The cytokine, transforming growth factor-β1 (TGF-β1), converts naive T cells into regulatory that prevent autoimmunity. However, in the presence of interleukin (IL)-6, TGF-β1 has also been found to promote differentiation IL-17-producing helper (Th17) are deeply involved autoimmunity and inflammation. it not clarified how IL-6 determine such a distinct fate. Here we master regulator for Th17, retinoic acid-related orphan receptor γt (RORγt), was rapidly induced by regardless IL-6. reduced...

Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-κB pathway was shown play an essential role in promoting inflammation-associated cancer, but JAK/STAT pathway, another important signaling proinflammatory cytokines, remains be investigated. Suppressor cytokine signaling-1 (SOCS1) acts as physiological regulator responses, and silencing SOCS1 gene by DNA methylation has been found several cancers. Here, we demonstrated that SOCS1-deficient...

Leukotriene B4 (LTB4) receptor type 2 (BLT2) is a G protein–coupled (GPCR) for 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and LTB4. Despite the well-defined proinflammatory roles of BLT1, in vivo functions BLT2 remain elusive. As mouse highly expressed epidermal keratinocytes, we investigated role 12-HHT/BLT2 axis skin wound healing processes. 12-HHT accumulated fluid mice, BLT2-deficient mice exhibited impaired re-epithelialization delayed closure after punching. Aspirin...

Heparin-binding EGF-like growth factor (HB-EGF) is first synthesized as a membrane-anchored form (proHB-EGF), and its soluble (sHB-EGF) released by ectodomain shedding from proHB-EGF. To examine the significance of proHB-EGF processing in vivo, we generated mutant mice targeted gene replacement, expressing either an uncleavable (HBuc) or transmembrane domain–truncated (HBΔtm) molecule. HBuc/uc developed severe heart failure enlarged valves, phenotypes similar to those null mice. On other...

The transcription factor STAT3 is activated by interleukin-6-related cytokines and has been implicated as an oncogene; it promotes cell proliferation anti-apoptotic. However, in some cases, shown to be pro-apoptotic, especially mammary epithelial cells. In this report, we generated SOCS3-deficient murine embryonic fibroblasts (MEFs), which activation extremely enhanced prolonged. We found that LIF induces caspase-3 apoptosis of SOCS3(-/-) MEFs. Exogenous expression the dominant negative form...

BLT2 is a low-affinity leukotriene B(4) (LTB(4)) receptor that activated by 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) and LTB(4). Despite the well-defined proinflammatory roles of BLT1, in vivo functions remain elusive. To clarify role BLT receptors intestinal inflammation, we assessed susceptibility to dextran sodium sulfate (DSS)-induced colitis mice lacking either BLT1 or BLT2. BLT2(-/-) exhibited increased sensitivity DSS as compared wild-type BLT1(-/-) mice, with more...

The double-stranded RNA analog, poly(I:C), extracellularly activates both the endosomal Toll-like receptor (TLR) 3 and cytoplasmic helicase, melanoma differentiation-associated gene 5, leading to production of type I interferons (IFNs) inflammatory cytokines. mechanism by which extracellular poly(I:C) is delivered TLR3-positive organelles cytoplasm remains be elucidated. Here, we show that lipid raft protein, Raftlin, essential for cellular uptake in human myeloid dendritic cells epithelial...

Abstract The clathrin-dependent endocytic pathway is crucial for endosomal TLR3- and TLR4-mediated Toll–IL-1R domain–containing adaptor molecule-1 (TICAM-1) signaling. TLR4 uses a different signaling platform, plasma membrane endosomes, activation of TIRAP-MyD88 TICAM-2–TICAM-1, respectively. LPS-induced endocytosis mandatory TICAM-1–mediated including IFN-β production. Several molecules/mechanisms such as CD14, clathrin, phosphatidylinositol metabolism have been reported to act inducers...

In macrophages and monocytes, microbial components trigger the production of pro-inflammatory cytokine through Toll-like receptors (TLRs). Although major TLR signaling pathways are mediated by serine/threonine kinases, including TAK1, IKK MAP tyrosine phosphorylation intracellular proteins ligands has been suggested in a number reports. Here, we demonstrated that peptidoglycan (PGN) Gram-positive bacterial cell wall component, TLR2 ligand lipopoysaccharide (LPS) TLR4 induced phospholipase...

Abstract The membrane microdomains known as lipid rafts have been shown to act platforms for the initiation of various receptor signals. Through proteomic analysis, we identified a novel protein termed Raftlin (raft-linking protein) major in rafts. To determine physiological and immunological functions mammals, generated Raftlin-deficient mice, well Raftlin-transgenic (Tg) mice. Although was originally B cells, observe no severe abnormalities cells these presumably due high expression...

The protein known as Spred1 (Sprouty-related Ena/VASP homology-1 domain-containing protein) has been identified a negative regulator of growth factor-induced ERK/mitogen-activated kinase activation. also implicated the target microRNA-126 (miR126), miRNA located within Egfl7 gene, and is involved in regulation vessel development through its role regulating VEGF signaling. In this study, we examined miR126 hematopoietic system, shown to be overexpressed leukemic cells. levels were...

Leukotriene B4 (LTB4) has been implicated in the pathogenesis of allergic diseases. BLT2, a low-affinity LTB4 receptor, is activated by and 12(S)-hydroxyheptadeca-5Z,8E,10E -trienoic acid (12-HHT). Although high-affinity receptor BLT1 shown to exert proinflammatory roles, role BLT2 inflammation not clarified. To study function development asthma, we used mice model ovalbumin (OVA)-induced airway disease. The 12-HHT levels were elevated bronchoalveolar lavage (BAL) fluids...

GPCRs are involved in numerous physiologic functions and important drug targets. Although the epithelial barrier is for protection from invading pathogens, correlation between function remains unknown. Leukotriene B4 (LTB4) receptor type 2 (BLT2), mainly expressed cells, a GPCR 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) LTB4. In our study, BLT2 localized at lateral membrane BLT2-overexpressing Madin-Darby canine kidney (MDCK) II cells small intestine of BLT2-transgenic mice....

We cloned a 38-kDa rat mitochondrial outer membrane protein (OM38) with structural homology to the central component of preprotein translocase fungal membrane, Tom40. Although it has no predictable α-helical transmembrane segments, OM38 is resistant alkaline carbonate extraction and inaccessible proteases polyclonal antibodies added from outside mitochondria, suggesting that embedded in probably β-barrel structure, as been similarly speculated for Immunoprecipitation demonstrated associated...

Lipopolysaccharide (LPS) activates macrophages through toll-like receptor (TLR) 4. Although the mechanism of TLR signaling pathway has been well documented, negative regulation in response to LPS, particularly LPS tolerance, is still poorly understood. In this study we identified and characterized a novel interferon- LPS-inducible gene, FLN29, which contains TRAF6-related zinc finger motif TRAF family member-associated NF-κB activator-related sequences. The induction FLN29 was dependent on...

Phagocytosis by macrophages is essential for host defense, i.e. preventing invasion of pathogens and foreign materials. Macrophages engulf immunoglobulin G (IgG)-opsonized particles through the action receptors Fc IgG (FcγRs). Leukotriene B(4) (LTB(4)) a classical lipid chemoattractant derived from arachidonic acid. receptor 1 (BLT1), high affinity LTB(4) receptor, expressed in variety immune cells such as neutrophils, macrophages, dendritic cells. Although has been shown to enhance...

Age-related macular degeneration (AMD), a progressive chronic disease of the central retina, is associated with aging and leading cause blindness worldwide. Here, we demonstrate that leukotriene B4 (LTB4) receptor 1 (BLT1) promotes laser-induced choroidal neovascularization (CNV) in mouse model for wet-type AMD. CNV was significantly less BLT1-deficient (BLT1-KO) mice compared BLT1-WT controls. Expression several proangiogenic profibrotic factors lower BLT1-KO eyes than eyes. LTB4 production...

Allergic conjunctivitis (AC) is one of the most common ocular surface diseases in world. In AC, T helper type 2 (Th2) immune responses play central roles orchestrating inflammatory responses. However, lipid mediators onset and progression AC remain to be fully explored. Although previous reports have shown beneficial effects supplementation ω-3 fatty acids asthma or atopic dermatitis, underlying molecular mechanisms are poorly understood. this study, a diet rich alleviated symptoms both...

Leukotriene B4 (LTB4) receptor 1 (BLT1), a high-affinity GPCR for LTB4, plays important roles in acute and chronic inflammatory diseases. Although the LTB4-BLT1 axis is known to promote inflammation, no studies have defined binding proteins that modulate signaling. In this study, advanced glycation end products (RAGE) interacted with BLT1 human cervical epithelial HeLa cells. RAGE increased LTB4-BLT1-dependent ERK phosphorylation inhibited activation of NF-κB up-regulation proinflammatory...

HB-EGF, a member of the EGF family growth factors, plays an important role in cardiac valve development by suppressing mesenchymal cell proliferation. Here, we show that HB-EGF must interact with heparan sulfate proteoglycans (HSPGs) to properly function this process. In developing valves, is synthesized endocardial cells but accumulates mesenchyme interacting HSPGs. Disrupting interaction between and HSPGs ex vivo model cushion explants resulted increased Moreover, homozygous knock-in mice...

Abstract Although pneumococcal infection is a serious problem worldwide and has high mortality rate, the molecular mechanisms underlying lethality caused by pneumococcus remain elusive. Here, we show that BLT2, G protein-coupled receptor for leukotriene B 4 12(S)-hydroxyheptadecatrienoic acid (12-HHT), protects mice from lung injury toxin, pneumolysin (PLY). Intratracheal injection of PLY lethal acute (ALI) in BLT2-deficient mice, with evident vascular leakage bronchoconstriction. Large...