due to low transfection efficiency (approximately 5% of cells). Liposome-mediated transfection of CFTE cells with rhodamine-labeled decoy oligonucleotides indicated a transfection efficiency close to 100%. TNF-α stimulated IL-8 secretion was reduced by approximately 40% using this approach. EMSA confirmed a significant decrease of NFκB activation. Decoy oligonucleotides may be a promising approach for reduction of NFκB-mediated pulmonary inflammation.

Anti-inflammatory gene therapy directed at the airway epithelium.

It is unclear whether inflammation in the cystic fibrosis (CF) lung relates predominantly to bacterial infection, or occurs as a direct consequence of mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein. Interleukin (IL)-8 secretion from CF and non-CF cell lines, and from CF and non-CF human primary nasal epithelial cells incubated with or without Pseudomonas aeruginosa , was measured. Activation of nuclear factor-κB (NF-κB) in unstimulated CF and non-CF nasal epithelial cells, cell lines and murine tissues was measured by gel-shift assays. No significant difference in basal IL-8 production or NF-κB activation was observed between CF and non-CF primary nasal cells. However, CF cells exhibited a significantly (p P. aeruginosa stimulation. Equalization of the increased P. aeruginosa adherence observed in CF cells, to non-CF levels, resulted in comparable IL-8 secretion. Further, IL-8 production did not differ with mutations which result in either correctly localized CFTR, or in partial/total mislocalization of this protein. Similar levels of NF-κB activation were observed in a number of organs of wild-type and CF mice. Finally, IL-8 secretion and NF-κB activity were not consistently increased in CF cell lines. Cos-7 cell transfection with plasmids expressing ΔF508 or G551D mutant CFTR protein resulted in increased activation of a p50-containing NF-κB complex, but IL-8 secretion was similar to wild-type cells. The authors conclude that the stimulus produced by Pseudomonas aeruginosa is the predominant inflammatory trigger in their models.

https://erj.ersjournals.com/content/erj/17/1/27.full.pdf

Inflammation in cystic fibrosis airways: relationship to increased bacterial adherence

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Anti-inflammatory gene therapy directed at the airway epithelium.

Inflammation in cystic fibrosis airways: relationship to increased bacterial adherence