bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mast Cell-Dependent Contraction of Human Airway Smooth Muscle Cell-Containing Collagen Gels: Influence of Cytokines, Matrix Metalloproteases, and Serine Proteases
Authors: Margulis Alexander , Nocka Karl H. , Brennan Agnes M. , Deng Bijia , Fleming Margaret , Goldman Samuel J. , Kasaian Marion T. 
Published: July 2009

AbstractIn asthma, mast cells infiltrate the airway smooth muscle cell layer and secrete proinflammatory and profibrotic agents that contribute to airway remodeling. To study the effects of mast cell activation on smooth muscle cell-dependent matrix contraction, we developed coculture systems of human airway smooth muscle cells (HASM) with primary human mast cells derived from circulating progenitors or with the HMC-1 human mast cell line. Activation of primary human mast cells by IgE receptor cross-linking or activation of HMC-1 cells with C5a stimulated contraction of HASM-embedded collagen gels. Contractile activity could be transferred with conditioned medium from activated mast cells, implicating involvement of soluble factors. Cytokines and proteases are among the agents released by activated mast cells that may promote a contractile response. Both IL-13 and IL-6 enhanced contraction in this model and the activity of IL-13 was ablated under conditions leading to expression of the inhibitory receptor IL-13Rα2 on HASM. In addition to cytokines, matrix metalloproteinases (MMPs), and serine proteases induced matrix contraction. Inhibitor studies suggested that, although IL-13 could contribute to contraction driven by mast cell activation, MMPs were critical mediators of the response. Both MMP-1 and MMP-2 were strongly expressed in this system. Serine proteases also contributed to contraction induced by mast cell-activating agents and IL-13, most likely by mediating the proteolytic activation of MMPs. Hypercontractility is a hallmark of smooth muscle cells in the asthmatic lung. Our findings define novel mechanisms whereby mast cells may modulate HASM-driven contractile responses.
SLP-76 Couples Syk to the Osteoclast Cytoskeleton
Authors: Reeve Jennifer L. , Zou Wei , Liu Yuli , Maltzman Jonathan S. , Ross F. Patrick , Teitelbaum Steven L. 
Published: July 2009

Abstract
The capacity of the osteoclast (OC) to resorb bone is dictated by cytoskeletal organization, which in turn emanates from signals derived from the αvβ3 integrin and c-Fms. Syk is key to these signals and, in other cells, this tyrosine kinase exerts its effects via intermediaries including the SLP adaptors, SLP-76 and BLNK (B cell linker). Thus, we asked whether these two SLP proteins regulate OC function. We find BLNK-deficient OCs are normal, whereas cytoskeletal organization of those lacking SLP-76 is delayed, thus modestly reducing bone resorption in vitro. Cytoskeletal organization and bone resorption are more profoundly arrested in cultured OCs deficient in BLNK and SLP-76 double knockout (DKO) phenotypes. In contrast, stimulated bone resorption in vivo is inhibited ∼40% in either SLP-76−/− or DKO mice. This observation, taken with the fact that DKO OCs are rescued by retroviral transduction of only SLP-76, indicates that SLP-76 is the dominant SLP family member in the resorptive process. We also find SLP-76 is phosphorylated in a Syk-dependent manner. Furthermore, in the absence of the adaptor protein, integrin-mediated phosphorylation of Vav3, the OC cytoskeleton-organizing guanine nucleotide exchange factor, is abrogated. In keeping with a central role of SLP-76/Vav3 association in osteoclastic resorption, retroviral transduction of SLP-76, in which the Vav binding site is disrupted (3YF), fails to normalize the cytoskeleton of DKO OCs and the resorptive capacity of the cells. Finally, c-Fms-activated Syk also exerts its OC cytoskeleton-organizing effect in a SLP-76/Vav3-dependent manner.
MicroRNA-98 and let-7 Confer Cholangiocyte Expression of Cytokine-Inducible Src Homology 2-Containing Protein in Response to Microbial Challenge
Authors: Hu Guoku , Zhou Rui , Liu Jun , Gong Ai-Yu , Eischeid Alex N. , Dittman Jared W. , Chen Xian-Ming 
Published: July 2009

Abstract
Posttranscriptional gene regulation by microRNAs (miRNAs) has been implicated in the fine-tuning of TLR-mediated inflammatory response. The cytokine-inducible Src homology 2-containing protein (CIS), one member of the suppressors of cytokine signaling family of proteins, is an important negative regulator for inflammatory cytokine signaling. Using in vitro models using normal human biliary epithelial cells (cholangiocytes), we demonstrated that LPS stimulation or infection with the parasitic protozoan Cryptosporidium parvum induced expression of CIS protein without a change in CIS mRNA levels by activating the TLR signaling pathway. Of those miRNAs expressed in cholangiocytes, we found that targeting of the 3′-untranslated region of CIS by microRNA-98 (miR-98) or let-7 resulted in translational repression, but not CIS mRNA degradation. LPS stimulation or C. parvum infection decreased cholangiocyte expression of miR-98 and let-7. Down-regulation of miR-98 and let-7 relieved miRNA-mediated translational suppression of CIS and contributed to LPS- and C. parvum-stimulated CIS protein expression. Moreover, gain-of-function (by overexpression of CIS) and loss-of-function (by siRNA interference) studies revealed that CIS could enhance IκBα degradation and regulate NF-κB activation in cholangiocytes in response to LPS stimulation or C. parvum infection. Our data suggest that miR-98 and let-7 confer cholangiocyte expression of CIS in response to microbial challenge, a process that may be relevant to the regulation of TLR-mediated epithelial innate immune response.
Human CD14+ Macrophages in Intestinal Lamina Propria Exhibit Potent Antigen-Presenting Ability
Authors: Kamada Nobuhiko , Hisamatsu Tadakazu , Honda Haruki , Kobayashi Taku , Chinen Hiroshi , Kitazume Mina Tokutake , Takayama Tetsuro , Okamoto Susumu , Koganei Kazutaka , Sugita Akira , Kanai Takanori , Hibi Toshifumi 
Published: July 2009

Abstract
Intestinal APCs are considered critical in maintaining the balance between the response against harmful pathogens and the induction of tolerance to commensal bacteria and food Ags. Recently, several studies indicated the presence of gut-specific APC subsets, which possess both macrophage and dendritic cell (DC) markers. These unique APC subsets play important roles in gut immunity, especially for immune regulation against commensal bacteria. Herein, we examined a unique macrophage subset, which coexpressed the macrophage (Mφ) marker CD14 and the DC marker CD209 in human intestinal lamina propria (LP). The LP Mφ subset in both normal control subjects or Crohn’s disease (CD) patients induced proliferation of naive CD4+ T cells as well as monocyte-derived DCs, and it expressed retinoic acid synthetic enzyme retinaldehyde dehydrogenase 2 and retinol dehydrogenase 10, which induced expression of gut homing receptors on T cells in a retinoic acid-dependent manner. Moreover, the LP Mφ subset strongly evoked differentiation of Th1 cells and slightly induced Th17 cells in both normal control subjects and CD patients; the inducing potential was highest in CD patients. In CD patients, Th17, but not Th1, induction by the LP Mφ subset was enhanced in the presence of commensal bacteria Ags. This enhancement was not observed in normal control subjects. The Th17 induction by the LP Mφ subset was inhibited by neutralization of IL-6 and IL-1β, but it was enhanced by blockade of retinoic acid signaling. These observations highlight a role for LP Mφ in the enhanced Th1, and potentially in Th17 differentiation, at the inflammatory site of inflammatory bowel diseases.
Fas Apoptosis Inhibitory Molecule Enhances CD40 Signaling in B Cells and Augments the Plasma Cell Compartment
Authors: Kaku Hiroaki , Rothstein Thomas L. 
Published: July 2009

Abstract
Fas apoptosis inhibitory molecule (FAIM) was cloned as a mediator of Fas resistance that is highly evolutionarily conserved but contains no known effector motifs. In this study, we report entirely new functions of FAIM that regulate B cell signaling and differentiation. FAIM acts to specifically enhance CD40 signaling for NF-κB activation, IRF-4 expression, and BCL-6 down-regulation in vitro, but has no effect on its own or in conjunction with LPS or anti-Ig stimulation. In keeping with its effects on IRF-4 and BCL-6, FAIM overexpression augments the plasma cell compartment in vivo. These results indicate that FAIM is a new player on the field of B cell differentiation and acts as a force multiplier for a series of events that begins with CD40 engagement and ends with plasma cell differentiation.
A Central Role for Transcription Factor C/EBP-β in Regulating CD1d Gene Expression in Human Keratinocytes
Authors: Sikder Hashmat , Zhao Yuming , Balato Anna , Chapoval Andre , Fishelevich Rita , Gade Padmaja , Singh Ishwar S. , Kalvakolanu Dhananjaya V. , Johnson Peter F. , Gaspari Anthony A. 
Published: July 2009

Abstract
CD1d is a nonclassical Ag-presenting molecule that presents glycolipid Ags to NKT cells that are involved in immune defense and tumor rejection. It also plays a role in immunoregulatory functions in the epidermis. The mechanisms controlling the expression of CD1d are not well understood. Therefore, we cloned the CD1d gene promoter and characterized its activities in primary human keratinocytes and other cell lines of epithelial origin. We found that a CCAAT box in the CD1d promoter is required for its expression in keratinocytes. We show here that transcription factor C/EBP-β binds to the CCAAT box in the CD1d promoter in vitro and in vivo. Consistent with these observations, deletion of the gene encoding for C/EBP-β caused a loss of CD1d expression. The in vivo regulation of CD1d has significant implications for the pathologic mechanisms of certain immunologic skin diseases in which NKT cells play a role, such as allergic contact dermatitis and psoriasis. Together, these data show a central role for C/EBP-β in regulating CD1d transcription.
Expression of a CD200 Transgene Is Necessary for Induction but Not Maintenance of Tolerance to Cardiac and Skin Allografts
Authors: Gorczynski Reginald M. , Chen Zhiqi , He William , Khatri Ismat , Sun Yang , Yu Kai , Boudakov Ivo 
Published: July 2009

Abstract
CD200, a type 2 transmembrane molecule of the Ig supergene family, can induce immunosuppression in a number of biological systems, as well as promote increased graft acceptance, following binding to its receptors (CD200Rs). Skin and cardiac allograft acceptance are readily induced in transgenic mice overexpressing CD200 under control of a doxycycline-inducible promoter, both of which are associated with increased intragraft expression of mRNAs for a number of genes associated with altered T cell subset differentiation, including GATA-3, type 2 cytokines (IL-4, IL-13), GITR, and Foxp3. Interestingly, some 12–15 days after grafting, induction of transgenic CD200 expression can be stopped (by doxycycline withdrawal), without obvious significant effect on graft survival. However, neutralization of all CD200 expression (including endogenous CD200 expression) by anti-CD200 mAb caused graft loss, as did introduction of an acute inflammatory stimulus (LPS, 10 μg/mouse, delivered by i.p. injection). We conclude that even with apparently stably accepted tissue allografts, disruption of the immunoregulatory balance by an intense inflammatory stimulus can cause graft loss.
Intracellular Replication-Deficient Leishmania donovani Induces Long Lasting Protective Immunity against Visceral Leishmaniasis
Authors: Selvapandiyan Angamuthu , Dey Ranadhir , Nylen Susanne , Duncan Robert , Sacks David , Nakhasi Hira L. 
Published: July 2009

Abstract
No vaccine is currently available for visceral leishmaniasis (VL) caused by Leishmania donovani. This study addresses whether a live attenuated centrin gene-deleted L. donovani (LdCen1−/−) parasite can persist and be both safe and protective in animals. LdCen1−/− has a defect in amastigote replication both in vitro and ex vivo in human macrophages. Safety was shown by the lack of parasites in spleen and liver in susceptible BALB/c mice, immune compromised SCID mice, and human VL model hamsters 10 wk after infection. Mice immunized with LdCen1−/− showed early clearance of virulent parasite challenge not seen in mice immunized with heat killed parasites. Upon virulent challenge, the immunized mice displayed in the CD4+ T cell population a significant increase of single and multiple cytokine (IFN-γ, IL-2, and TNF) producing cells and IFN-γ/IL10 ratio. Immunized mice also showed increased IgG2a immunoglobulins and NO production in macrophages. These features indicated a protective Th1-type immune response. The Th1 response correlated with a significantly reduced parasite burden in the spleen and no parasites in the liver compared with naive mice 10 wk post challenge. Protection was observed, when challenged even after 16 wk post immunization, signifying a sustained immunity. Protection by immunization with attenuated parasites was also seen in hamsters. Immunization with LdCen1−/− also cross-protected mice against infection with L. braziliensis that causes mucocutaneous leishmaniasis. Results indicate that LdCen1−/− can be a safe and effective vaccine candidate against VL as well as mucocutaneous leishmaniasis causing parasites.
Antigen Specificity Is not Required for Modulation of Lung Allergic Responses by Naturally Occurring Regulatory T Cells
Authors: Joetham Anthony , Takeda Katsuyuki , Okamoto Masakazu , Taube Christian , Matsuda Hiroyuki , Dakhama Azzeddine , Gelfand Erwin W. 
Published: July 2009

Abstract
Naturally occurring Foxp3+CD4+CD25+ T cells isolated from lungs of naive mice regulate lung allergic airway hyperresponsiveness, inflammation, levels of Th2 cytokines, and mucus production. OVA-specific (αβTCR+) CD4+CD25+ T cells suppressed ragweed-induced airway hyperresponsiveness and inflammation as did anti-TCR-treated OVA-specific CD4+CD25+ T cells, suggesting that Ag-specificity was not required for expression of regulatory activities. Suppression was associated with increased levels of IL-10 and TGF-β; decreased levels of IL-4, IL-5, and IL-13 in bronchoalveolar lavage fluid; and reduced recruitment and activation of CD8+ T cells in the airways. Following intratracheal administration, OVA-specific CD4+CD25+ T cells were identified in both the airway lumens and lung parenchyma, and in some instances in close proximity to host CD8+ T cells. These results demonstrate that the regulatory activities of naturally occurring Foxp3+CD4+CD25+ T cells on lung allergic responses are Ag-nonspecific and thus, independent of Ag-specific recognition.
Anti-CD40 Monoclonal Antibody Synergizes with CTLA4-Ig in Promoting Long-Term Graft Survival in Murine Models of Transplantation
Authors: Gilson Christopher R. , Milas Zvonimir , Gangappa Shivaprakash , Hollenbaugh Diane , Pearson Thomas C. , Ford Mandy L. , Larsen Christian P. 
Published: July 2009

Abstract
Blockade of the CD40/CD154 signaling pathway using anti-CD154 Abs has shown promise in attenuating the alloimmune response and promoting long-term graft survival in murine model systems, although side effects observed in humans have hampered its progression through clinical trials. Appropriately designed anti-CD40 Abs may provide a suitable alternative. We investigated two isoforms of a novel monoclonal rat anti-mouse CD40 Ab (7E1) for characteristics and effects mirroring those of anti-CD154: 7E1-G1 (an IgG1 isotype); and 7E1-G2b (an IgG2b isotype). In vitro proliferation assays to measure the agonist properties of the two anti-CD40 Abs revealed similar responses when plate bound. However, when present as a soluble stimulus, 7E1-G1 but not 7E1-G2b led to proliferation. 7E1-G2b was as effective as anti-CD154 when administered in vivo in concert with CTLA4-Ig in promoting both allogeneic bone marrow chimerism and skin graft survival, whereas 7E1-G1 was not. The protection observed with 7E1-G2b was not due to depletion of CD40-bearing APCs. These data suggest that an appropriately designed anti-CD40 Ab can promote graft survival as well as anti-CD154, making 7E1-G2b an attractive substitute in mouse models of costimulation blockade-based tolerance regimens.
Expression of Diabetes-Associated Genes by Dendritic Cells and CD4 T Cells Drives the Loss of Tolerance in Nonobese Diabetic Mice
Authors: Hamilton-Williams Emma E. , Martinez Xavier , Clark Jan , Howlett Sarah , Hunter Kara M. , Rainbow Daniel B. , Wen Li , Shlomchik Mark J. , Katz Jonathan D. , Beilhack Georg F. , Wicker Linda S. , Sherman Linda A. 
Published: July 2009

Abstract
In humans and NOD mice, defects in immune tolerance result in the spontaneous development of type-1-diabetes. Recent studies have ascribed a breakdown in tolerance to dysfunction in regulatory T cells that is secondary to reduced IL-2 production by T cells having the NOD diabetes susceptibility region insulin-dependent diabetes 3 (Idd3). In this study, we demonstrate a peripheral tolerance defect in the dendritic cells of NOD mice that is independent of regulatory T cells. NOD CD8 T cells specific for islet Ags fail to undergo deletion in the pancreatic lymph nodes. Deletion was promoted by expression of the protective alleles of both Idd3 (Il2) and Idd5 in dendritic cells. We further identify a second tolerance defect that involves endogenous CD4 T cell expression of the disease-promoting NOD alleles of these genetic regions. Pervasive insulitis can be reduced by expression of the Idd3 and Idd5 protective alleles by either the Ag-presenting cell or lymphocytes.
An Engineered GM-CSF-CCL2 Fusokine Is a Potent Inhibitor of CCR2-Driven Inflammation As Demonstrated in a Murine Model of Inflammatory Arthritis
Authors: Rafei Moutih , Berchiche Yamina A. , Birman Elena , Boivin Marie-Noëlle , Young Yoon Kow , Wu Jian Hui , Heveker Nikolaus , Galipeau Jacques 
Published: July 2009

Abstract
CCR2 is a chemokine receptor widely expressed by lymphomyeloid cells involved in maladaptive autoimmune ailments. Therefore CCR2 is of great interest as a biological target for immune suppression due to its direct implication in autoimmune diseases such as rheumatoid arthritis. We have generated a novel fusion protein using GM-CSF and an N-terminal truncated version of MCP-1/CCL2 (6–76, GMME1) and investigated its utility as a CCR2-specific immune suppressor. Using BRET studies, we found that distinct to CCL2, GMME1 binding to CCR2 led to altered conformational changes in the CCR2 homodimer and did not induce the recruitment of β-arrestin 2 to the receptor. However, CCR2-dependent calcium mobilization, BAX induction and caspase-3 activation followed by cell death was observed. Using Th17 cells harvested from DBA/1 mice ill with bovine collagen-induced arthritis, we demonstrate that GMME1 is capable of blocking their production of IL-17 in vitro. Upon its delivery to mice symptomatic with inflammatory arthritis, a robust clinical recovery occurred with decreased paw thickness to normal levels and a significant reduction in anti-collagen Ab titer and rheumatoid factor titer, as well as reduction of proinflammatory cytokines levels both intraarticular and systemic. Our data demonstrate that GMME1 is a powerful synthetic suppressor cytokine that coopts CCR2-dependent cellular signaling and blunts the effects of CCR2-expressing lymphomyeloid cells causative of autoimmune arthritis.
Gene Regulation and Chromatin Remodeling by IL-12 and Type I IFN in Programming for CD8 T Cell Effector Function and Memory
Authors: Agarwal Pujya , Raghavan Arvind , Nandiwada Sarada L. , Curtsinger Julie M. , Bohjanen Paul R. , Mueller Daniel L. , Mescher Matthew F. 
Published: July 2009

Abstract
A third signal that can be provided by IL-12 or type I IFN is required for differentiation of naive CD8 T cells responding to Ag and costimulation. The cytokines program development of function and memory within 3 days of initial stimulation, and we show here that programming involves regulation of a common set of ∼355 genes including T-bet and eomesodermin. Much of the gene regulation program is initiated in response to Ag and costimulation within 24 h but is then extinguished unless a cytokine signal is available. Histone deacetylase inhibitors mimic the effects of IL-12 or type I IFN signaling, indicating that the cytokines relieve repression and allow continued gene expression by promoting increased histone acetylation. In support of this, increased association of acetylated histones with the promoter loci of granzyme B and eomesodermin is shown to occur in response to IL-12, IFN-α, or histone deacetylase inhibitors. Thus, IL-12 and IFN-α/β enforce in common a complex gene regulation program that involves, at least in part, chromatin remodeling to allow sustained expression of a large number of genes critical for CD8 T cell function and memory.
Uncoordinated 119 Protein Controls Trafficking of Lck via the Rab11 Endosome and Is Critical for Immunological Synapse Formation
Authors: Gorska Magdalena M. , Liang Qiaoling , Karim Zunayet , Alam Rafeul 
Published: July 2009

Abstract
The activation of T cells through the TCR is essential for development of the adaptive immune response. TCR does not have any enzymatic activity and relies on the plasma membrane-associated lymphocyte-specific protein tyrosine kinase (Lck) for initiation of signaling. Here we uncover a mechanism that is responsible for plasma membrane targeting of Lck. We show that Lck is transported to the membrane via a specific endosomal compartment. The transport depends on the adaptor protein Uncoordinated 119 (Unc119), on the GTPase rat brain 11 (Rab11), and on the actin cytoskeleton. Unc119 regulates the activation of Rab11. Consequently, Unc119 orchestrates the recruitment of the actin-based motor protein, myosin 5B, and the organization of multiprotein complexes on endosomes. The Unc119-regulated pathway is essential for immunological synapse formation and T cell activation.
Human B Cells Secrete Granzyme B When Recognizing Viral Antigens in the Context of the Acute Phase Cytokine IL-21
Authors: Hagn Magdalena , Schwesinger Elisabeth , Ebel Verena , Sontheimer Kai , Maier Julia , Beyer Thamara , Syrovets Tatiana , Laumonnier Yves , Fabricius Dorit , Simmet Thomas , Jahrsdörfer Bernd 
Published: July 2009

Abstract
Human B cells are currently not known to produce the proapoptotic protease granzyme B (GrB) in physiological settings. We have discovered that BCR stimulation with either viral Ags or activating Abs in the context of the acute phase cytokine IL-21 can induce the secretion of substantial amounts of GrB by human B cells. Importantly, GrB response to viral Ags was significantly stronger in B cells from subjects recently vaccinated against the corresponding viruses as compared with unvaccinated subjects. GrB-secreting B cells featured a homogeneous CD19+CD20+CD27−CD38−IgD− phenotype, improved survival, and enhanced expression of costimulatory, Ag-presenting and cell-adhesion molecules. B cell-derived GrB was enzymatically active and its induction required the activation of similar signaling pathways as those in CTLs. Our findings suggest that GrB-secreting B cells support the early antiviral immune response against viruses with endosomal entry pathways, thereby counteracting overwhelming viral replication at the beginning of an infection until virus-specific T cells from draining lymph nodes arrive at the site of infection. Our data may also explain the elevated serum GrB levels found in the early phase of various viral diseases.