Tangible document sharing: handing over paper documents across a videoconferencing display.

Conventional techniques for sharing paper documents in teleconferencing tend to introduce two inconsistencies: 1) media inconsistency: a paper document is converted into a digital image on the remote site; 2) space inconsistency: a workspace deliberately inverts the partner's handwriting to make a document easy to read. In this paper, we present a novel system that eliminates these inconsistencies. The media and space inconsistencies are resolved by reproducing a real paper document on a remote site and allowing a user to handover the paper document to a remote partner across a videoconferencing display. From a series of experiments, we found that reproducing a real paper document contributes to a higher sense of information sharing. We also found that handing over a document enhances a sense of space sharing, regardless of whether the document is digital or paper-based. These findings provide insights into designing systems for sharing paper documents across distances.

Glucocorticoid-induced TNF receptor family-related protein functions as a costimulatory molecule for murine eosinophils.

Eosinophils are typical effector cells associated with type 2 immune responses and play key roles in the pathogenesis of allergic diseases. These cells are activated by various stimuli, such as cytokines, chemokines, and growth factors, but the regulatory mechanisms of eosinophil effector functions remain unclear. Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR), a transmembrane protein belonging to the tumor necrosis factor (TNF) receptor superfamily, is a well-known regulatory molecule for T cell activation. Here, we show that GITR is also constitutively expressed on eosinophils and functions as a costimulatory molecule for these cells. Although degranulation was unaffected by GITR engagement of murine bone marrow-derived eosinophils, secretion of inflammatory cytokines such as interleukin (IL)-4, IL-6, and IL-13 from IL-33-activated bone marrow-derived eosinophils was augmented by anti-mouse GITR agonistic antibody (DTA-1). In conclusion, our results provide a new regulatory pathway of cytokine secretion from eosinophils in which GITR functions as a costimulatory molecule.

Myeloid differentiation protein-2 has a protective role in house dust mite-mediated asthmatic characteristics with the proinflammatory regulation of airway epithelial cells and dendritic cells.

BACKGROUND: Myeloid differentiation protein-2 (MD-2) is a lipopolysaccharide-binding protein involved in lipopolysaccharide signalling via Toll-like receptor 4 (TLR4). TLR4 plays an essential role in HDM-mediated allergic airway inflammation. Moreover, MD-2 is structurally similar to Der f 2, a major allergen from house dust mite (HDM). OBJECTIVES: We aimed to clarify the role of MD-2 in the pathogenesis of HDM-mediated allergic airway inflammation. METHODS: Wild-type (WT), TLR4 knockout and MD-2 knockout mice were subjected to intranasal instillation of HDM extract, and asthmatic features were evaluated. We also evaluated gene sets regulated by MD-2 in HDM-treated airway epithelial cells and examined the function of dendritic cells from lymph nodes and from lungs. RESULTS: Aggravated allergic airway inflammation with increased airway hyperresponsiveness was observed in MD-2 knockout mice compared with WT and TLR4 knockout mice. Global gene expression analysis revealed an MD-2 regulated proinflammatory response and reconstituted TLR4 signalling in airway epithelial cells. The ability of dendritic cells to evoke an allergic immune response was enhanced in MD-2 knockout mice. CONCLUSIONS & CLINICAL RELEVANCE: MD-2 plays a protective role in HDM-induced airway allergy with the proinflammatory regulation of airway epithelial cells and dendritic cells. MD-2 may serve as a therapeutic target in the treatment of asthma.

Anti-TLR7 Antibody Protects Against Lupus Nephritis in NZBWF1 Mice by Targeting B Cells and Patrolling Monocytes.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and multiple organ damage. Toll-like receptor 7 (TLR7), an innate immune RNA sensor expressed in monocytes/macrophages, dendritic cells (DCs), and B cells, promotes disease progression. However, little is known about the cellular mechanisms through which TLR7 drives lupus nephritis. Here, we show that the anti-mouse TLR7 mAb, but not anti-TLR9 mAb, protected lupus-prone NZBWF1 mice from nephritis. The anti-TLR7 mAb reduced IgG deposition in glomeruli by inhibiting the production of autoantibodies to the RNA-associated antigens. We found a disease-associated increase in Ly6Clow patrolling monocytes that expressed high levels of TLR7 and had upregulated expression of lupus-associated IL-10, CD115, CD31, and TNFSF15 in NZBWF1 mice. Anti-TLR7 mAb abolished this lupus-associated increase in patrolling monocytes in the circulation, spleen, and glomeruli. These results suggested that TLR7 drives autoantibody production and lupus-associated monocytosis in NZBWF1 mice and, that anti-TLR7 mAb is a promising therapeutic tool targeting B cells and monocytes/macrophages.

Crucial role of stimulator of interferon genes-dependent signaling in house dust mite extract-induced IgE production.

Stimulator of interferon genes (STING) is a DNA sensor that responds to pathogens and induces type I interferon production. Herein, the role of STING in house dust mite extract (HDM)-induced allergic asthma was investigated. C57BL/6 wild-type (WT) and Sting-/- mice were intratracheally sensitized with HDM, and the bronchoalveolar lavage fluid (BALF), sera, lungs, and mediastinal lymph nodes (MLNs) were analyzed. The total and HDM-specific serum IgE levels were lower in Sting-/- mice than in WT mice. B cell and IgE-positive B cell proportion in BALF and MLNs, respectively, was significantly lower in Sting-/- mice than in WT mice. Additionally, cyclic GMP-AMP, a STING ligand, augmented total and HDM-specific serum IgE levels and B cell proportion in BALF when applied in combination with HDM. To elucidate the role of STING in IgE production, follicular helper T (Tfh) cells, which are involved in B cell maturation, were investigated. Tfh cell proportion in MLNs decreased in Sting-/- mice, and IL-4 and IL-13 production by HDM-restimulated MLN cells from HDM-sensitized mice was decreased in Sting-/- mice compared with WT mice. Thus, STING plays an important role in the maturation and class switching of IgE-producing B cells in allergic inflammation via Tfh cells.

TLR9-IL-2 axis exacerbates allergic asthma by preventing IL-17A hyperproduction.

Allergic asthma is one of most famous allergic diseases, which develops lung and airway inflammation. Recent studies have revealed the relationship between the pathology of allergic asthma and the increase of host-derived DNA in inflamed lung, but the role of the DNA-recognizing innate immune receptor for the inflammation is unknown well. Here we investigated the role of Toll-Like Receptor 9 in the pathogenesis of allergic asthma without synthesized CpG-ODNs. To examine that, we analyzed the pathology and immunology of house-dust-mite (HDM)-induced allergic asthma in Tlr9-/- mice and TLR9-inhibitory-antibody-treated mice. In Tlr9-/- mice, airway hyperresponsiveness (AHR) and the number of eosinophils decreased, and production of the Th2 cytokines IL-13, IL-5, and IL-4 was suppressed, compared with in wild-type mice. Interestingly, unlike Th2 cytokine production, IL-17A production was increased in Tlr9-/- mice. Furthermore, production of IL-2, which decreases IL-17A production, was reduced in Tlr9-/- mice. Blockade of TLR9 by treatment with TLR9-inhibitory-antibody, NaR9, effectively suppressed the development of allergic asthma pathology. IL-17A production in NaR9-treated mice was enhanced, which is comparable to Tlr9-/- mice. These results suggest that the TLR9-IL-2 axis plays an important role in Th2 inflammation by modulating IL-17A production in HDM-induced allergic asthma and that targeting of TLR9 might be a novel therapeutic method for allergic asthma.

Pilot study for risk assessment of aspiration pneumonia based on oral bacteria levels and serum biomarkers.

BACKGROUND: Aspiration pneumonia is a serious problem among elderly patients; it is caused by many risk factors including dysphagia, poor oral hygiene, malnutrition, and sedative medications. The aim of this study was to define a convenient procedure to objectively evaluate the risk of aspiration pneumonia in the clinical setting. METHODS: This prospective study included an aspiration pneumonia (AP) group, a community-acquired pneumonia (CAP) group, and a control (Con) group (patients hospitalized for lung cancer chemotherapy). We used the Oral Health Assessment Tool (OHAT), which assesses oral hygiene, and evaluated performance status, body mass index, serum albumin levels, substance P values in plasma, and oral bacterial counts. RESULTS: The oral health as assessed by the OHAT of the aspiration pneumonia group was significantly impaired compared with that of the CAP group and the control (5.13 ± 0.18, 4.40 ± 0.26, 3.90 ± 0.22, respectively; p < 0.05). The oral bacterial count in the aspiration pneumonia group (7.20 ± 0.11) was significantly higher than that in the CAP group (6.89 ± 0.12), consistent with the OHAT scores. Oral bacterial count was significantly reduced by oral care. CONCLUSIONS: OHAT and oral bacterial counts can be a tool to assess the requirement of taking oral care and other preventive procedures in patients at high risk of aspiration pneumonia.

Activation through toll-like receptor 2 on group 2 innate lymphoid cells can induce asthmatic characteristics.

BACKGROUND: Type 2 innate lymphoid cells (ILC2s) are one of the sources of IL-5 and IL-13 in allergic airway inflammation. Innate immune receptors such as Toll-like receptors (TLRs) expressed on epithelial cells could contribute to ILC2 activation through IL-33 production, but a direct effect of TLRs on ILC2s remains to be elucidated. OBJECTIVES: We hypothesized that TLRs can directly activate lung ILC2s and participate in the pathogenesis of asthma. METHODS: After intranasal administration of IL-33 to wild-type (WT), TLR2KO and TLR4KO female mice, ILC2s were isolated from harvested lungs. ILC2s were incubated with IL-2 and TLR stimulants (pam3csk4 (PAM), house dust mite extract (HDM)). In some experiments, TLR2 or dectin-1 signalling inhibitors were used. As an in vivo model, the mice were treated with IL-33 and rested until lung recruitment of eosinophils regressed. Then they were treated intranasally with PAM + HDM or vehicle and analysed. RESULTS: In vitro stimulation of isolated ILC2s showed that PAM could induce IL-13 and IL-5 production, and HDM had a synergistic effect on this stimulation. Both effects were dependent on TLR2 and NF-κB signalling. PAM + HDM stimulation of WT mice led to increased ILC2s, airway hyperresponsiveness and increased levels of both neutrophils and eosinophils in bronchoalveolar lavage fluid. These observations were dependent on TLR2. CONCLUSIONS & CLINICAL RELEVANCE: TLR2 can directly activate lung ILC2s, an effect that is augmented by HDM. Asthmatic characteristics mediated through the TLR2 pathway were evident in the in vivo mice model. These data implicate a new pathway of ILC2 activation in the pathogenesis of asthma.

Age-related immune-modulating properties of seminal fluid that control the severity of asthma are gender specific.

Reproductive organs play a pivotal role in asthma development and progression, especially in women. Endocrine environment changes associated with the menstrual cycle, pregnancy, and menopause can exacerbate the clinical features of asthma. Factors secreted by reproductive organs may be responsible for the gender difference and age-related changes in adult asthma. Here, we show that mammalian seminal fluid has anti-asthma effects exclusively in females. Exposure to murine seminal fluid markedly reduced eosinophilic airway inflammation in 2-month-old female mice upon ovalbumin inhalation. The anti-asthma effect with seminal fluid from 10-month-old males was double that with fluid from 2-month-old males, suggesting that it depended on male sexual maturation. We further found that seminal fluid from middle-aged human volunteers had beneficial effects in asthmatic female mice; these effects were associated with transcriptional repression of osteopontin and IL-17A, which are poor prognostic factors for asthma. In 2-month-old male mice, however, human seminal fluid failed to decrease asthmatic features and even enhanced osteopontin and IL-17A transcription. Our data demonstrate that age-related seminal fluid exerts opposing effects in asthmatic male and female mice. These findings may help the development of novel approaches to control the prevalence and age-related progression of asthma in women.

[Association between Elimination Half-life of Benzodiazepines and Falls in the Elderly: A Meta-analysis of Observational Studies].

Benzodiazepine receptor agonists (BZDRAs) have been associated with an increased risk of falls in the elderly. However, the association between the elimination half-life (t1/2) of BZDRAs and the difference between benzodiazepines (BZDs) and non-benzodiazepines (Z-drugs) has not been clarified. By conducting a meta-analysis of observational studies, we compared the risk of falls with respect to 1) short-acting BZDRAs (t1/2<12 h) vs. long-acting BZDRAs (t1/2≥12 h) and 2) BZDs vs. Z-drugs in elderly patients. Data were retrieved from MEDLINE, the Cochrane Library, and Igaku Chuo Zasshi. In total, 13 observational studies from 12 articles were included in our study (short-acting BZDRAs, n=12; long-acting BZDRAs, n=9; BZDs, n=13; Z-drugs, n=7). The risk of falls was significantly increased by the use of short-acting BZDRAs [Odds ratio (OR) (95% Confidence interval (CI)): 2.00 (1.46-2.73)], long-acting BZDRAs [OR (95%CI): 2.16 (1.61-2.89)], BZDs [OR (95%CI): 1.67 (1.31-2.13)], and Z-drugs [OR (95%CI): 2.42 (1.35-4.34)] compared to the risk in BZDRAs non-users. The increased risk of falls in elderly patients was similar in each group and unrelated to t1/2. This study suggested that all BZDRAs including Z-drugs should be avoided in elderly patients.

Leukotriene receptor antagonist attenuated airway inflammation and hyperresponsiveness in a double-stranded RNA-induced asthma exacerbation model.

BACKGROUND: Viral infections are the most common triggers of asthma exacerbation, but the key molecules involved in this process have not been fully identified. Although cysteinyl leukotrienes (cysLTs) have been postulated as the key mediators, their precise roles remain largely unclear. To investigate the roles of cysLTs in virus-induced asthma exacerbation, we developed a murine model using a viral double-stranded RNA analog, polyinosinic-polycytidylic acid (poly I:C), and analyzed the effect of leukotriene receptor antagonist (LTRA) administration. METHODS: A/J mice were immunized with ovalbumin (OVA) + alum (days 0, 28, 42, and 49), followed by intranasal challenge with OVA (phase 1: days 50-52) and poly I:C (phase 2: days 53-55). Montelukast was administered during poly I:C challenge (phase 2) in the reliever model or throughout the OVA and poly I:C challenges (phases 1 and 2) in the controller model. Airway responsiveness to acetylcholine chloride was assessed, and bronchoalveolar lavage (BAL) was performed on day 56. RESULTS: Administration of poly I:C to OVA-sensitized and -challenged mice increased the number of eosinophils and levels of IL-13, IL-9, CCL3, and CXCL1 in BAL fluid (BALF) and tended to increase airway responsiveness. Montelukast significantly attenuated the poly I:C-induced increase in the number of eosinophils and levels of IL-13, IL-9, and CCL3 in BALF and airway hyperresponsiveness in both the reliever and controller models. CONCLUSIONS: This is the first report showing that LTRA functionally suppressed the pathophysiology of a virus-induced asthma exacerbation model, suggesting the importance of cysLTs as a potential treatment target.

IFN Regulatory Factor 3 Potentiates Emphysematous Aggravation by Lipopolysaccharide.

Acute exacerbation of chronic obstructive pulmonary disease (COPD) is often induced by infection and often has a poor prognosis. Bacterial LPS activates innate immune receptor TLR4 followed by activation of a transcriptional factor IFN regulatory factor-3 (IRF3) as well as NF-κB, resulting in upregulation of various inflammatory mediators. To clarify the role of IRF3 in the pathogenesis of LPS-triggered COPD exacerbation, porcine pancreatic elastase (PPE) followed by LPS was administered intranasally to wild-type (WT) or IRF3-/- male mice. Sequential quantitative changes in emphysema were evaluated by microcomputed tomography, and lung histology was evaluated at the sixth week. WT mice treated with PPE and LPS exhibited enlarged alveolar spaces, whereas this feature was attenuated in similarly treated IRF3-/- mice. Moreover, LPS-induced emphysema aggravation was detected only in WT mice. Analysis of acute inflammation induced by PPE plus LPS revealed that the lungs of treated IRF3-/- mice had decreased mRNA transcripts for MCP-1, MIP-1α, TNF-α, and IFN-γ-inducible protein-10 but had increased neutrophils. IRF3 was involved in the production of mediators from macrophages, alveolar epithelial cells, and neutrophils. Furthermore, compared with isolated WT neutrophils from inflamed lung, those of IRF3-/- neutrophils exhibited impaired autophagic activation, phagocytosis, and apoptosis. These results suggest that IRF3 accelerated emphysema formation based on distinct profiles of mediators involved in LPS-induced COPD exacerbation. Regulation of the IRF3 pathway can affect multiple cell types and contribute to ameliorate pathogenesis of infection-triggered exacerbation of COPD.

Ovary-dependent emphysema augmentation and osteopontin induction in adult female mice.

Biological differences between the sexes greatly impact the development and severity of pulmonary disorders such as emphysema. Recent studies have demonstrated crucial roles for osteopontin (OPN, also known as SPP1) in lung inflammation and alveolar destruction in human and experimental emphysema, but the impact of gender on OPN action remains unknown. Here, we report ovary-dependent induction of Opn mRNA with augmentation of experimental emphysema in adult female mice. Both male and female mice developed emphysematous lungs following intra-tracheal administration of porcine pancreatic elastase; however, compared with male mice, female mice developed more severe injury-related inflammation and pathologic alterations of the lungs. Notably, we observed female-specific induction of the Opn gene upon lung injury. Ovariectomy blocked this induction, with attenuation of lung inflammation and alveolar destruction, demonstrating the essential role of ovaries in injury-related Opn induction and augmentation of emphysema in adult female mice. Lastly, pre-treatment of adult female mice with pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid, which blocks ATP-mediated wound response, suppressed Opn mRNA induction upon lung injury, resulting in attenuation of enhanced lung inflammation. Together, our findings define a novel, ovary-dependent mechanism underlying gender-specific augmentation of emphysema through transcriptional control of the Opn gene.

Toll-like receptors required for dermatophagoides farinae to activate NF-κB.

Body and excrement extracts from Dermatophagoides farinae were used to study stimulation of Toll-like receptors (TLRs). The excrement extract stimulated nuclear factor (NF)-κB-dependent reporter activity to an extent similar to lipopolysaccharide (LPS) in a mouse macrophage cell line, J774A.1, but the activity of the body extract was negligible. The excrement extract also activated NF-κB in HEK293 cells expressing TLR1/TLR2, TLR2/TLR6 and CD14/TLR4/MD-2, whereas no activation was observed in cells expressing TLR3, TLR5, TLR7, TLR8 or TLR9. Although the excrement extract required co-expression of CD14, TLR4 and MD-2 in HEK293 cells to activate NF-κB, efficient activation was still observed in I-13.35 cells, a bone-marrow macrophage cell line established from LPS-hypo-responsive C3H/HeJ mice. The excrement extract activated NF-κB in HEK293 cells expressing TLR2 alone, but the activation was significantly increased by co-expression of CD14. Polymyxin B inhibited CD14/TLR4/MD-2- and CD14/TLR2-mediated activation of NF-κB but not the activation in I-13.35 cells. These results indicate that CD14/TLR4/MD-2-dependent and CD14/TLR2-dependent mechanisms are involved in the activation of NF-κB by the excrement extract of D. farinae and suggest that the extract also contains substances that activate NF-κB through non-TLR-mediated mechanisms.

Effect of secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) on airway epithelial cells.

Acetylcholine (ACh) exerts various anti-inflammatory effects through α7 nicotinic ACh receptors (nAChRs). We have previously shown that secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1), a positive allosteric modulator of α7 nAChR signaling, is down-regulated both in an animal model of asthma and in human epithelial cells treated with an inflammatory cytokine related to asthma. Our aim of this study was to explore the effect of SLURP-1, signal through α7 nAChR, in the pathophysiology of airway inflammation. Cytokine production was examined using human epithelial cells. Ciliary beat frequency of murine trachea was measured using a high speed camera. The IL-6 and TNF-α production by human epithelial cells was augmented by siRNA of SLURP-1 and α7 nicotinic ACh receptor. The cytokine production was also dose-dependently suppressed by human recombinant SLURP-1 (rSLURP-1). The ciliary beat frequency and amplitude of murine epithelial cells were augmented by PNU282987, a selective α7 nAChR agonist. Those findings suggested that SLURP-1 and stimulus through α7 nicotinic ACh receptors actively controlled asthmatic condition by stimulating ciliary beating and also by suppressing airway inflammation.

Immunochemoradiotherapy for patients with oral squamous cell carcinoma: augmentation of OK-432-induced helper T cell 1 response by 5-FU and X-ray irradiation.

Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-ß but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-ß. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression.

Suppressive effects of a pyrazole derivative of curcumin on airway inflammation and remodeling.

To advance the control of airway epithelial cell function and asthma, we investigated the effects of a new curcumin derivative, CNB001, which possesses improved pharmacological properties. Normal human bronchial epithelial (NHBE) cells were stimulated with synthetic double-stranded RNA, Poly(I:C). CNB001 significantly suppressed IL-6, TNF-α, and GM-CSF production by NHBE cells, and did so more effectively than did curcumin or dexamethasone (DEX). CNB001 significantly inhibited the decrease of E-cadherin mRNA expression and increase of vimentin mRNA expression observed in NHBE cells induced by a combination of TGF-ß1 and TNF-α, which are markers of airway remodeling. In NHBE cells stimulated by TGF-ß1, CNB001 significantly downregulated the level of active serine peptidase inhibitor clade E member (SERPINE) 1, which is also reported to be related to airway remodeling. Whereas DEX alone significantly increased the active SERPINE1 level, the combination of DEX and CNB001 significantly suppressed active SERPINE1. In addition, CNB001 significantly suppressed neutrophil infiltration, IL-6, TNF-α, IL-13 and active SERPINE1 production in bronchoalveolar lavage fluid of the murine asthma model, which was not observed in the case of DEX. In conclusion, the curcumin derivative, CNB001, is a promising candidate to treat asthma associated with neutrophilic airway inflammation and remodeling.

The role of CCR7 in allergic airway inflammation induced by house dust mite exposure.

House dust mite (HDM), the most common allergen, activate both the IgE-associated and innate immune responses. To clarify the process of sensitization, we investigated the role of the CCL21, CCL19, and CCR7 axis in a mouse model of HDM-induced allergic asthma. HDM inhalation without systemic immunization resulted in a HDM-specific IgE response. CCR7-knockout (CCR7KO) mice exhibited greater airway inflammation and IgE responses compared to wild-type mice. We examined FoxP3 expression in these mice to clarify the contribution of regulatory cells to the responses. FoxP3 expression was higher in the lungs but not in the lymph nodes of CCR7KO mice compared to wild-type mice. In CCR7KO mice, FoxP3-positive cells were found in lung, but we observed higher release of IL-13, IL-5, TGF-ß, IL-17, and HMGB1 in bronchoalveolar lavage fluid. We demonstrate here that immuno-regulation through CCR7 expression in T cells plays a role in HDM-specific sensitization in the airway.

Growth inhibition and apoptosis by an active component of OK-432, a streptococcal agent, via Toll-like receptor 4 in human head and neck cancer cell lines.

Toll-like receptor 4 (TLR4) plays a significant role in cancer therapy as receptors of bacteria-derived immunotherapeutic agents such as OK-432, a streptococcal immunotherapeutic agent. In addition, recent reports demonstrated that TLRs, including TLR4, are also expressed in cancer cells as well as in immunocompetent cells. It is a problem in cancer therapy that the immunoadjuvant may activate survival signals such as nuclear factor (NF)-κB or mitogen-activated protein kinases (MAPKs) in cancer cells via TLRs. In the current study, we investigated responsiveness of human head and neck cancer cell lines against TLR4 ligands, OK-PSA, an active component of OK-432, and a lipopolysaccharide (LPS). Stimulation with LPS or OK-PSA resulted in the activation of NF-κB in these cell lines expressing TLR4 and MD-2 that is a significant coreceptor for TLR4 signaling. Interestingly, OK-PSA induced cell-growth inhibition, while LPS enhanced the proliferation of the cancer cells. OK-PSA induced NF-κB activation more slowly than that induced by LPS. In addition, phosphorylation of p38 MAPK by OK-PSA was only slight compared with that by LPS. OK-PSA also induced apoptosis of the cancer cells mediated by the activation of caspase 1, 3 and 8 in a p53-independent manner. These findings strongly suggest that active components of OK-432 may elicit anti-cancer effects via enhancing host immunity as well as via directly inducing the growth inhibition and apoptosis of head and neck cancer cells through TLR4 signal.