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This paper is the first in a series papers devoted to the study of the rigorous derivation of the nonlinear Schrödinger (NLS) equation as well as other related systems starting from a model coming from the gravity-capillary water wave system in the long-wave limit. Our main goal is to understand resonances and their effects on having the nonlinear Schrödinger approximation or modification of it or having other models to describe the limit equation. In this first paper, our goal is not to derive NLS but to allow the presence of an arbitrary sequence of frequencies around which we have a modulation and prove local existence on a uniform time. This yields a new class of large data for which we have a large time of existence. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the dynamics of Kupffer cell (KC) phagocytosis by performing both in vivo and in vitro studies using Sonazoid (GE Healthcare, Oslo) in a rat nonalcoholic steatohepatitis (NASH) model. Methods: Contrast enhanced ultrasonography (CEUS) was performed on a rat NASH model induced by a methionine choline deficient diet (MCDD) and control rats, and Sonazoid was used to measure the signal intensity in the liver parenchyma. The uptake of Sonazoid by the KCs was observed by intravital microscopy. Their phagocytic capability was evaluated in vitro using isolated and cultured KCs. The uptake of fluorescein isothiocyanate (FITC)-labeled latex beads was observed and quantitatively analyzed by flow cytometry. Results: In the MCDD group, liver parenchymal enhancement was reduced 20 min after the Sonazoid injection. Microscopic observation of the isolated and cultured KCs revealed that the number of phagocytosed Sonazoid microbubbles was significantly decreased. Confocal laser scanning microscopic (CLSM) observation showed a decrease in the uptake of the latex beads. A decreased phagocytic capacity in the MCDD group was suggested by the quantitative analysis using flow cytometry, as well as by intravital microscopy. Conclusions: CEUS with Sonazoid is a powerful evaluation tool to diagnose NASH from an early stage of the disease. [ABSTRACT FROM AUTHOR]

Basophils and mast cells are important effector cells in helminth-infected host and IgE-mediated allergic inflammation. Although they have the same progenitors, basophils and mast cells complete their terminal differentiation in the bone marrow and peripheral tissues, respectively, and only basophils circulate in the blood. Although it is recognized that basophils are important for Th2 responses, and it is also well established that IL-4 is required for Th2 differentiation from naïve CD4 T cells, the nature of the cells that produce 'early' IL-4, remained elusive until recently. Three groups independently demonstrated that basophils are the predominant APC in inducing Th2 response against helminth parasites and allergens. Basophils express MHC class II and CD80/86, have the potential to take-up and process protein Ag (particularly Ag-IgE complex) and to present peptide in the context of MHC class II, and to produce IL-4. These Ag-pulsed basophils induce the development of Th2 cells both in vitro and in vivo. Thus, basophils contribute to Th2/IgE response by the production of IL-4 and presentation of MHC class II/peptide complex to naïve CD4 T cells, in contrast to the Th1-inducing action of DC. In this review, we summarize what is known regarding basophil function in allergy and parasite infection, examine the novel Ag-presenting function of basophils and discuss potential clinical implications of this finding. [ABSTRACT FROM AUTHOR]

Administration of heat-killed Propionibacterium acnes renders mice highly susceptible to LPS. After LPS challenge P. acnes-primed mice promptly show hypothermia, hypercoagulation (disseminated intravascular coagulation), elevation of serum proinflammatory cytokine levels, and highmortality. The surviving mice develop liver injury. As previously reported, IL-18 plays a pivotal role in the development of this liver injury.Many cell types including macrophages constitutively store IL-18 as biologically inactive precursor (pro) form. Upon appropriate stimulation exemplified by TLR4 engagement, the cells secrete biologically active IL-18 by cleaving pro-IL-18 with caspase-1. Caspase-1 is also constitutively produced as a zymogen in macrophages. Recently, NLRP3, a cytoplasmic pathogen sensor, has been demonstrated to be involved in the activation of caspase-1. Here, we review the molecular mechanisms for the liver injuries, particularly focusing on the TLR4/NLRP3-mediated caspase-1 activation process, with a brief introduction of the mechanism underlying P. acnes-induced sensitization to LPS. [ABSTRACT FROM AUTHOR]

Interleukin-18 (IL-18) has been regarded as a proinflammatory cytokine because of its potent interferon-γ-inducing activity. However, mutant mice that release excess amounts of IL-18 spontaneously develop pruritic chronic dermatitis-like atopic dermatitis (AD), suggesting the importance of IL-18 for the development of AD. Intriguingly, depletion of IL-18 but not state, an essential transcriptional factor for IL-4 signaling, rescues the mice from AD, indicating IL-18-dependent, T-helper 2 (Th2) cell-independent AD. This type of AD is classified as innate-type allergy in contrast to Th2 cell-dependent ordinary allergy. Consistent with the previous studies, mice transferred with antigen-specific Th1 cells exhibit no airway hyperresponsiveness and respiratory eosinophilic inflammation after challenge with antigen alone. However, they suffer from asthma upon challenge with antigen plus IL-18. with comparable levels of both the alterations as in those transferred with Th2 cells following challenge with antigen. The former type of asthma is categorized as Th1-associated allergy. Therefore, it is definitely necessary to evaluate whether individual allergic disorders involve either of these IL-18-mediated pathways or a Th2-mediated one. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) initiate a signalling cascade via association with an adaptor molecule, myeloid differentiation factor 88 (MyD88) and/or TIR domain-containing adaptor inducing-IFN-β (Trif), to induce various pro-inflammatory cytokines for microbial eradication. After stimulation of TLR4 with lipopolysaccharide (LPS), both IL-1β and IL-18 are processed, depending on the activation of caspase-1, although its mechanism remains unclear. ASC is an adapter protein possibly involved in the activation of procaspase-1. To unravel the requirement of ASC, we generated Asc−/– mice. Upon stimulation with LPS, Asc−/– macrophages failed in the processing of procaspase-1 and maturation of pro-IL-1β and pro-IL-18, but normally produced other pro-inflammatory cytokines including TNF-α and IL-6. MyD88−/– and Trif−/– macrophages showed normal activation of caspase-1, demonstrating a dispensable role for MyD88 and Trif. After, LPS-challenged Asc−/– mice lacked serum elevation of IL-1β and IL-18. Moreover, the Asc−/– mice exhibited neither acute liver injury nor lethal shock. These results demonstrate critical roles for ASC in the release of IL-1β/IL-18 via activation of caspase-1 and provide new insights into the inflammatory responses for host defence and diseases. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (aGVHD) after allogeneic bone marrow transplantation (BMT) is mediated by grafted T lymphocytes after their polarization into type 1 T cells. Interleukin (IL)-18, a novel immunoregulatory cytokine, strongly stimulates type 1 T cells, therefore we postulated that IL-18 may be involved in the pathogenesis of aGVHD. Using an enzyme-linked immunosorbent assay (ELISA), we serially measured serum levels of IL-18 in 37 patients with haematological malignancy before and after allogeneic BMT. Patients with aGVHD had high levels of IL-18 that strongly correlated with the severity of aGVHD. We also found that they showed reduced serum levels of IL-18 after appropriate treatment or at a state of resolution. IL-18 levels were not affected by the pretransplant regimen, engraftment or bacterial infection. Compared with circulating interferon (IFN)-γ or IL-12 levels, serum levels of IL-18 showed a more sensitive and specific correlation with the disease status of aGVHD. These findings suggest that IL-18 may play important roles in the pathogenesis of aGVHD and that measurement of serum IL-18 levels can be useful indicator of aGVHD. [ABSTRACT FROM AUTHOR]

Innate immune response to microbes sometimes determines the nature of the following specific response. Kupffer cells, a potent constituent of innate immunity, play a key role in developing the type 1 immune response by interleukin (IL)-12 production. Furthermore, Kupffer cells have the potential to induce liver injury by production of IL-18. Propionibacterium acnes-primed lipopolysaccharide (LPS)-challenged liver injury is the prototype of IL-18-induced tissue injury, in which IL-18 acts on natural killer cells to increase Fas ligand (FasL) that causes liver injury by induction of Fas-dependent hepatocyte apoptosis. LPS induces IL-18 secretion from Kupffer cells in a caspase-1-dependent manner. Indeed, caspase-1-deficient mice are resistant to P. acnes and LPS-induced liver injury. However, administration of soluble FasL induces acute liver injury in P. acnes-primed caspase-1-deficient mice but does not do so in IL-18-deficient mice, indicating that IL-18 release in a capsase-1-independent fashion is essential for this liver injury. Therefore, a positive feedback loop between FasL and IL-18 plays an important role in the pathogenesis of endotoxin-induced liver injury. [ABSTRACT FROM AUTHOR]

Background: NF-κB is an ubiquitously expressed transcription factor that plays an important role in the immune, anti-apoptotic and inflammatory responses. NF-κB is normally sequestered in the cytoplasm by interacting with inhibitory IκB molecules. Upon stimulation, IκB is phosphorylated and subsequently degraded by the proteasome, allowing NF-κB to translocate into the nucleus where they regulate target gene expression. Two kinases, IKK-α and IKK-β, which are responsible for IκB phosphorylation were recently identified. We have recently identified a cytokine inducible IKK-i, a kinase related to IKK-α and -β. IKK-i significantly induced NF-κB activation upon over-expression, as did IKK-α and IKK-β. Unlike IKK-α and IKK-β, IKK-i phosphorylated Ser36 but not Ser32 in vitro, suggesting that IKK-i activates NF-κB by distinct mechanisms from the conventional IKKs. Results: I-TRAF/TANK was isolated as a molecule that interacts specifically with inducible IκB kinase (IKK-i) by the yeast two-hybrid screening procedure. The association of IKK-i and I-TRAF is mediated via the interaction between the N-terminal domain of I-TRAF and the C-terminal portion of IKK-i. In vitro kinase assays demonstrate that IKK-i phosphorylates I-TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I-TRAF/TRAF2 complex after I-TRAF phosphorylation. NF-κB activation by IKK-i is significantly blocked by coexpression of the N-terminal domain of I-TRAF, dominant negative TRAF2, and dominant negative NIK and IKK-β. IKK-i over-expression also induced c-Jun N-terminal kinase. These results show that I-TRAF is a substrate of IKK-i. NF-κB activation by IKK-i may be mediated through phosphorylation of I-TRAF by IKK-i and subsequent liberation of TRAF2. Conclusion: These results indicate that NF-κB activation by IKK-i is mediated through phosphorylation of... [ABSTRACT FROM AUTHOR]

Liver regeneration following partial hepatectomy (PH) requires several steps including innate immune responses, particularly interleukin-6 (IL-6) and tumor necrosis factor-(TNF-)α production by Kupffer cells, although the activation processes are still unknown. Toll-like receptors (TLR) act as innate immune signal sensors and play central roles in host defense. Myeloid differentiation factor (MyD) 88 is a common adaptor molecule required for signaling mediated by TLR. When the receptors are activated, cells bearing TLR produce various pro-nflammatory cytokines in a MyD88-dependent manner. The authors investigated whether TLR/MyD88 signaling is critical for induction of innate immune responses after PH. In Myd88-/- mice after PH, induction of expression of immediate early genes involved in hepatocyte replication and phosphorylation of signal transducer and activators of transcription 3 (STAT3) in the liver, and production of TNF-α/IL-6 by and activation of NF-κB in the Kupffer cells were grossly subnormal and were associated with impaired liver regeneration, while TLR2, 4 and 9, which recognize Gram-negative and -positive bacterial products, are not essential for NF-κB activation and IL-6 production after PH. In conclusion, the TLR/MyD88 pathway is essential for liver restoration after PH, particularly its early phase. [ABSTRACT FROM AUTHOR]

Objective: To generate a mouse model of reactive arthritis (ReA), an aseptic synovitis that develops in joints distant from the primary bacterial infection site, to examine roles for Toll-like receptors (TLRs) that recognize bacterial components involved in the development of this arthritis, and to identify the cytokine(s) relevant to this arthritis., Methods: Mice were treated with cell wall extract from Escherichia coli (ECW) gram-negative bacterium by injection into the footpads. Seven days later, the mice were challenged with lipopolysaccharide (LPS), a TLR-4 ligand, which was injected into the knee joint cavity. To investigate the cytokine(s) involved in this arthritis, mice deficient in various arthritogenic cytokines, such as interleukin-6 (IL-6), IL-12, IL-18, interferon-gamma, and tumor necrosis factor alpha (TNFalpha), were sequentially treated with ECW and LPS., Results: ECW-primed mice manifested acute severe arthritis after intraarticular challenge with ECW or LPS, while unprimed mice exhibited modest changes after these challenges. Mutant mice lacking functional TLR-4 or myeloid differentiation factor 88 (MyD88), an adaptor molecule of TLR-4 signaling, were resistant to this arthritis. Although both TNFalpha and IL-6 were equally expressed in the joint after LPS challenge, Il6(-/-) mice, but not Tnf(-/-) mice, were resistant to ECW/LPS-induced arthritis., Conclusion: Our present results clearly indicate the importance of priming with ECW and the requirement of TLR-4/MyD88-mediated IL-6, but not TNFalpha, for the development of ECW/LPS-induced arthritis. LPS-induced IL-6, in the absence of TNFalpha, mediates LPS-induced arthritis. These results suggest that IL-6 is a rational target for therapeutic regimens for inflammatory arthritis, including ReA and rheumatoid arthritis.