bluuebunny/crossref_metadata_2025_split huggingface dataset:
POPULATION GENETICS AND BIOCHEMICAL CHARACTERIZATION OF HUMAN CASPASE-12 (100.16)
Authors: Hermel Evan , Yavari Mehdy , Parsi Katayoun Edalat , Klapstein Kevin Daniel 
Published: January 2023

Abstract
Casp12 encodes the protein caspase 12 (casp12), which has a downregulatory effect upon IL-1 activation and subsequent inflammatory immune reactions. Casp12 is primarily a pseudogene (Casp12p1) in most humans, but ~20% of people of African ancestry have a functional, intact form of Casp12. This allele is increased in African-American individuals with severe sepsis. We examined Casp12 allele distribution in populations of Indians and Central Asians and in a pilot screen found that a small number of Tamils (2 of 10; 20%) possess the intact Casp12 allele. Gujratis, Punjabis and other Central Asians (Baluchi, Iranian, Pakistani or Afghani) were all homozygous for Casp12p1, as were nearly all other Indians (18/19; 95%). Thus, small but distinct populations outside of Africa still harbor Casp12. To examine the biochemical properties of the protein, we expressed recombinant human casp12. By fractionation techniques, casp12 was found exclusively in the cytosol. In order to better characterize the role of casp12 in the inflammatory process, we generated a rabbit polyclonal antiserum to casp12 and used it to determine if the protein interacted directly with components of the inflammasome. Immunoprecipitation of casp12 revealed that the protein did not interact with ASC, Cardinal, or Caspase 5. Casp12 may thus exert its downregulatory effects by direct interaction with IL1.
Prostaglandin E2 induces MMP-9 production in myeloid dendritic cells (100.3)
Authors: Yen Jui-Hung , Ganea Doina 
Published: January 2023

Abstract
Dendritic Cells (DCs) play an important role in the initiation of the immune response. Immature DCs take up antigen, mature and migrate to the regional lymph nodes where they activate antigen-specific naïve T cells. Prostaglandins such as PGE2 are essential for the migration of DCs to the lymph nodes. Matrix metalloproteinases (MMPs) play an essential role in DC migration, through the degradation of extracellular matrix (ECM) and basement membranes. MMP-2, and particularly MMP-9, are essential for dendritic cell migration in vitro through a reconstituted basement membrane (Matrigel), as well as in vivo to the draining lymph nodes. In this study, we show that PGE2 induces membrane-bound and secreted MMP-9 production in BM-DCs through the EP2/EP4-cAMP-PKA signaling pathway. Furthermore, PGE2-induced MMP-9 expression promotes migration of cytokine (TNF-alpha+IFN-alpha)-matured DCs in vitro through Matrigel and to the draining lymph nodes in vivo in B10.A mice. Our results describe a new mechanism for the effect of PGE2 on dendritic cell migration, which could lead to new therapeutic approaches in using DC as vaccination tools.
Grant support: 2RO1 AI0562306 (DG) and Dissertation Fellowship from Rutgers University (J-H Y).
Anaphylatoxins play a key role in the development of experimental lupus cerebritis (100.4)
Authors: Alexander Jessy John , Quigg Richard John 
Published: January 2023

Abstract
Complement activation generates the C3a and C5a anaphylatoxins, which act through specific G-protein coupled receptors (R). Anaphylatoxins correlate with flares in patients with systemic lupus erythematosus. C3aR and C5aR mRNA and protein expression were significantly increased in brains of the lupus mouse model, MRL/lpr mice compared to those of the non-diseased congenic MRL/+ strain. To examine the role of C3aR and C5aR signaling in brain, specific antagonists, N2-[(2,2-diphenylethoxy)acetyl]-L-arginine and acetyl-Phe-(Orn-Pro-D-cyclohexylalanine)-Trp-Arg, respectively, were administered to MRL/lpr mice. Littermate controls were given vehicle alone. Control MRL/lpr mice had increased infiltration of blood cells into brain and an increase in a number of relevant cytokines and cell-bound accessory molecules (γ-IFN, TNF-α, IL-1β, MIP-2, MCP-1, RANTES, TNFR1, and ICAM-1) which were reduced by inhibition of C3aR and C5aR. In addition, the number of apoptotic cells that were increased in MRL/lpr mice compared to MRL/+ mice, was significantly reduced by inhibition of C3aR and C5aR, with a corresponding increase in Iκβα and phosphorylated Akt, and decrease in Bcl-xL and phosphorylated BAD. Thus, pharmacological blockade of anaphylatoxin receptors reduces pathological features in the brain in experimental lupus and represents a potentially viable treatment for human lupus cerebritis.
Nicotinamide as an anti-inflammatory agent: an in vivo and in vitro study in a mouse model of septic shock. (100.7)
Authors: van gool frederic , Galli Mara , Rongvaux Anthony , Fabien Andris , Leo Oberdan 
Published: January 2023

Abstract
Tumor necrosis factor alpha is an important mediator of inflammation. Inhibition of TNF production is beneficial in several inflammatory diseases, and numerous efforts have been devoted in the design of therapies aimed at blocking the production of this cytokine. In the present work, we have analysed the anti inflammatory properties of nicotinamide (NAm), in a mouse model of acute septic shock. NAm was found to protect mice from a lethal injection of LPS, even when administered 2 h post treatment. NAm was found to inhibit TNF secretion while leading to increased IL-10 production in vivo. These observations have been corroborated by in vitro studies, in which NAm was found to inhibit TNF secretion by all the cell types tested. Our observations indicate that NAm only marginally affect TNF mRNA production while inhibiting TNF synthesis, suggesting an effect at a post-transcriptional stage. NAm represents an inhibitor of several classes of NAD dependent enzymes. To confirm the role of a NAD dependent step in the regulation of TNF, we took advantage of a novel pharmacological agent known to inhibit NAD synthesis (FK866). Use of this compound has led us to demonstrate that optimal TNF synthesis requires adequate intracellular NAD concentration. Collectively these studies establish a functional link between metabolism and inflammation, and suggest an important role for NAD dependent enzymes in the regulation of TNF synthesis.
Mast Cell Deficiency Leads to Decreased Expression of Cyclooxygenase-1 (COX1), COX2, Toll-Like Receptor-4 (TLR4) and Endothelial Nitric Oxide Synthase (eNOS) mRNA in Mouse Aorta (100.8)
Authors: Tan Xiaoyu , Idiculla Arun , Smith Donald D , Stechschulte Daniel J , Dileepan Kottarappat N. 
Published: January 2023

Abstract
Mast cells (MC) are well known for their contribution to vascular inflammation and atherosclerosis. We have shown that MC proteases and histamine amplify lipopolysaccharide (LPS)-induced inflammatory responses in human coronary artery endothelial cells via stimulation of TLR4 expression. This study examined mRNA levels of COX1, COX2, TLR4 and eNOS in aortic tissues of MC-deficient (W/Wv) mice and wild type controls (WT) to gain insight into the role of MC in vascular pathophysiology. We also determined the effect of MC degranulation on gene expression in aortas 24 h after intraperitoneal injection of MC degranulation agent compound 48/80 (1 μg/g body wt). We found that, in comparison to WT, aortic tissues of W/Wv mice express lower levels of COX1, COX2, TLR4 and eNOS mRNA. Injection of compound 48/80 resulted in marked stimulation of expression of these genes in aortas of WT, but not in W/Wv mice, confirming the involvement of MC degranulation products in this process. To determine whether a deficiency of MC and/or decreased COX expression in W/Wv mice is associated with changes in prostanoid homoeostasis, the levels of prostacyclin and thromboxane A2 metabolites in urine samples were analyzed. The levels of 6-keto PGF1α and 11-dehydro TXB2 in 24 h urine of both genotypes were comparable when normalized for the volume and creatinine excretion. These results suggest that, although MC deficiency suppresses the expression of COX1 and COX2 genes in the vasculature, the systemic prostanoid homeostasis remains protected.
(Supported by NIH R01-HL070101 and Carey Arthritis Fund)
PGE2 mediates cAMP-dependent Epac1/Rap1 signaling in primary rheumatoid synovial fibroblasts (100.9)
Authors: Kojima Fumiaki , Kapoor Mohit , Yang Lihua , Kawai Shinichi , Crofford Leslie J 
Published: January 2023

Abstract
Exchange protein directly activated by cAMP (Epac1 and Epac2) are recently identified targets for cAMP signaling. Epac activates Rap1 by catalyzing the conversion of GDP-Rap1 to GTP-Rap1, which is independent of classical cAMP/PKA signaling. In this study, we examined the activation of Epac/Rap1 signaling by prostaglandin E2 (PGE2), a proinflammatory lipid mediator, in synovial fibroblasts (RASF) from rheumatoid arthritis (RA) patients. Expression of Epac1 mRNA and protein were observed in RASF, whereas Epac2 expression was absent. Rap1 was also expressed and its active form, GTP-Rap1, was rapidly increased by PGE2 and it was further enhanced in the presence of IBMX, a phosphodiesterase inhibitor. In addition, the effect of PGE2 on Rap1 was mimicked by forskolin, (a direct activator of adenylate cyclase) and butaprost (an EP2 agonist) but not by sulprostone (an EP1 & EP3 agonist), which were correlated to elevation of cAMP. Furthermore, Rap1 activation was also observed by 8-CPT-2Me-cAMP (an Epac agonist) as well as 6-Bnz-cAMP (a PKA agonist). Epac1/Rap1 signaling via EP receptor associated to the elevation of cAMP may act in concert with classical PKA signaling after exposure to PGE2. Epac1/Rap1 signaling may be an alternate signaling pathway in addition to PKA signaling for PGE2 mediated pathophysiology of chronic inflammatory diseases such as RA.
Grant Support: Arthritis Foundation Biomedical Sciences Grant and NIH/NIAMS AR49010.
Interleukin 6 modulates genes associated with fibroblast migration and function (101.10)
Authors: Gallucci Randle M , Luckett Lerin R , Mickle Bethany M 
Published: January 2023

Abstract
Interleukin 6 deficient mice (IL-6KO) display significantly delayed cutaneous wound healing, characterized by decreased granulation tissue formation. Dermal fibroblasts are one of the principal cell types found in granulation tissue and mediate numerous processes during healing including collagen deposition. Polyvinyl alcohol sponge matrices implanted seven days in IL-6KO mice showed far fewer infiltrating fibroblasts as compared to wild-type C57. It was also found that full thickness wounds from IL-6KO mice showed higher expression of MMP-2 and TIMP-2 as compared to wild-type from 1 to 5 days post wounding. Treatment of IL-6KO fibroblast populated free-floating collagen lattices with various concentrations of rmIL-6 showed a dose response decrease in MMP-2 TIMP-2 mRNA and protein expression. The expression of TGFβ’s 1, and 3 as well as TGFβRII, which can mediate collagen formation, were increased in IL-6KO mouse skin treated intradermally with rmIL-6 in a dose response manner. Expression of TGFβ1, 3, and RII were induced as well in IL-6KO fibroblast collagen lattice cultures in a similar manner. These results indicate that IL-6 may influence on collagen deposition during granulation tissue formation in skin wounds. The mechanism of this may involve both the inhibition of MMP function, and the induction of TGFβ genes.
This research was supported by a grant from NIH/NIGMS (5R01GM067745-03).
Adenosine A2a receptor activation reduces lymphocyte-mediated liver injury induced by alpha-galactosylceramide in vivo (101.11)
Authors: Chen Lanlin , Linden Joel M 
Published: January 2023

Abstract
NKT cells play a key role in initiating an inflammatory cascade during liver ischemia/reperfusion injury (IRI). Cytokine production by NKT cells is inhibited by A2A adenosine receptor (A2AAR) activation. To further investigate the mechanism of A2AAR-mediated liver protection, we selectively activated NKT cells in vivo with α-galactosylceramide (α-GalCer, 4 μg/mouse) a glycolipid that is presented by CD1d to invariant NKT cell receptors. Liver injury and lymphocyte activation were assessed by measuring serum alanine transaminase (ALT) which peaked in 18 h, and proinflammatory cytokines in various cells by FACS. Mice treated with the selective A2AAR agonist ATL313 (1 ng/kg/min) prior to and during α-GalCer treatment had significantly reduced serum ALT and interferon (IFN)- 1 _ levels. In NKT cells, ATL313 reduced intracellular IFN-γ, TNF-α and IL-2 by 30–60%. Peak IFN-γ production occurred earlier (&lt; 2 hr) in NKT cells than in NK cells (&gt; 4 hr) suggesting that NK cell activation is downstream of NKT cell activation. All of the effects of ATL313 were abolished in A2AAR KO mice. In IFN-γ KO mice there was a 58% and 70% reduction in TNF-α and IL-2, respectively in response to α-GalCer, suggesting a primary role by IFN-γ in triggering a cytokine cascades that drives liver injury. In summery, selective NKT cell-activation by α-GalCer causes liver injury which is reduced by the A2AAR activation. It appears that ATL313 exerts its action on NKT and possibly other lymphocytes primarily by limiting IFN-γ production from these cells during early inflammatory processes.
Supported by NIH R01 HL37942
Tetracyclines tigecycline and doxycycline inhibit LPS-induced nitric oxide production by RAW 264.7 murine macrophages. (101.3)
Authors: Kaushik Vidhu , Beduya Dino , Kalampokis Ioannis , Kohlhoff Stephan , Joks Rauno O , Durkin Helen G , Nowakowski Maja 
Published: January 2023

Abstract
We previously reported that minocycline and doxycycline strongly suppress serum IgE and decrease IgE production by PBMC from patients with asthma (Smith-Norowitz et al, Ann Allergy, Asthma, & Immunol 2002; 89:172–9; Durkin et al, AAAAI Annual Meeting San Diego, Feb 23–27, 2007). We have now studied the effects of doxycycline and tigecycline on LPS-induced nitric oxide (NO) production by murine macrophages (RAW 264.7). Cell cultures were incubated for 1 – 5 days with or without LPS (200ng/mL, phenol extracted from Salmonella typhimurium) and doxycycline or tigecycline (1 – 10 μg/ml). Accumulation of nitrite, stable metabolite of NO, was determined using a modified colorimetric Griess reaction. Both doxycycline, and to a lesser extent tigecycline, consistently suppressed LPS-induced nitric oxide production in dose-dependent manner (doxycycline: 23–30%, tigecycline: 10–23%). The tetracycline mediated suppression of NO production by macrophages in culture is independent of antimicrobial activities, but the underlying mechanism of this effect remains to be elucidated. Since nitric oxide is an important mediator of inflammatory responses, our results suggest that the anti-inflammatory effects of tetracyclines may be utilized in the treatment of IgE mediated allergic disorders and may decrease exhaled breath nitric oxide, an emerging biomarker of allergic airway disease.
Oxylipins Derived from Docosapentaenoic Acid (DPAn-6) Possess Potent Anti-inflammatory Activity (101.4)
Authors: Arterburn Linda M , Dangi Bindi , Nauroth Julie , Teymourlouei Mah , Obeng Marcus 
Published: January 2023

Abstract
Background: The resolution of inflammation is an active process mediated by endogenous lipids formed by lipoxygenases and cyclo-oxygenases at the site of inflammation. Enzymatically oxygenated derivatives (oxylipins) of the omega-3 fatty acids DHA and EPA (resolvins) have potent resolution activity.
Objectives: To determine if oxylipins are enzymatically synthesized from the omega-6 fatty acid DPAn-6 and whether these molecules possess pro-resolution, anti-inflammatory properties.
Results: Two major metabolites, 17-hydroxy-DPAn-6 and 10,17-dihydroxy-DPAn-6, were formed from DPAn-6 following reaction with soybean 15-lipoxygenase. The identity of these metabolites was confirmed by LC/MS/MS, NMR, and UV analysis. 17-hydroxy-DPAn-6 was also formed following incubation of DPAn-6 with whole human blood. In a mouse air pouch model of acute inflammation, local administration of 100 ng (0.005 mg/kg) of either 17-hydroxy-DPAn-6 or 10,17-dihydroxy DPAn-6 resulted in 70–80% reduction in leukocyte trafficking, comparable to that observed following indomethacin (5 mg/kg ip) administration. The anti-inflammatory activity of both compounds was confirmed in a rat hind paw edema model of acute inflammation. Intravenous administration of 5 μg (~0.025 mg/ml) of either compound resulted in ~25% reduction in paw edema post carrageenan challenge. Both DPAn-6 oxylipins were also active in the hind paw model after oral administration.
Conclusions: Oxylipins derived from DPAn-6 are natural compounds possessing potent anti-inflammatory activity. These compounds or analogs thereof are candidates for new drugs that act uniquely to resolve inflammation.
A potential role for Citalopram as an immunoenhancer on morphine-induced immunosuppression (101.9)
Authors: Nguyen Thao , Vallejo Ricardo , Benyamin Ramsin , Kramer Jeff , Vogel Laura A. 
Published: January 2023

Abstract
Chronic pain patients are often challenged with depression stemming from the long-term physiopsychological effects of their condition. Consequently, chronic pain patients are often treated with morphine, which can induce immunosuppression, along with an antidepressant. The antidepressant, Citalopram, is a serotonin reuptake inhibitor that may have immunomodulatory effects. We investigated whether Citalopram has immunoenhancing effects on morphine-induced immune suppression. Adult mice were pretreated for 7 days with either saline or Citalopram (10 or 30 mg/kg, twice daily intraperitoneal injections), followed by immunosuppression by subcutaneous implantation of a 25 mg morphine pellet for 48 h. Spleen, thymus, and lymph nodes were harvested to analyze total cell numbers. Total splenocyte numbers in all Citalopram-treated animals were significantly higher than saline-treated animals, while no differences were found in the thymus or lymph nodes. More specifically, a high dose of Citalopram (30 mg/kg) resulted in significantly higher B cell numbers in the lymph nodes, where T cell and NK cell numbers were not different. Interestingly, splenic lymphocyte populations did not differ between treatments. In summary, Citalopram may have a specific potential in the attenuation of morphine’s immunosuppressive effect by enhancing splenocyte numbers and lymph node B cell populations.
DONOR SPLENOCYTES DECORATED WITH A NOVEL FORM OF FASL INDUCES TOLERANCE TO CARDIAC ALLOGRAFTS (102.11)
Authors: Yolcu Esma Shirwan , Zhao Hong , Gu Xiao , Lacelle Chantale , Bandura-Morgan Laura , Askenasy Nadir , Shirwan Haval 
Published: January 2023

Abstract
AICD is critical to tolerance to self antigens and apoptosis induced by Fas/FasL interaction plays a critical role in this process. We recently developed a novel approach designated as ProtEx™ that allows for the generation of chimeric immunological ligands with core streptavidin (SA) and their display on biotinylated cells in a rapid and effective manner. Importantly, the chimeric proteins have potent immunological activities possibly due to their ability to form tetramers and higher structures. We generated a chimeric form of FasL (SA-FasL) with potent apoptotic activity and previously demonstrated that the treatment of ACI rats with WF splenocytes decorated with SA-FasL pre- and post-transplantation of WF hearts resulted in tolerance. We herein tested if pre- or post-treatment alone results in tolerance to cardiac allografts. Pre-treatment of ACI rats with unmodified donor WF splenocytes (13x106) on days -6 to mobilize alloreactive T cells and prime them for apoptosis followed by two doses of SA-FasL-decorated cells administered on days -3 and -1 resulted in tolerance to &gt;80% of the WF hearts transplanted on day 0. Posttreatment with SA-FasL-decorated donor cells on days +1, +3, and +5 resulted in tolerance to &gt;60% of the WF hearts without the use of any adjuvant immunosuppression. In marked contrast, all the animals treated with donor splenocytes decorated with control SA protein rejected their grafts in a normal tempo. Immunomodulation with donor cells decorated with SA-FasL represents a practical, effective, and safe alternative approach to gene therapy for the induction of transplantation tolerance. NIH (R21 DK61333, R01 AI47864, R21 AI057903, R21 HL080108), ADA (1-05-JF-56).
IL-10-mediated Induction of regulatory Foxp3+CD4+ T cells by F4/80+ macrophages in mixed allogeneic chimeras (102.12)
Authors: Zhao Yong , Liu Guangwei , Ma Haixia 
Published: January 2023

Abstract
Antigen-presenting cells including macrophages play a crucial role in shaping immune response to pathogens or allografts. The immune regulatory function of macrophages has not been fully understood. In the present study, the ability of donor F4/80+ splenic macrophages (SPMs) to induce recipient regulatory T cells (Treg) was studied using a B6--&gt;Balb/c mixed chimeric mouse model, in which transplantation tolerance has been achieved. B6 F4/80+ SPMs in mixed chimeras induced significantly lower cell proliferation, more IL-10 and TGF-â products, and less IL-2 and IFN-ã products of recipient CD4+ T cells than B6 F4/80+ SPMs in non-chimeric B6 mice did, whereas they showed similar immunogenicity to the third part C3H CD4+ T cells. Importantly, donor B6 F4/80+ SPMs in mixed chimeras could induce recipient Foxp3+CD4+ Tregs from Foxp3-CD25-CD4+ T cells. Furthermore, donor B6 F4/80+ SPMs in mixed chimeras produced more IL-10 and less IFN-ã than those in non-chimeric mice when cultured with recipient Balb/c but not the third party CD4+ T cells. The induction of CD4+ Tregs by donor F4/80+ SPMs could be significantly blocked by anti-IL-10, but not TGF-â mAb. Therefore, donor F4/80+ SPMs may have the ability to induce recipient Foxp3+CD4+ Tregs partially via IL-10-dependent pathway. This study identified an additional mechanism for macrophages to induce and/or maintain transplant tolerance in mixed allogeneic chimeras.
Dendritic cells supply IL-2 for gain of Treg function in vitro (102.14)
Authors: Nasr Mohamed Elmahadi 
Published: January 2023

Abstract
The CD4+CD25+ regulatory T cell plays an important role in controlling immunity to self and foreign antigens. CD4+CD25+ require T cell receptor and IL-2 receptor activation for in vivo development/ expansion, in vitro expansion and for in vitro function, but the source of IL-2 remains unknown.
we used the DO11.10 transgenic mouse model, whose T cell receptor shows allogeneic cross-reactivity to B6. Purified dendritic cells from WT or IL-2 −/− B6 were labeled with cell tracker green and cultured overnight with natural CD4+CD25+ Tregs from DO11.10 transgenic mice, the RD6 inhibitory hybridoma, or the control RD6N non-inhibitory hybridoma. DCs were FACS sorted then used to stimulate fresh CD4+CD25− DO11.10 effectors T cells in an IL-2 ELISPOT assay. CD4+CD25+ cells suppressed CD4+CD25− effectors cells up to 90% when stimulated with WT dendritic cells, but only 29% when stimulated with IL-2 −/− DCs. Similar results were obtained using the RD6 inhibitory hybridoma&gt; RD6 suppressed a mean of 97% with WT dendritic cells and only 25% with IL-2 −/− dendritic cells. The result supports a model that Tregs require signal 3 activation for the APC to gain inhibitory function.