bluuebunny/crossref_metadata_2025_split huggingface dataset:
TLR2-mediated IL-27 and chemokine production by respiratory epithelial cells promotes bleomycin-induced pulmonary fibrosis by inhibiting IL-17 production and recruiting immune cells, respectively (162.7)
Authors: Kim Hye sung , Chung Doo Hyun 
Published: January 2023

Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic disease that is characterized by destruction of the lung parenchyma. Toll-like receptor 2(TLR2) is a key innate mediator by sensing tissue injury. Recently reported that TLR2 promote bleomycin-induced pulmonary fibrosis(BIPF), but the mechanism remains unclear. To address this, we compared TLR2 knockout(KO) and wild type(WT) mice in the BIPF model. TLR2 KO mice attenuated BIPF in terms of inflammation, and hydroxyproline levels. The levels of IL-17 and-producing CD4+ and γδ T cells in bronchoalveolar lavage fluid of TLR2 KO mice were higher than those of WT mice. Moreover, IL-17 blockade in TLR2 KO mice increased the hydroxyproline and TGF-β levels. Using Bone-marrow chimeric mice revealed that TLR2 expressed on non-hematopoietic cells rather than immune cells reduced IL-17 production but enhanced the levels of hydroxyproline. Moreover, upon stimulation with TLR2 ligands, respiratory epithelial cells from WT mice produced IL-27, CC, and CXC chemokines, depending on IRF complex and MyD88. Blockade of IL-27 in WT mice enhanced IL-17 production, resulting in reducing amounts of hydroxyproline, whereas injection of chemokine cocktail to TLR2 KO mice enhanced recruitment of inflammatory cells into the lungs. Taken together, TLR-2 mediated production of IL-27 and chemokines by respiratory epithelial cells inhibits IL-17 production and recruits inflammatory cells into the lungs, respectively, which results in promoting BIPF.
Notch signaling promotes MUC5AC expression through epidermal growth factor receptor-extracellular regulated kinase pathway (163.1)
Authors: Kim Su Hwan , Kang Jin Hyun , Uhm Tae Ki , Kim Do Jin , Chung Il Yup 
Published: January 2023

Abstract
Airway mucus hypersecretion and goblet cell hyperplasia plays an important role in the pathogenesis of several major airway inflammatory diseases. MUC5AC is a major component of the mucus produced by airway epithelial cells and considered to be a marker of mucus cell hyperplasia. In the study we investigate the involvement of Notch signaling in EGF-mediated expression of MUC5AC in human epithelial NCI-H292 cells. EGF stimulated the generation of Notch intracellular domain (NICD) in a RBP-Jκ-dependent manner. Treatment with γ-secretase inhibitor (GSI) or introduction of small interfering RNA directed against Notch1 reduced EGF-induced expression of MUC5AC mRNA and protein. The inhibitory effect of both GSI and Notch1 silencing on MUC5AC expression was accompanied by reduced generation of NICD and reduced expression of a Notch downstream target, Hes-1. Blockage of the Notch signaling with the two agents resulted in a decrease in ERK phosphorylation induced by EGF stimulation. ERK inhibitor inhibited MUC5AC production. These results indicate that ERK activation is necessary for Notch signaling to regulate the EGFR-mediated MUC5AC expression. Collectively, these results suggest that Notch signaling regulates the EGF-induced expression of MUC5AC through modulation of ERK activity.
Genetic analysis of arginase 1 in Th2-dominated lung inflammation (163.12)
Authors: Barron Luke , Smith Amber , El Kasmi Karim , Qualls Joseph , Huang Xiaozhu , Wynn Thomas , Murray Peter 
Published: January 2023

Abstract
Arginase 1 (Arg1) expression in myeloid lineage cells, and especially alternatively-activated macrophages, increases dramatically in the lungs of mice with acute and chronic Th2-driven inflammation. Arg1 has been proposed to contribute to asthma pathogenesis by regulating at least four pathways: inhibiting the production of nitric oxide by substrate competition, regulating fibrosis and polyamine supply, regulating the bioavailability of arginine in the lung, and inhibiting T cell proliferation. Here we used mice lacking Arg1 in myeloid lineage cells, to investigate the contribution of Arg1 to asthma pathophysiology and lung inflammation. In six distinct model systems encompassing acute and chronic Th2-mediated inflammation, we observed neither a pathogenic nor protective role for myeloid-expressed Arg1 in any measured parameter of lung pathophysiology. Collectively, our results argue that (i) attempts to inhibit arginases in the lung by small molecule arginase inhibitors or RNAi should be examined with caution and (ii) whether macrophages use Arg1 to limit Th2 responses depends on the organ and type of infection or injury.
Cys-leukotrienes mediate lung dysfunction but not histopathologies in an IL-5/Eotaxin-2 double transgenic mouse model of severe asthma (163.13)
Authors: Ochkur Sergei , Protheroe Cheryl , Li Wen , Colbert Dana , Zellner Katie , Lee James , Lee Nancy 
Published: January 2023

Abstract
Products of the 5-lipoxygenase (5-LO) pathway (i.e., cys-leukotrienes and LTB4), are contributors to lung inflammation, airway remodeling, and hyperresponsiveness associated with allergic respiratory inflammation. Eosinophils are capable of leukotriene synthesis/secretion and chemotactically respond to these compounds. However, the in vivo role of eosinophils in leukotriene mediated events during asthmatic airway inflammation is not defined. To study the link between eosinophils and leukotrienes we used the I5/E2 double transgenic mouse model of severe asthma, over-expressing IL-5 systemically and eotaxin-2 in airways, in which lung pathologies are entirely dependent on the presence of eosinophils. We show that airway levels of cysteinyl leukotrienes and LTB4 are significantly elevated in I5/E2 mice. Crosses of I5E2 mice with 5-LO knockout animals abolished AHR in the I5/E2 parental model without significant effects on lung histopathology. Administration of a cys-leukotriene receptor antagonist (Montelukast®) to I5/E2 mice replicates the effects of the total leukotriene loss in I5/E2/5-LO-/- animals. In contrast, I5/E2 mice crossed with BLT-1-/- mice which are deficient of the LTB4 receptor fail to display effects on the pulmonary pathologies occurring in the I5/E2 parental model. These data demonstrate a unique role for cys-leukotrienes in the development of AHR independent of lung remodeling events occurring in this transgenic model of severe asthma.
TSLP augments Th9-mediated allergic inflammation (163.23)
Authors: Yao Weiguo , Zhang Yanlu , Kaplan Mark , Zhou Baohua 
Published: January 2023

Abstract
Thymic stromal lymphopoietin (TSLP) is an epithelial cell derived cytokine important for the initiation and development of Th2-driven allergic inflammation in asthma and atopic dermatitis. The role of TSLP in Th9-mediated inflammation has not been identified. In this study, we investigated the role of TSLP on Th9 differentiation and IL-9 production both in vitro and in vivo. Our data showed that Th9 cells expressed greater amounts of TSLP receptor than Th2 cells, and addition of TSLP to Th9 cultures increased IL-9 production in vitro. Lung-specific transgenic expression of TSLP stimulated IL-9 production in BALF and lung. To further characterize the role of TSLP on Th9-mediated allergic inflammation in vivo, we transferred OVA-differentiated Th2 or Th9 DO11.10 CD4+ T cells to wild type recipient followed by OVA or OVA+TSLP challenge. Our data showed that challenge with OVA+TSLP, but not with OVA alone increased IL-9 production and allergic inflammation in mice injected with Th9 cells, with less effect on Th2 cells. Therefore, Th9 cells can mediate TSLP-mediated exacerbation of allergic airway inflammation. These results suggest that, while both Th2 and Th9 promote allergic inflammation, Th9 cells along are sufficient to respond to TSLP for increased allergic inflammation. Our findings provide a potential role of TSLP on the development of Th9-mediated allergic inflammation.
The role of the keratinocyte in chemical-induced adaptive immune responses (163.4)
Authors: Summerfield Vicki , Maxwell Gavin , White Andrew , Chain Benjamin 
Published: January 2023

Abstract
Allergic contact dermatitis results from the induction of an adaptive immune response to a chemical allergen following repeated skin exposure. The initiation of this response requires the production of an inflammatory microenvironment, created in part by the response of epidermal keratinocytes to chemical exposure. The molecular pathways that regulate inflammatory mediator release and the function of keratinocyte-derived mediators in dendritic cell (DC) migration and maturation have not yet been fully characterised. We have established that HaCaT immortalised human keratinocytes (our experimental model for epidermal keratinocytes) transcribe and release IL-6, IL-8, IL-1β and GM-CSF in response to our model skin allergen (1-chloro-2, 4-dinitrobenzene). A global transcriptomic analysis was performed to investigate the molecular mechanisms behind the inflammatory mediator release, which uncovered significant differential expression of 1728 genes, many of which map to components of stress induced pathways such as NF-κB and Nrf-2. Investigation of upstream signal transduction cascades revealed activation of the MAPK pathways, specifically phosphorylation of p38 and JNK, and some evidence of NF-κB translocation. The mechanism by which chemical allergens trigger this response remains unknown, however experiments are ongoing to characterise the role of reactive oxygen species production in disease induction.
Prostaglandin I2-IP signaling promotes the generation of IL-17-producing γδ T cells that associate with the airway epithelium during allergic lung inflammation (163.5)
Authors: Ferrini Maria , Roberts Kevan , Jaffar Zeina 
Published: January 2023

Abstract
γδ T cells rapidly produce cytokines that eliminate pathogens, regulate inflammation and promote homeostatic functions in response to tissue stress and environmental insult. Here, we demonstrated that an innate IL-17-producing γδ T cell response developed in tandem with allergic lung inflammation and that these cells expressed the αEβ7 integrin and are closely associated with the airway epithelium. Although PGI2-IP receptor signaling downregulated allergic pulmonary inflammation, it promoted the emergence of intraepithelial IL-17-expressing γδ T cells in the airways. In keeping with these findings, a pronounced reduction of IL-17-producing γδ T cells was observed in the thymus, as well as lungs, of IP deficient mice implying a key role for PGI2 in programming IL-17 production by natural γδ T cells. Consistently, iloprost, a stable analog of PGI2, augmented IL-17 production by γδ T cells. Moreover, the Vγ4+ subset of γδ T cells in the airways served to limit the allergic inflammation. Overall, these findings reveal that PGI2 plays a key immunoregulatory role by promoting the programming of innate intraepithelial IL-17-producing γδ T cells.
Curcumin attenuates the scurfy-induced immune disorder (164.14)
Authors: Lee Gihyun , Nam Ji-Young , Shin Minkyu , Hong Moochang , Bae Hyunsu 
Published: January 2023

Abstract
The scurfy mutant mouse is the genetic and phenotypic equivalent of the single-gene human autoimmune disease immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX). Scurfy mice have a deletion in the forkhead domain of Foxp3, fail to develop thymic-derived Foxp3+ regulatory T cells, and develop a fatal lymphoproliferative syndrome with multiorgan inflammation. Curcumin(1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a naturally occurring polyphenolic phytochemical isolated from the rhizome of the medicinal plant Curcuma longa. It has profound anti-inflammatory activity and been traditionally used to treat inflammatory disorders. Recent studies have shown that curcumin ameliorates multiple sclerosis, rheumatoid arthritis, psoriasis, and inflammatory bowel disease by regulating inflammatory cytokines such as IL-1, IL-6, IL-12, TNF-α and IFN-γ and associated JAK-STAT, AP-1, and NF-κB signaling pathways in human or animal models. In this study we have examined the remedial value of curcumin on the condition of scurfy mice. In vivo treatment with curcumin significantly prolonged survival time and reduced clinical severity. In addition, it decreased inflammatory cytokines and CD4+ T cells proliferation owing to diease. These findings highlight the fact that curcumin inbibits symptoms arose from Foxp3 hypoplasia and suggest its use in the treatment of IPEX.
p38 MAP kinase controls pathogenic T cell responses in experimental allergic encephalomyelitis (164.8)
Authors: Krementsov Dimitry , Noubade Rajkumar , del Rio Roxana , Nagaleekar Viswas , Saligrama Naresha , Sabio Guadalupe , Davis Roger , Rincon Mercedes , Teuscher Cory 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an autoimmune disease characterized by progressive demyelination of the central nervous system (CNS). Therapies with limited efficacy are currently available for MS. The presence of autoreactive CD4 T helper (Th)1 and Th17 cells in the CNS is thought to be important for MS pathogenesis. Here, we show that pharmacological inhibition of p38 MAP kinase (MAPK) by SB203580 (SB) significantly ameliorates clinical EAE elicited by immunization of C57BL/6J mice with MOG35-45 (chronic EAE) and SJL/J mice with PLP135-151 (remitting-relapsing EAE). While SB treatment of actively immunized animals did not prevent immune infiltration of the CNS, it reduced production of IL-17, but not IFNγ by antigen-specific Th cells. Interestingly, when EAE was induced by passive transfer of encephalitogenic Th1-polarized cells, administration of SB to recipients also resulted in prevention of disease, along with reduced CNS infiltration and antigen-specific IFNγ and IL-17 production. Importantly, we show that genetic manipulation of p38 MAPK activity specifically in T cells was sufficient to alter EAE progression and IL-17 production. Taken together, our results indicate that p38 MAPK activation in Th1 and Th17 cells controls their pathogenic functions in autoimmune inflammatory disease of the CNS, suggesting that pharmacological targeting of components of this pathway specifically in T cells may be useful in the treatment of MS.
Promotion of breast cancer development via Th2 polarization by TSLP (165.2)
Authors: Xu Kangling , Pedroza-Gonzalez Alexander , Wu Te-Chia , Aspord Caroline , Shafer Sasha , Marches Florentina , Gallegos Michael , Burton Elizabeth , Hori Toshiyuki , Tanaka Yuetsu , Zurawski Sandra , Zurawski Gerard , Bover Laura , Liu Yong-Jun , Banchereau Jacques , Palucka A. Karolina 
Published: January 2023

Abstract
Inflammation can promote both oncogenesis and tumor rejection. Chronic inflammation promotes cancer cell survival and metastasis, while acute inflammation triggers cancer cell destruction. Chronic inflammation is often linked with the presence of type 2-polarized macrophages (M2), which are induced by TH2 cytokines, IL-4 and IL-13. Human breast cancer tumor microenvironment displays features of Th2 inflammation that promote tumor development. The underlying molecular mechanisms are unknown. Here we show that breast cancer cells produce cytokine TSLP that induces DCs to express OX40L in vitro. OX40L+ DCs were found in primary breast cancer tumor infiltrates. These DCs drive IL- 13+TNFα+IL-10negCD4+ inflammatory Th2 cell development in vitro. TSLP-neutralizing antibodies block the upregulation of OX40L by DCs induced by breast cancer cells, thereby blocking their capacity to induce inflammatory Th2 cells in vitro. Antibodies neutralizing TSLP, OX40L, or TSLPR inhibit tumor development and IL-13 secretion in the xenograft model. Furthermore,PAR2-signaling is involved in TSLP regulation in cancer cells. Thus, TSLP-driven inflammation might contribute to breast cancer pathogenesis and development via Th2 polarization; and TSLP production by cancer cells is regulated via PAR2-signaling.
Sub-lethal irradiation of human carcinoma cells modulates expression of important modulators of effector CTL anti-tumor activity (165.20)
Authors: Garnett Charlie , Ifeadi Victoria 
Published: January 2023

Abstract
Sub-lethal doses of radiation can alter the phenotype of target tissue by modulating gene products that may make tumor cells more susceptible to T-cell-mediated immune attack. Previously, we demonstrated that colorectal cancer lines responded to radiation by up-regulating surface expression of 5 CTL relevant proteins (Fas, ICAM-1, CEA, MUC and MHC-I). The present study was designed to determine the extent of CTL relevant changes induced by radiation in human colorectal carcinoma cells. Here, SW620, HCT116, and Widr cells were examined for their response to various sub-lethal doses of radiation (0-15 Gy). Experiments quantified changes in the expression of genes that could result in enhanced CTL activity against irradiated tumor cells. One to seven d post-irradiation, changes in expression of other death receptors (DR4, DR5, LTβR and TNF-R1), as well as expression of other molecules involved in T cell mediated lysis of target cells (c-FLIP, bcl-xL, and survivin) were examined. All cell lines altered expression of one or more of these molecules post-irradiation. Furthermore, we found that the expression of effector co-stimulatory molecules, such as 41BBL, ICOSL and OX40L, was also altered. Altered expression of these gene products may enhance the tumor cells’ susceptibility to T-cell-mediated immune attack. Overall, the results of this study suggest that non-lethal doses of radiation can be used to make human tumors more amenable to immune system attack.
Innate immunity, but not adaptive immunity, induced by a therapeutic oral vaccine of colorectal cancer is crucial for tumor elimination in APCMin/+ hCEA mice (165.23)
Authors: Zhong Zhenyu , Zhai Yougang , Qiao Liang 
Published: January 2023

Abstract
We developed a colorectal cancer vaccine, comprised of a human CEA gene-containing plasmid packaged inside the bovine papillomavirus like particles (VLP-CEA vaccine). Oral immunization of APCMin/+ hCEA mice (a model of colorectal cancer) with VLP-CEA vaccine greatly reduced the tumor number compared with those received PBS. Surprisingly, CEA-specific adaptive immunities are dispensable for tumor elimination as similar tumor number reductions are seen in the APCMin/+ or APCMin/+ hCEA mice that are immunized with either VLP-CEA or VLP-GFP (VLPs packaging a GFP-containing plasmid). Consistently, we found that CTL responses are not required for tumor eradication since depleting CD8 T cells prior to vaccinations didn’t impair the vaccine efficacy. We confirmed that the hCEA-specific cellular and antibody responses were generated after vaccination with VLP-CEA but not with VLP-GFP. Importantly, we found that VLP-CEA and VLP-GFP are both able to activate the NLRP3 inflammasome which potentially facilitates colorectal tumor eradication. Thus, our data indicate that the innate immunity, but not adaptive immunity, is required to abolish colorectal tumorigenesis, and the understanding of the immune mechanism by which pseudovirus vaccines eliminate colorectal tumorigenesis will further our knowledge for designing vaccines for other cancers.
The role of Type I interferons in antitumor responses: implications in radiation therapy (165.30)
Authors: Lim Joanne , Gerber Scott , Lord Edith 
Published: January 2023

Abstract
Interferon-alpha (IFN-α) is clinically approved for treatment of melanoma. Besides having direct antitumor effects, type I IFNs (IFN-α/β) can also enhance IFN-γ responses in cells. Previously, we found that local treatment with a single high dose of radiation induced an increase of IFN-γ within the tumor microenvironment, and this increase is important for radiation-induced antitumor responses. Since the interplay between IFN-α/β and IFN-γ has been shown to be important in several immunological processes, we hypothesize that the lack of type I IFN signaling will result in poor radiation-induced IFN-γ responses and as a consequence, a lack of tumor control. To test our hypothesis, we first compared the growth of B16 tumors between wild type (WT) mice and IFN-α/β receptor knockout (KO) mice. Interestingly, tumor growth was faster in KO mice than WT mice, suggesting that type I IFNs play a role in antitumor immunity. In mice that were treated with 15Gy radiation, the tumor burden reduction observed in KO mice was comparatively smaller than that in WT mice. Corresponding to lower reduction in tumor growth after radiation treatment, KO mice have limited levels of radiation-induced intratumoral IFN-γ and number of tumor-infiltrating CD8+ T cells compared to that in radiation-treated WT mice. Taken together, our data suggest that type I IFN signaling within host cells is important for antitumor immunity, including IFN-γ-mediated responses induced by radiation treatment.
Role of the AIM2 inflammasome in nasopharyngeal carcinoma (165.35)
Authors: Chen Lih-Chyang , Wang Li-Jei , Tsang Nang-Ming , Ojcius David M. , Chang Yu-Sun 
Published: January 2023

Abstract
Inflammation is a hallmark of cancer, especially in the infection-associated cancer. IL-1β, a major proinflammatory cytokine in tumor milieu, is regulated by inflammasome in response to pathogen and damage. Nasopharyngeal carcinoma (NPC) is a cancer prominent in Taiwanese population and is closely associated with Epstein-Barr virus (EBV) infection. We have examined the AIM2 inflammasome expression in Epstein-Barr virus (EBV)-associated NPC tissues. We found that the AIM2 inflammasome is overexpressed in tumor cells and significantly correlated with better local-recurrence- and disease-free survival of NPC patients after treatment. In addition, the AIM2 inflammasomes was induced by dsDNA in NPC cells, which could be inhibited by caspase inhibitor. The new findings in this study may open a new direction for future therapy or drug development for cancer by inflammation modulation.
Dendritic cell generation from PBMC obtained from jaundiced patients with pancreatic adenocarcinoma — a potential role for STAT-1? (165.48)
Authors: do Carmo Joao Paulo , Treglia Marisa , Jukemura Jose , Matheus Andre , Rodrigues Joaquim Jose , da Cunha Jose Eduardo , Machado Marcel , Bergami-Santos Patricia , Barbuto Jose Alexandre 
Published: January 2023

Abstract
Pancreatic adenocarcinoma (PAdc) is an aggressive malignancy with poor prognosis, urging for new therapeutic strategies. DC-based vaccination is one of such promising approaches since DC are the most potent APCs. However, in cancer patients, DC generation and function may be deficient. Here, we describe the in vitro generation of DC from jaundiced patients with PAdc and also the effect of jaundiced plasma (JP) in DC generation. PBMC from 16 patients and 16 healthy donors were separated and adherent cells were cultured with GM-CSF, IL-4 and TNF-α. Cultures were supplemented with 10% JP or normal plasma (NP). Non-adherent cells were harvested at day 7, labeled and analyzed by flow cytometry. Patients’ cells, cultured in 10% JP, had significantly lower expression of CD11c, CD80, CD86 and HLA-DR. Healthy donors’ cell culture supplementation with JP decreased the percentage of HLA-DR+, CD11c+ and CD86+ cells, but not to the same extent as that of patients’ cells. When patients’ PBMC were cultured in NP, there was a significant increase in HLA-DR and a tendency to increase CD86 expression. Preliminary data suggest that these alterations may be related to low levels of phosphorylated STAT-1 in patients’ DC after activation. Altogether, these data demonstrate an impairment in PAdc patients’ PBMC ability to differentiate into DC in vitro, a phenomenon to be considered when designing DC-based vaccination strategies for these patients.