bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced effects of cigarette smoke extract (CSE) on inflammatory cytokine expression in IL-1beta-activated mast cells are regulated via the NF-kB pathway (93.16)
Authors: Chi David S , Lin Ta-Chang , Soike Thomas , Hall Kenton , Ha Tuanzhu , Li Chuanfu , Wu Zong Doa , Moorman Jonathan , Krishnaswamy Guha 
Published: January 2023

Abstract
Human mast cells are multifunctional cells capable of inflammatory responses and associated with allergy, asthma, and atherosclerosis. This study aims to examine effects and mechanisms of CSE on the expression of inflammatory cytokines in mast cells. Main- (Ms) and Side-stream (Ss) cigarette smoke were collected onto fiber filters and extracted in RPMI-1640 medium. Two ml of HMC-1 at 1 x 106 cells / mL were cultured with CSE in the presence or absence of IL-1β (10 ng / mL) for 24 hrs. The expression of IL-6 and IL-8 was assessed by ELISA and RT-PCR. NF-κB activation was measured by electrophoretic mobility shift assay (EMSA) and IκBα degradation by Western blot. Both Ms and Ss CSE significantly increased IL-6 and IL-8 production (p &lt; 0.001) in IL-1β-activated HMC-1. CSE increased NF-κB activation and decreased cytoplasmic IκBα proteins in IL-1β-activated HMC-1. These results suggest that CSE enhance the expression of inflammatory cytokines through increased NF-κB activation and IκBα degradation, which may partially explain why cigarette smoke contributes to lung and cardiovascular diseases. (Supported by the Ruth R. Harris Endowment and RDC of ETSU)
Characterization of a selective Protein Kinase C theta (PKCθ) inhibitor for blocking T Cell responses (93.21)
Authors: Chaudhary Divya , Boschelli Diane , Bree Andrea , Brennan Agnes , Chen Joan , Deng Bijia , Fitz Lori , Goldman Samuel , Ho Melisa , Kasaian Marion , Lee Julie , Wang Daniel , Wei Shui-Qing , Williams Cara , Yang Xiaoke 
Published: January 2023

Abstract
PKC theta (PKCθ) regulates T cell activation in lung inflammation and airway hyperresponsiveness, and in mouse models of multiple sclerosis, arthritis, and inflammatory bowel disease. We investigated inhibition of PKCθ enzyme activity by a small molecule as a strategy for modulating T cell mediated responses. Screening and lead optimization identified Compound A, a potent PKCθ inhibitor in both enzymatic and cell based assays, with low nM inhibitory activities. Compound A was highly selective (&gt;1000 fold) over 50 kinases including representative serine/threonine, tyrosine, and phosphoinositol kinases, and the conventional and atypical PKCs, PKCβ and PKCξ. Compound A was 10 fold selective against PKCε, and 60 to 100 fold selectivity against PKCδand PKCη, respectively. We found that compound A strongly inhibited IL-2 production in antiCD3/anti-CD28 activated whole blood, using both human and mouse blood, with submicromolar potency. Based on these findings, we evaluated compound A- mediated inhibition of anti-CD3 induced IL-2 production in vivo. The results show a dose dependent inhibitory effect of compound A in this 4 hour cytokine production model. Additional cytokines inhibited by compound A in this model are IFNγ, IL-4, and TNF. IL-5 production was not reduced. We propose that compound A is a selective PKCθ inhibitor for further evaluating blockade of T cell responses in inflammation.
The adenosine A1 receptor is a critical component in the modulation of cutaneous hypersensitivity by perceived stress (93.22)
Authors: Oliver Stephen J , Cronstein Bruce N 
Published: January 2023

Abstract
Differential effects of acute and chronic stress on skin immunity occur in the rodent restraint stress model, with acute stress enhancing and chronic stress suppressing cutaneous hypersensitivity (CHS). Extracellular adenosine levels modulate diverse biological activities in the CNS and peripheral tissues and serve an important protective function against physiological stressors such as inflammation and ischemia. We used the restraint stress model and the skin sensitizing hapten DNFB to test if perceived stress influences CHS through an adenosine A1 receptor-mediated mechanism. We subjected hapten-sensitized A1 receptor knockout (A1KO) mice and their wild type (WT) littermates to either acute (2.5h) or chronic (5h daily x 4 weeks) restraint stress, or no stress (controls), followed by hapten re-challenge of the pinna. In WT mice, 48h pinna swelling augmented with acute stress (p = 0.008) and suppressed after chronic stress (p = 0.038). In contrast, CHS responses in the A1KO mice were not affected by acute or chronic stress. Absence of the adenosine A1 receptor did not affect levels of plasma corticosterone or urine catecholamines under these stressful conditions but was associated with elimination of stress-induced neutrophila otherwise observed in WT animals. These results suggest that the adenosine A1 receptor pathway plays a critical role in how perceived psychological stress influences CHS responses.
Phosphoinositide 3-kinase p110delta regulates natural antibody production, marginal zone and B-1 B cell function, and autoantibody responses (93.23)
Authors: Durand Caylib A , Hartvigsen Karsten , Fogelstrand Linda , Kim Shin , Vanhaesebroeck Bart , Witztum Joseph L , Puri Kamal D , Gold Michael R 
Published: January 2023

Abstract
B-1 and marginal zone (MZ) B cells produce natural antibodies, make antibody responses to microbial pathogens, and contribute to autoimmunity. Although the delta isoform of the phosphoinositide 3-kinase p110 catalytic subunit (p110δ) is essential for development of these innate-like B cells, its role in mature B-1 and MZ B cells is not known. Using IC87114, a selective inhibitor of p110δ activity, we show that p110δ is important for B-1 and MZ B cell responses to anti-Ig antibodies, the Toll-like receptor (TLR) ligands LPS and CpG DNA, and the chemoattractants CXCL13 and sphingosine 1-phosphate. Moreover, we found that TLR-induced antibody responses by B-1 and MZ B cells, as well as the localization of MZ B cells in the spleen, depend on p110δ activity. Finally, we show that in vivo production of both protective and self-reactive natural antibodies requires p110δ and that p110δ inhibitors can reduce in vivo autoantibody responses. Thus targeting p110δ may be a novel approach for regulating innate-like B cells and treating antibody-mediated autoimmune diseases.
Supported by a grant to M.R.G. from the Canadian Institutes of Health Research, by NIH grants to J.L.W., and a grant to J.L.W. from the Leducq Foundation.
Glycogen Synthase Kinase-3β regulates antigen/SCF-mediated cytokine production and SCF-mediated chemotaxis in human mast cells (93.6)
Authors: Radinger Madeleine , Kuehn Hye Sun , Kim Mi-Sun , Metcalfe Dean D , Gilfillan Alasdair M 
Published: January 2023

Abstract
Glycogen Synthase Kinase-3β (GSK3β) is a serine threonine kinase downstream of PI3K, which has been implicated in cellular responses including tumorigenesis; cell growth, migration and survival; and cytokine generation. In this study we investigated the role of GSK3β in antigen/SCF-mediated mast cell responses. Short hairpin RNA (shRNA), introduced by lentiviral transfection, was used to knockdown GSK3β in human mast cells. Cytokine production and activation of transcription factors were measured by ELISA and immunoblot analysis. SCF-mediated mast cell chemotaxis was assessed with a transwell migration assay. GSK3β knockdown significantly decreased antigen/SCF-mediated GM-CSF and IL-8 production and SCF-mediated mast cell chemotaxis compared to control treated cells. The decrease in chemotaxis and cytokine production was associated with a pronounced reduction in antigen/SCF-mediated phosphorylation of JNK and the transcription factors c-jun and ATF2. These data are consistent with the conclusion that GSK3β is an essential component of the signalling cascade that regulates antigen/SCF-mediated transcriptional activity and chemotaxis in human mast cells. Thus, targeting GSK3β?may provide one means for down-regulation of these mast cell responses when associated with the allergic inflammatory reaction.
Supported by the Division of Intramural Research, NIH, USA.
High Fat Diet Induces Lung Remodeling in Apoe Deficient Mice: An Association with an Increase In Circulatory and Lung Inflammatory Factors (94.31)
Authors: Boulares Hamid A , Naura Amarjit S , Hans Chetan P , Zerfaoui Mourad , Errami Youssef , Ju Jihang , Kim Hogyoung , Kim Jong 
Published: January 2023

Abstract
Hypercholesterolemia is increasingly considered the basis for not only cardiovascular pathologies but also several complications affecting other organs including lungs. Here, we examined the effect of hypercholesterolemia on lung integrity using a mouse model (ApoE−/−) of high fat (HF) diet-induced atherosclerosis. A twelve-week HF diet regimen induced systemic production of TNF-α, IFN-γ, GMC-SF, RANTES, IL-1α, IL-2, and IL-12 with TNF-α as the predominant cytokine in ApoE−/− mice. Concomitantly, TNF-α, IFN-γ, and MIP-1α were detected in brochoalveolar lavage fluids of these mice, coinciding with lung inflammation consisting primarily of monocytes/macrophages. Such lung inflammation correlated with marked collagen deposition and an increase in matrix metalloproteinase-9 activity in ApoE−/− mice without mucus production or the mucus-promoting IL-13. Although TGF-β was undetectable in brochoalveolar lavage fluid of ApoE−/− mice on HF diet, it displayed a much wider tissue distribution compared to that of control animals. Direct intratracheal TNF-α-administration induced a lung inflammation pattern in wild-type mice that was strikingly similar to that induced by HF diet in ApoE−/− mice. TNF-α administration induced expression of several factors known to be critically involved in lung remodeling including MCP-1, IL-1β, TGF-β1, adhesion molecules, collagen type-1, and TNF-α itself in the lungs of treated mice. These results suggest that hypercholesterolemia may promote chronic inflammatory conditions in lungs that are conducive to lung remodeling potentially through TNF-α-mediated processes.
Differing contributions of CCR4, E-selectin and VLA-4 to the migration of CD4 memory and activated CD4+CD25+ T cells to dermal inflammation. (95.2)
Authors: Issekutz Thomas B , Gehad Ahmed , Al-Banna Nadia , Haidl Ian , Vaci Maria 
Published: January 2023

Abstract
CCR4 is on T cells in dermal inflammation and may mediate homing to skin. Our objective was to determine the expression and interaction of CCR4, E-selectin ligand (ESL) and a4β1 on memory and activated T cells in recruitment to dermal inflammation. A mAb to CCR4 (CR4.1) was developed. CCR4 was on ~10% of memory CD4 cells and 15% of these were ESL+. CCR4 and ESL were markedly increased on activated T cells. CCR4+ memory CD4 cells (memCCR4+) migrated 8-10 fold more to inflammation induced by cytokines, TLR agonists and DTH, than memCCR4- cells, and homed less to LNs. CCR4+ anti-TCR activated CD4 cells (actCCR4+) migrated only 50% better to skin than actCCR4- cells. E-selectin blockade inhibited 50-75% of actCCR4+, but not memCCR4 cell migration. a4β1 blockade had an inverse effect, i.e. inhibiting memCCR4+ more than actCCR4+ cells, while P-selectin blockade had no effect. Thus, CCR4 is on a subset of memCD4 cells with dermal tropism, but this selective homing is reduced on activated CD4+CD25+cells. The role of ESL and a4β1 also differs between activated and memory CCR4+ cells, with a decrease in the role of ESL and an increase in a4β1 with differentiation to long-term memory. (Supported by the CIHR).
TNFRSF25 promotes IL-17 and TL1A expression in murine CD4+ T cells (96.10)
Authors: Wolf Dietlinde , Deyev Vadim , Podack Eckhard R. 
Published: January 2023

Abstract
TNFRSF25 or Death Receptor 3 (TNFR25; DR3) is a member of the TNF-receptor family with TL1A (TNFSF15) as its ligand. TNFR25 is expressed constitutively on murine CD4+ and CD8+ T cells at low levels and up-regulated after T cell activation. IL-17 is a pleiotropic cytokine associated with inflammation and autoimmunity.
Using purified CD4+ T cells from transgenic mice over-expressing A. a full length (FL) TNFR25, B. a natural occurring splice variant, lacking exon 5 and 6 (Δ5,6), C. a dominant negative (DN) TNFR25, lacking the intracellular domain, and D. TL1A knockout mice, we investigated the role of TNFR25 signals in IL-17 expression. CD4+ T cells from full length and, to a lesser extend, those from Δ5,6 transgenic mice showed a significant increase in IL-17 secretion compared to wild type (wt) CD4+ T cells after primary and secondary stimulation under ThN and Th17 conditions in vitro. IL-17 levels in DN and TL1A-/- CD4+ T cells were comparable to wt. Cytokine levels of IFN-γ were comparable between wild type and transgenic/knockout mice, while Th2 cytokines were also increased in FL and Δ5,6 mice, as reported previously. Importantly, we detected highly elevated TL1A mRNA levels in un-stimulated full lenght CD4+ T cells.
Our data indicate that TNFR25 signals cause increased secretion of both Th2 and Th17 cytokines and elevate TL1A expression by CD4+ T cells. TNFR25 signals thus support inflammatory and allergic immune responses.
Cutaneous immune responses to 2, 4-dinitrochlorobenzene (DNCB): role of interleukin (IL)-2 (97.15)
Authors: Dearman Rebecca J , Portsmouth Craig , Cumberbatch Marie , Griffiths Christopher EM , Kimber Ian 
Published: January 2023

Abstract
Prolonged topical exposure of BALB/c strain mice to the contact allergen DNCB, or to the respiratory sensitiser trimellitic anhydride, results in T helper (h) 1 and Th2 cell polarisation, respectively. In addition, a single application of allergen results in discrete cutaneous cytokine profiles and the migration of Langerhans' cells (LC) with different tempos. Of note, DNCB only induced a rapid and transient increase in cutaneous IL-2. We have now explored the role of IL-2 in DNCB-induced LC migration. BALB/c mice received an intradermal injection of recombinant IL-2 or IL-1β (50ng/ear); the latter is known to provoke LC migration. LC densities were determined in epidermal sheets by immunofluorescence staining. Cytokine production by skin explants was measured by protein array. Intradermal injection of IL-1β decreased epidermal LC numbers significantly after 4 and 16h whereas IL-2 was without effect. Prior systemic administration of neutralising anti-IL-2 antibody failed to influence LC migration monitored 6h after DNCB treatment. Migration was blocked by treatment with an anti-tumor necrosis factor-α antibody, a cytokine regulator of LC migration. Administration of IL-2 did result in increased expression of cutaneous IL-17. These data show that IL-2 is not involved in LC migration, however, the selective up-regulation of IL-2 by DNCB may play a role in the subsequent polarisation of the immune response.
Anti-IL-21 monoclonal antibody reduces disease severity and inflammatory cytokines in a murine model of psoriasis and colitis (97.16)
Authors: Lewis Katherine E. , Bort Susan , Bilsborough Janine , Bontadelli Kristen , Maurer Mark , Waggie Kimberly , Kresja Cecile M. , Dillon Stacey R. 
Published: January 2023

Abstract
IL-21 plays a role in many autoimmune and inflammatory diseases, including psoriasis and inflammatory bowel disease (IBD). To investigate IL-21 antagonism in disease, we evaluated a neutralizing anti-mouse IL-21 mAb in a CD4+CD25- T cell transfer SCID mouse model of psoriasis and colitis. Mice treated prophylactically with IL-21 mAb had significant reductions in colitis and psoriatic-like skin symptoms compared to mice treated with PBS or isotype control mAb. IL-21 mAb-treated mice had 5-7-fold lower average lesional skin scores, 6-7-fold lower average clinical colitis scores and significant reductions in histological indices of colitis compared to controls. Mice treated with IL-21 mAb also had significantly lower serum IL-6, RANTES, TNF-α, and MIP-1β levels compared to controls, further supporting an anti-inflammatory role for IL-21 mAb. In a delayed dosing study, mice treated with IL-21 mAb starting 12 days after T cell transfer had significant reductions in colitis, with 3.5-4-fold lower average colitis scores than control-treated mice. Dose-related reductions in lesional skin scores were also observed. Efficacy of IL-21 mAb was equivalent to or better than an anti-mouse IL-12/23p40 active control mAb. These results demonstrate that IL-21 mAb reduces psoriasis-like disease and colitis in a murine model and suggest that an anti-human IL-21 mAb may have clinical utility in treatment of psoriasis and IBD.
Identification of the role of both IL-17RB and IL-17RA in mediating IL-25 induced activities and investigation of IL-17 and IL-25 in a mouse asthma and EAE model (97.9)
Authors: Rickel Erika , Siegel Lori , Rottman James , Hensley Kelly , Swart David , Tocker Joel E , Budelsky Alison 
Published: January 2023

Abstract
IL-25 is an IL-17 family ligand that promotes Th2 inflammatory responses. Intranasal (IN) administration of IL-25 into naïve mice induces pulmonary inflammation similar to allergic asthma. IL-25 has been reported to bind and signal through IL-17RB. Recently, it was shown that IL-17A signals through a heteromeric receptor composed of IL-17RA and IL-17RC. Using knockout (KO) mice and antagonistic antibodies, we investigated whether IL-25 also used a heteromeric receptor complex. Splenocytes from IL-17RA KO mice did not produce IL-5 or IL-13 in response to IL-25 and IL-17RA KO mice did not respond to IN administration of IL-25. Treatment of BALB/c mice with antagonistic antibodies to IL-25, IL-17RB or IL-17RA completely blocked IL-25 induced pulmonary inflammation and airway hyperresponsiveness. These data demonstrate that murine IL-25 mediated activities require murine IL-17RA. We also investigated the roles of IL-25, IL-17A, IL-17RB, and IL-17RA in a mouse asthma and EAE model. Blocking antibodies to IL-25, IL-17RA, or IL-17RB significantly attenuated the mouse asthma model, while anti-IL-17A had no effect. Conversely, blocking antibodies to IL-17RA and IL-17A significantly reduced disease in our EAE model, while anti-IL-25 had no significant effect. These data provide evidence that we can differentiate the activities of IL-25 and IL-17A acting through IL-17RA in different in vivo models of inflammation.
This research was supported by Amgen Inc.
CD38 modulates CXCL12-mediated chemotaxis: a novel mechanism in homing of chronic lymphocytic leukemia cells (98.7)
Authors: Deaglio Silvia , Vaisitti Tiziana , Aydin Semra , Bergui Luciana , Rossi Davide , Bonello Lisa , Chiorino Giovanna , Gaidano Gianluca , Malavasi Fabio 
Published: January 2023

Abstract
Human CD38, an ectoenzyme involved in the catabolism of NAD, can also bind the non-substrate ligand CD31, resulting in activation and proliferation of distinct lymphocyte populations.
CD38 is clinically used as a negative prognostic marker for chronic lymphcytic leukemia (CLL) patients. We adopted CLL as a model to study the relevance of CD38 in vivo. CD38 signals trigger proliferation and increase survival of CLL cells. Further, the simultaneous expression of CD38 and ZAP-70 defines a genetically distinct subset of CLL cells with heightened responses to CXCL12, a critical chemokine in CLL homing from blood to lymphoid organs.
Here we show that CD38 is directly involved in CXCL12-mediated homing. CD38 signals facilitate short- (ERK1/2 phosphorylation) and long-term (chemotaxis) effects induced by CXCL12. Assays using i) a specific inhibitor of CD38 enzymatic activities, ii) agonistic mAbs, and iii) microarray technology indicate that increased homing depends on the receptor functions of CD38. Conversely, blocking anti-CD38 mAbs significantly weaken CXCL12 responses. This is due to physical association on the membrane between CD38 and CXCR4 (the CXCL12 receptor), as shown by i) co-immunoprecipitation, ii) confocal microscopy and iii) measurement of CXCL12 binding to its receptor. These results indicate that CD38 modulates CXCL12 signals, representing a novel mechanism in CLL chemotaxis and homing.
Altered autoimmune response in NOD-Alox15null mice (99.13)
Authors: Morris Margaret A , Butcher M. , McDuffie M. , Nadler J. 
Published: January 2023

Abstract
12/15-lipoxygenase (12/15-LO) reacts with fatty acids to produce pro-inflammatory lipids, enhance IL-12 production by macrophages (MΦ), and its product 12-(S)-HETE induces pancreatic β-cell apoptosis at nM concentrations. Congenic NOD mice deficient in 12/15-LO (NOD-Alox15null) show a significant decrease in Type 1 diabetes (T1D) development (2.5 vs. &gt;60% in ♀ by 30 wks). We tested the effects of the deficiency on the immune system in NOD-Alox15null vs. NOD mice. Adoptive transfer of diabetic (diab) or non-diabetic (non-diab) NOD, and non-diab NOD-Alox15null splenocytes (cells) determined ability of T1D disease transfer in NOD.scids. Both diab and non-diab NOD cells conferred T1D in NOD.scid hosts, but non-diab NOD-Alox15null cells did not (&gt;8 wks post-transfer). NOD-Alox15null.scids were also injected with either NOD (diab and non-diab) or NOD-Alox15null (non-diab) cells. NOD cells still transferred disease, but NOD-Alox15null cells did not. As transferred splenocytes were mainly T and B cells, we tested for 12/15-LO mRNA expression in these subsets. 12/15-LO levels were minimally detectable, suggesting that immune effects are likely due to indirect effects on B and T cells. To study the mechanism, we looked at the role of 12/15-LO on APCs. Fewer MΦ infiltrate the pancreas of NOD-Alox15null mice at 4 wks of age compared to NOD controls. Also, MΦ from 10-wko NOD-Alox15null mice show reduced IL-12 expression compared to age-matched NODs. Therefore, 12/15-LO is a key regulator of the autoimmune response leading to T1D.
MOG intravenous tolerance modulates macrophage classical activation and antigen presentation in experimental autoimmune encephalomyelitis (EAE) (99.2)
Authors: li hongmei , Rostami Abdolmohamad 
Published: January 2023

Abstract
Macrophages act as the first line of self defense by mounting an inflammatory response to antigen exposure and as antigen presenting cells to initiate the adaptive immune response. Inhibition of macrophage activation is one of the possible approaches towards modulating inflammation. Intravenous (i.v.) tolerance has proved to be an effective method for ameliorating experimental autoimmune diseases. Whether macrophages are involved in tolerance induction is still largely undefined. In the present study we found that MOG i.v. down-regulated the expression of B7.1, B7.2 and MHC class II molecules, and reduced phagocytosis of GFP-transfected- Escherichia coli by both peritoneal macrophages and adherent splenocytes. Macrophages from tolerized mice were associated with a significantly impaired response of MOG-sensitized T cells to MOG. A distinct decrease in IFN-ã and IL-2 production by T cells in response to autostimulation was also observed. After MOG i.v. macrophages produced low levels of pro-inflammatory molecules IL-12, TNF-á, IL-1â, RANTES and MCP-1 and high levels of IL-10 and TGF-â. Administration of anti-TGF-â led to a reduction of IL-10 in MOG i.v-tolerized mice. These findings suggest that MOG i.v. inhibits macrophage classical activation and APC function and increases macrophage alternative activation, producing IL-10 and TGF-â, which, in turn, induce enhanced production of IL-10 in macrophages in MOG i.v. mice.