Interleukin-32β Propagates Vascular Inflammation and Exacerbates Sepsis in a Mouse Model

Inflammation is associated with most diseases, which makes understanding the mechanisms of inflammation vitally important.Here, we demonstrate a critical function of interleukin-32beta (IL-32beta) in vascular inflammation. IL-32beta is present in tissues from humans, but is absent in rodents. We found that the gene is highly expressed in endothelial cells. Three isoforms of IL-32, named IL-32alpha, beta, and epsilon, were cloned from human endothelial cells, with IL-32beta being the major isoform. Pro-inflammatory cytokines (TNFalpha and IL-1beta) induced IL-32beta expression through NF-kappaB. Conversely, IL-32beta propagated vascular inflammation via induction of vascular cell adhesion molecules and inflammatory cytokines. Accordingly, IL-32beta increased adhesion of inflammatory cells to activated endothelial cells, a paramount process in inflammation. These results illustrate a positive feedback regulation that intensifies and prolongs inflammation. Importantly, endothelial/hematopoietic expression of IL-32beta in transgenic mice elevated inflammation and worsened sepsis. This was demonstrated by significant elevation of leukocyte infiltration and serum levels of TNFalpha and IL-1beta, increased vascular permeability and lung damage, and accelerated animal death. Together, our results reveal an important function of IL-32 in vascular inflammation and sepsis development.Our results reveal an important function of IL-32 in vascular inflammation and sepsis development

Long Term Functional and Esthetic Outcomes After Fibula Free Flap Reconstruction of the Mandible

Objectives: To report functional and esthetic outcomes, after fibula free flap (FFF) reconstruction of the mandible for oral cancer, assessed by physicians, non-clinicians and patients. Materials and Methods: Twenty-five long term survivors from oral cancer after FFF reconstruction were recalled for head and neck examination by surgeons and patient reported outcomes, using EORTC, QLQ C-30, H&N-35 and FACE-Q questionnaires. Results: Physicians reported 64% restoration of functionality compared to normal. Patients reported high scores on QLQ-C30, but lower scores on H&N-35. Esthetic scores were reported higher by clinicians than non-clinicians. The decline in function and appearance was attributed to loss of lower dentition, trismus, mal occlusion, xerostomia and tissue atrophy. Conclusion: To minimize the decline in function and appearance, immediate dental implants in FFF, better reconstruction of the temporomandibular joint, newer methods of radiotherapy to minimize xerostomia and oral exercises to prevent trismus should be considered

Aberrant activation of NF-κB signaling in mammary epithelium leads to abnormal growth and ductal carcinoma in situ

Gating strategy for FLOW cytometry data in Fig.  7b . An average of 100,000 events were counted for each sample. To start, all samples were taken through the first three gates (top, labeled 1, 2, 3), which excluded artifacts that were not single-cells based on forward and side scatter. From there, DAPI stain was used to determine viability (gate 4). All DAPI negative cells were carried to gate 5, where cells were split into CD45 positive and CD45 negative populations. The CD45 positive population was then gated using F4/80 on the x axis and CD45 on the y axis (gate 6). Circles indicate CD45 + F4/80+ cells. Values for the graph in Fig. 7b were obtained by taking the total number of CD45+F4/80+ cells counted for each sample and dividing that value by the total number of viable cells counted in the sample (DAPI negative). (PDF 309 kb

NF-kappa B Inducing Kinase, NIK Mediates Cigarette Smoke/TNF alpha-Induced Histone Acetylation and Inflammation through Differential Activation of IKKs

Peer reviewe

Specific effects of bortezomib against experimental malignant pleural effusion: a preclinical study

BACKGROUND: We have previously shown that nuclear factor (NF)-κB activation of mouse Lewis lung carcinoma (LLC) specifically promotes the induction of malignant pleural effusions (MPE) by these cells. In the present studies we hypothesized that treatment of immunocompetent mice with bortezomib tailored to inhibit cancer cell NF-κB activation and not proliferation specifically inhibits MPE formation by LLC cells. RESULTS: Treatment of LLC cells with low concentrations of bortezomib (100 ng/ml) inhibited NF-κB activation and NF-κB-dependent transcription, but not cellular proliferation. Bortezomib treatment of immunocompetent C57BL/6 mice bearing LLC-induced subcutaneous tumors and MPEs significantly blocked tumor-specific NF-κB activation. However, bortezomib treatment did not impair subcutaneous LLC tumor growth, but was effective in limiting LLC-induced MPE. This specific effect was evidenced by significant reductions in effusion accumulation and the associated mortality and was observed with both preventive (beginning before MPE formation) and therapeutic (beginning after MPE establishment) bortezomib treatment. The favorable impact of bortezomib on MPE was associated with suppression of cardinal MPE-associated phenomena, such as inflammation, vascular hyperpermeability, and angiogenesis. In this regard, therapeutic bortezomib treatment had identical favorable results on MPE compared with preventive treatment, indicating that the drug specifically counteracts effusion formation. CONCLUSIONS: These studies indicate that proteasome inhibition tailored to block NF-κB activation of lung adenocarcinoma specifically targets the effusion-inducing phenotype of this tumor. Although the drug has limited activity against advanced solid lung cancer, it may prove beneficial for patients with MPE

The Chemical Composition of Carbon-Rich, Very Metal-Poor Stars: A New Class of Mildly Carbon-Rich Objects Without Excess of Neutron-Capture Elements

We report on an analysis of the chemical composition of five carbon-rich, very metal-poor stars based on high-resolution spectra. One star, CS22948-027, exhibits very large overabundances of carbon, nitrogen, and the neutron-capture elements, as found in the previous study of Hill et al.. This result may be interpreted as a consequence of mass transfer from a binary companion that previously evolved through the asymptotic giant branch stage. By way of contrast, the other four stars we investigate exhibit no overabundances of barium ([Ba/Fe]<0), while three of them have mildly enhanced carbon and/or nitrogen ([C+N]+1). We have been unable to determine accurate carbon and nitrogen abundances for the remaining star (CS30312-100). These stars are rather similar to the carbon-rich, neutron-capture-element-poor star CS22957-027 discussed previously by Norris et al., though the carbon overabundance in this object is significantly larger ([C/Fe]=+2.2). Our results imply that these carbon-rich objects with ``normal'' neutron-capture element abundances are not rare among very metal-deficient stars. One possible process to explain this phenomenon is as a result of helium shell flashes near the base of the AGB in very low-metallicity, low-mass (M~< 1M_sun) stars, as recently proposed by Fujimoto et al.. The moderate carbon enhancements reported herein ([C/Fe]+1) are similar to those reported in the famous r-process-enhanced star CS22892-052. We discuss the possibility that the same process might be responsible for this similarity, as well as the implication that a completely independent phenomenon was responsible for the large r-process enhancement in CS22892-052.Comment: 53 pages, 8 figures, to appear in Ap

Cyclopentenone Isoprostanes Inhibit the Inflammatory Response in Macrophages

Although both inflammation and oxidative stress contribute to the pathogenesis of many disease states, the interaction between the two is poorly understood. Cyclopentenone isoprostanes (IsoPs), highly reactive structural isomers of the bioactive cyclopentenone prostaglandins PGA2 and PGJ2, are formed non-enzymatically as products of oxidative stress in vivo. We have, for the first time, examined the effects of synthetic 15-A2- and 15-J2-IsoPs, two groups of endogenous cyclopentenone IsoPs, on the inflammatory response in RAW264.7 and primary murine macrophages. Cyclopentenone IsoPs potently inhibited lipopolysaccharide-stimulated IkappaB alpha degradation and subsequent NF-kappaB nuclear translocation and transcriptional activity. Expression of inducible nitric-oxide synthase and cyclooxygenase-2 were also inhibited by cyclopentenone IsoPs as was nitrite and prostaglandin production (IC50 approximately 360 and 210 nM, respectively). 15-J2-IsoPs potently activated peroxisome proliferator-activated receptor gamma (PPARgamma) nuclear receptors, whereas 15-A2-IsoP did not, although the anti-inflammatory effects of both molecules were PPARgamma-independent. Interestingly 15-A2-IsoPs induced oxidative stress in RAW cells that was blocked by the antioxidant 4-hydroxy-TEMPO (TEMPOL) or the mitochondrial uncoupler carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone. TEMPOL also abrogated the inhibitory effect of 15-A2-IsoPs on lipopolysaccharide-induced NF-kappaB activation, inducible nitricoxide synthase expression, and nitrite production, suggesting that 15-A2-IsoPs inhibit the NF-kappaB pathway at least partially via a redox-dependent mechanism. 15-J2-IsoP, but not 15-A2-IsoP, also potently induced RAW cell apoptosis again via a PPAR gamma-independent mechanism. These findings suggest that cyclopentenone IsoPs may serve as negative feedback regulators of inflammation and have important implications for defining the role of oxidative stress in the inflammatory response