bluuebunny/crossref_metadata_2025_split huggingface dataset:
NF-κB activation is critical for bacterial lipoprotein tolerance-enhanced bactericidal activity in macrophages during microbial infection (116.15)
Authors: Liu Jing Hua , Jiang Yong , Redmond H. Paul , Wang Jiang Huai 
Published: January 2023

Abstract
Tolerance to bacterial cell-wall components including gram-positive bacterial lipoprotein (BLP) represents an essential regulatory mechanism during bacterial infection. Our previous work has demonstrated that BLP-induced tolerance, characterised by hyporesponsiveness in producing proinflammatory cytokines and simultaneously enhanced antimicrobial functions, protects against microbial sepsis-related lethality. However, the underlying mechanisms remain unidentified. In this study we reported that upon S. aureus or E. coli challenge, significantly enhanced IκBα phosphorylation and p65 translocation into the nucleus were observed in BLP-tolerised bone marrow-derived macrophages (BMM), indicating that NF-κB is activated in BLP-tolerised macrophages during bacteria infection. To further clarify whether activation of the NF-κB pathway is required for efficient bacterial killing by BLP-tolerised macrophages, we used two NF-κB inhibitors, SN50 and SC-154. Both inhibitors substantially restrained BLP-tolerised macrophage-induced intracellular bacterial killing, and this was closely associated with delayed phagolysosome fusion. Furthermore, the expression of LAMP-1 and Rab5, two membrane-trafficking regulators participated the process of phagosome maturation was significantly downregulated when the NF-κB pathway was blocked. Collectively, our results highlight a novel role of the NF-κB pathway in bactericidal activity displayed by BLP-tolerised macrophages during microbial infection.
A carboxyl terminal loop structure is the client-binding domain of gp96 (Hsp90B1, Grp94) in chaperoning Toll-like receptors and integrins (116.22)
Authors: Wu Shuang , Gewirth Daniel , Li Zihai 
Published: January 2023

Abstract
gp96, known also as grp94 and HSP90b1, is a molecular chaperone for Toll-like receptors (TLRs) and integrins. Unlike its cytosolic counterpart HSP90, the structure-function relationship of gp96 remains obscure. In particular, the client-binding domain (CBD) of gp96 has not been identified, although a C-terminal loop structure of gp96 may fulfill such a function from a recent crystallographic study. Herein, we provide genetic and biochemical evidence to definitively demonstrate that this loop structure is the CBD of gp96 for TLRs and integrins. Deletion of the CBD completely abolishes the chaperoning ability of gp96. Further fine mapping of this region demonstrates critical residues within the CBD for the folding of integrins but not TLRs. Moreover, we demonstrate that the binding of TLR9 to CBD is dependent on the C-terminal dimerization domain but not the N-terminal ATP-binding pocket of gp96. As both TLRs and integrins play important roles in inflammation, sepsis, autoimmunity and cancer, the identification of the CBD of gp96 in their folding may facilitate the design of gp96-selective inhibitors for the treatment of a variety of pathological conditions.
Toll-like receptors and NOD-like receptors in otitis media with effusion (116.24)
Authors: Yeo Seung Geun , Lee So Yoon , Park Dong Choon 
Published: January 2023

Abstract
Objectives; Bacterial infection in a normally sterile environment of the middle ear cavity usually triggers host immune response which innate immune system plays a dominant role as host’s first line of defense mechanism. Here, we evaluated pediatric patients with otitis media with effusion (OME) in order to assess expression levels of Toll-like receptors (TLRs) -2, -4, -5, -9, and nucleotide-binding oligomerization domain-containing proteins (NODs) -1 and -2 which are all related to bacterial infection. Methods; The study population consisted of 46 pediatric patients with OME, of whom all had ventilating tubes inserted. The expression levels of TLR-2, -4, -5, -9, NOD-1 and -2 mRNA in middle ear effusion were assessed by performing real-time PCR. Results; All effusion fluid samples collected from patients with OME showed expressions of TLR-2, -4, -5, -9, NOD-1, and -2 mRNA. However, we found no significant correlation among expression levels of pattern recognition receptors (PRRs) in relation to characteristics of exudates, presence of bacteria, comorbidity with allergic rhinitis, and frequencies of ventilation tube insertion (p&gt;0.05). Conclusion; This finding suggests that expression of PRRs during bacterial infection may possibly be associated with the development of OME in children.
RLR signaling is amplified by reactive oxygen species and dysfunctions in autophagy (116.25)
Authors: Tal Michal , Sasai Miwa , Iwasaki Akiko 
Published: January 2023

Abstract
Infected cells utilize the RIG-I-like receptors (RLRs) to recognize the presence of RNA viruses in the cytosol. RLRs signal through IPS-1, which is localized to the mitochondrial membrane, resulting in the production of pro-inflammatory and antiviral cytokines. We are interested in the functional implications for the cellular localization of RLR signaling as it is clear that this is a point of intersect for important cellular processes and antiviral defense. We show that pro-inflammatory cytokine production in response to viral ligands is increased in several situations in the absence of autophagy due to increased levels of oxidative stress. The process of autophagy maintains the integrity of cellular organelles such as mitochondria and long-lived proteins by transporting them to the lysosomes for degradation. We have examined the role of defective autophagy and aging on cytosolic antiviral signaling using several ssRNA viruses as well as the dsRNA analog Poly I:C. We found that autophagy contributes to homeostatic regulation of innate antiviral defense through the clearance of dysfunctional mitochondria, and revealed that ROS associated with mitochondria play a key role in potentiating RLR signaling. We also present that RLR mediated cytokine production is increased in a human physiological condition that is known to involve decreased autophagy and increased oxidative stress.
Aberrant glycogen synthase kinase 3β phosphorylation contributes to abnormal cytokine secretion in obese subjects. (116.29)
Authors: Yen Chia-Liang , Shieh Chi-Chang K. 
Published: January 2023

Abstract
To clarify the role of obesity in the immune responses, we investigated the relationship between insulin-induced signaling and Toll-like Receptor (TLR)-induced leukocyte cytokine secretion in obese subjects. Peripheral blood samples were collected from metabolically normal (MNO) and metabolically abnormal (MAO) obese subjects and stimulated with TLR agonists. We found elevated IL-1β, IL-10 and decreased IL-6, IFN-γ secretion in both MNO and MAO leukocytes with TLR stimulation when compared with normal leukocytes. Changes in TLR-induced cytokine secretion correlated with biochemical markers including fasting glucose, insulin, homeostasis model assessment (HOMA) index, and body mass index (BMI). Moreover, peripheral blood mononuclear cells (PBMCs) collected from MAO subjects showed enhanced basal Akt / Glycogen Synthase Kinase 3β (GSK3β) phosphorylation which was not further increased by insulin and lipopolysaccharide (LPS). We also found IκB accumulation in PBMCs isolated from normal subjects treated with GSK3β inhibitor lithium chloride. These findings indicate that TLR-induced cytokine secretion is affected by obesity even in subjects who have not reached the criteria of metabolic syndrome. Enhanced leukocyte GSK3β phosphorylation may contribute to aberrant immune response in obese subjects.
Characterization and functional study of CPAP-associated protein-1(CPAPAP-1) in NF-κB-mediated transcriptional activation (116.3)
Authors: Fu Ru-Huei , Liu Shih-Ping , Huang Chin-Mao , Lin Ya-Hsien , Shyu Woei-Cherng , Lin Shinn-Zong 
Published: January 2023

Abstract
Nuclear factor-kappaB (NF-κB) is a Rel transcription factor that controls the gene expression involved in immune response, inflammation, apoptosis, and proliferation. Centrosomal P4.1-associated protein (CPAP) is an associating partner of the p65 subunit (RelA) of NF-κB. Molecular biology assays and cell biology experiments showed that the role of CPAP is a coactivator of NF-κB-mediated transcription. The C-terminal region of CPAP appears to contribute NF-κB-mediated transcriptional activation. However, knowledge about the factors that interact with the C-terminal region of CPAP is still little. In a yeast two-hybrid screen using the C-terminal region of CPAP as bait, we isolated a novel associating partner named CPAP-associated protein-1 (CPAPAP-1, GenBank: BC114945). CPAPAP-1 has the effector domain (cAMP) of the CAP family of transcription factors. We confirmed that CPAPAP-1 associates with C-terminal region of CPAP by using Glutathione S-transferase pull-down assays and co-immunoprecipitation experiments. After treatment with TNFα, a portion of CPAPAP-1 was observed to accumulate in the nucleus. We also confirmed that CPAPAP-1 controlled activation of TNFα-induced NF-κB by using NF-κB-dependent reporter gene expression assay and RNA interference technique. These results suggest that CPAPAP-1 functions as a coactivator of NF-κB-mediated transcription.
Low dose ionizing radiation exposure can alter unmotivated mouse behavior and brain-based inflammatory mediators (116.34)
Authors: York Jason , Blevins Neil , Peterlin Molly , Cengel Keith , Freund Gregory 
Published: January 2023

Abstract
Individuals exposed to ionizing radiation (IR) experience acute radiation syndrome, the prodromal phase of which includes symptoms such as malaise and fatigue. These symptoms and related adverse biobehaviors have mental, physical and motivational elements that can be difficult to experimentally isolate. We’ve developed an experimental system to test IR-induced fatigue in mice using gamma rays to deliver total body IR in both motivated and unmotivated settings. 6h after a 50cGy dose of 137Cs whole body radiation, mice had a 34% reduction in spontaneous distance moved and average velocity of movement compared to non-irradiated mice. In contrast, the motivated behavior social exploration of a novel juvenile showed non-statistically significant trends toward reduced activity up to 6h post-IR. Examination of brain-based immunity showed whole brain TNF-α mRNA was significantly increased at 4 and 6h post-IR and this increase was coupled to 1) an up-regulation of IL-1RA and down-regulation of IL-6 mRNAs 4h post-IR and 2) a down-regulation of IL-1β, IFN-γ and F4/80 mRNAs at 6h post-IR. Together these data show that shortly after low-dose IR, mouse activity is reduced but can be overcome via a motivator. This altered locomotion is tied to a brain-based alteration in pro/anti-inflammatory balance. These data suggest anti-inflammatory therapies such as corticosteroids or anti-TNF/IL-1 agents may be effective countermeasures for prodromal symptoms due to IR exposure.
The role of IL-1β on IKKβ inhibitors induced neutrophilia (116.4)
Authors: Lee Chih-Yuan , Lai Ting-Yu , Hsu Li-Chung , Yeh Tzu-Wen , Enzler Thomas , Karin Michael 
Published: January 2023

Abstract
Transcription factor NF-κB and its activating kinase IκB Kinase β (IKKβ) are critical for inflammation and immunity. Pharmacological inhibitors of IKKβ-NF-κB could be used for the treatment of inflammation. It was unexpected that IKKβ inhibitors (MLN120B) cause neutrophilia in mice but the mechanism remained unknown. IL-1β acted as a growth factor for myeloid progenitors and a survival factor for mature neutrophils. We tried to investigate the role of IL-1β on IKKβ inhibitors induced neutrophilia. Using conditional deletion of loxP-flanked Ikbkb alleles in myeloid cells in mice, we found severe neutrophilia after IKKβ deletion. Without any stimulus, Ikkβ-deleted mice produced more circulating IL-1β than age-matched wild-type mice. Isolated Ikkβ-deleted monocytes and macrophages secreted higher amounts of IL-1β than wild-type controls without stimulation. Treatment of wild-type mice with IKKβ inhibitors also led to neutrophilia within 8 days, which would be prevented by concomitant treatment with IL-1 receptor antagonis. Neutrophilia in mice after deletion of IKKβ seems IL-1β dependent. Excessive IL-1β signaling is responsible for the uncontrolled neutrophilia and inflammation in IKKβ-deleted mice. Enhanced IL-1β production represents a compensatory mechanism for maintaining immunity when NF-κB is inhibited and compensates for loss of NF-κB-dependent antibacterial immunity.
Role of novel microRNAs in immunological dysfunction associated with PTSD (117.13)
Authors: Zhou Juhua , Nagarkatti Prakash , Zhong Yin , Ginsberg Jay , Nagarkatti Mitzi 
Published: January 2023

Abstract
The immunological dysfunction in combat veterans with post-traumatic stress disorder (PTSD) has not been understood. The current study aimed to evaluate the role of novel microRNAs (miRNAs) in immunological dysfunction associated with PTSD. Our studies demonstrated that both PBMC and CD4+ T cells in peripheral blood significantly increased in PTSD patients as compared with controls. Further studies showed that the percentage of IFN-γ producing Th1 cells was much higher in PTSD patients than normal donors. Multiple cytokine assays indicated that PBMC from PTSD patients produced more IL-1β, IL-2, IL-17, G-CSF and IFN-γ than those from controls. Our results demonstrate that PTSD is associated with proinflammatory response. High-throughput miRNA array hybridization analysis showed that several novel miRNAs such as miR-664 and miR-1291were significantly up-regulated, whereas miR-125a and miR-181c were dramatically down-regulated in PTSD patients. Real-time PCR confirmed that several of these miRNAs such as miR-125a and miR-181c significantly decreased in PTSD patients. Our further studies demonstrated that down-regulation of miR-125a may be responsible for increased IFN-γ production in PTSD patients. The results suggest that some novel miRNAs may play a role in immunological dysfunction associated with PTSD and such novel miRNAs may be used as biomarkers for diagnosis or as a therapeutic remedy for PTSD.
In a murine model of sepsis, IL-6 increases early and remains high until week 4, when its decrease may be related to late-phase immunodeficiency. (117.27)
Authors: Valdes-Ferrer Sergio , Rosas-Ballina Mauricio , Olofsson Peder , Pavlov Valentin , Ochani Mahendar , Chavan Sangeeta , Tracey Kevin 
Published: January 2023

Abstract
Chronic sepsis survival is still an unchartered territory, where system-wide, sometimes perennial dysfunction occurs, usually with dire consequences. In the present study, polimicrobial abdominal sepsis -or sham surgery- was induced using the CLP model. Long-term survivors (&gt;7 days) were sacrificed at weekly intervals, and blood and spleen were collected. Splenic and circulating leukocyte populations were analyzed by flow cytometry. Cytokines were measured by bead-array assay. We found an early increase in splenic size and weight, followed by massive, significant influx of granulocytes, monocytes, and B-cells. Splenic monocytes and granulocytes remained high until week 4. In contrast, splenic T-cell populations remained stable after sepsis, and B-cells returned to baseline by week 3. In peripheral circulation, we found early increases in IL-6 (25-fold; p=0.01), and TNF (7-fold; p=0.01). Other cytokines, including IL-2, IFN-γ, and IL-17A were not different between groups. Serum IL-6 concentration dropped back to levels similar to those of sham mice by week 4. Strikingly, around this time all surviving mice developed spontaneous abdominal abscesses. This is interesting since IL-6 levels have been shown to be a good predictor of early mortality. The fact that a late-phase decrease may be related to a the development of a state of imunosuppression opens new avenues to understanding CARS syndrome/immunoparalysis state known to be devastating in long term septic patients.
INCB38579 is a novel, potent and selective histamine H4 receptor antagonist with activity in rodent models of inflammatory pain (117.28)
Authors: Shin Niu , Covington Maryanne , Bian Di , Bowman Kevin , Li Yanlong , Soloviev Maxim , Yao Wenqing , Newton Robert , Sherle Peggy 
Published: January 2023

Abstract
The histamine H4 receptor (H4) has been considered as an attractive therapeutic target for a number of diseases, such as allergy, asthma, atopic dermatitis and inflammatory pain. INCB38579 is a novel human and rodent active H4 receptor antagonist, with at least 50-fold selectivity over the human H1, H2 and H3 receptors and good pharmacokinetic properties in rats and mice. The compound potently inhibits histamine binding to and signaling through recombinant human and mouse H4 and blocks histamine-induced migration of human and mouse dendritic cells, as well as cell shape change and migration of human eosinophils. This novel H4 inhibitor is efficacious in blocking histamine-induced pruritus in mice and carrageenan-induced acute inflammatory pain in rats. Interestingly, when examined in a formalin pain model, INCB38579 could significantly reduce the relatively long lasting inflammation associated pain. A good correlation between the predicted protein binding adjusted potency from in vitro studies and the analgesic effect in vivo was observed. These results suggest that INCB38579 can serve as a useful tool for pharmacologic characterization of H4 and further supports the hypothesis that the H4 receptor is a target for the development of new therapeutics for various inflammatory diseases.
IL-33 expression by mast cells is regulated by a Sphk-calcium-NFAT dependent pathway (117.5)
Authors: Hsu Chia-Lin , Bryce Paul 
Published: January 2023

Abstract
IL-33 is an IL-1 family cytokine that can act extracellularly via its receptor, T1/ST2 or intracellularly. Functionally, it promotes Th2-associated immunity by enhancing several cell type activation and survival. However, the regulation of IL-33 expression is still unclear. Previously, we showed that basal expression of IL-33 in mast cells was upregulated upon IgE activation. Ca2+ mobilization was sufficient and necessary to enhance IL-33 expression in mast cells. We wanted to further investigate the pathway that drives IL-33 expression. Two major Ca2+-dependent pathways induced in mast cells are inositol trisphosphate (IP3) bound to its receptor, IP3R, and sphingosine kinase 1/2 (Sphk1/2) generated sphingosine-1-phosphate (S1P). PI3K is the upstream regulator for Sphk1. Here, we demonstrate that inhibition of PI3K and Sphk activity decreases IL-33 expression via IgE activation while ionomycin stimulation, which bypasses the inhibition, restores IL-33 expression. Interruption of NFAT and calcineurin interaction, which is downstream of Ca2+ mobilization, also decreases IL-33 expression and ionomycin can not restore it. Blocking of IP3R or NF-kB does not influence IL-33 expression but inhibits another IL-1 family cytokine, IL-1b. In summary, IL-33 is upregulated upon cross-linking of IgE receptors on mast cells and expression is dependent on Ca2+ mobilization and regulated by a PI3K-Sphk1-NFAT pathway.
IL-27 promotes IL-10 production and B7-H1 expression by plasmacytoid DC and augments their expansion of allogeneic Foxp3+ CD4+ T cells (147.2)
Authors: Matta Benjamin , Raimondi Giorgio , Thomson Angus 
Published: January 2023

Abstract
IL-27 is an immunoregulatory cytokine that influences T cell responses and can promote Treg function. Plasmacytoid dendritic cells (pDC) possess immunoregulatory properties that can favor induction of immune tolerance. We investigated the influence of IL-27 on pDC phenotype, function, and interaction with allogeneic T cells. pDC (mPDCA-1+) were immunobead-purified from livers and spleens of Flt3L-treated C57BL/6 mice. Cells were cultured with CpG B, IL-27, or both, and their phenotype and cytokine production analyzed by flow cytometry. T cell allostimulatory capacity of pDC was determined in CFSE MLR, including analysis of Foxp3 expression. CpG B upregulated MHC class II and CD86 on pDC, however, liver pDC expressed greater levels of the coregulator B7-H1, IL-27p28, IL-10, and the IL-27 receptor (R)/WSX-1 compared to spleen pDC. Exposure to exogenous IL-27 augmented B7-H1 and IL-10 but decreased CD86 expression only on liver pDC. Inhibition of STAT3 blunted upregulation of B7-H1. Liver pDC exposed to exogenous IL-27 selectively expanded CD4+Foxp3+ T cells, despite no change in overall CD4+ T cell proliferation. In conclusion, IL-27 enhances the immunoregulatory potential of pDC through upregulation of B7-H1 and IL-10, but not CD86. IL-27-conditioned liver pDC exhibit enhanced ability to expand allogeneic CD4+Foxp3+ T cells compared to spleen pDC. IL-27 may facilitate immunoregulation through the modulation of pDC function and subsequent control of allogeneic T cell responses.
Comparison of in vitro immunomodulatory effects of rhesus bone marrow-derived MSC and MAPC, and dermal fibroblasts (147.22)
Authors: Sindberg Greg , Lindborg Beth , Bansal-Pakala Pratima , O'Brien Timothy 
Published: January 2023

Abstract
In the transplant community, natural suppressive cells derived from animals offer vast advantages over traditional chemical immunosuppressive agents that have very harsh side effects on both the transplant and the patient. The bulk of this research has focused on T regulatory cells (Tregs), given their known role of quelling and suppressing immune responses to natural infection. Other cells, such as mesenchymal stem cells (MSC), have also been observed to exert suppressive capabilities. As therapeutic immunomodulatory cells, MSCs have an advantage over Tregs in that they are much less immunogenic and may potentially be utilized from allogeneic derivations whereas Tregs require patient specific development in the form of autogenic isolations from blood, which greatly limits the available supply. In addition to MSCs, fibroblasts and multipotent adult progenitor cells (MAPCs), which are phenotypically very similar to MSCs, have each been considered to have immunomodulatory potential but mechanisms are poorly understood. Using Rhesus bone marrow-derived MSC and MAPC and dermal fibroblasts we showed that all 3 types of cells strongly (80-90%) inhibited proliferation of (αCD3 stimulated) CD4 and CD8 T-lymphocytes in an in vitro assay. Suppression was maximal with 1:1 cell ratios and effects diminished with serial dilution of test cells. The findings suggest that all 3 lineages have potential as an alternative to Tregs for immunosuppression in organ transplantation.