bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prophylactic and therapeutic targeting of the neurokinin-1 receptor limits neuroinflammation in a murine model of streptococcal meningitis (161.7)
Authors: Chauhan Vinita , Marriott Ian 
Published: January 2023

Abstract
Bacterial meningitis is a rapid, severe and highly damaging infection of the central nervous system (CNS) that is accompanied with high degree of inflammation. We have previously determined an important role for the neuropeptide substance P (SP) in the initiation and progression of bacterially-induced CNS inflammation. In the present study, we provide evidence that SP augments inflammatory glial responses to the important Gram-positive CNS pathogen Streptococcus pneumoniae, and show that endogenous SP/NK-1 receptor interactions play a critical role in the development of neuroinflammation and neurological damage in a mouse model of streptococcal meningitis. Moreover, we show that therapeutic intervention with a systemically delivered NK-1 receptor antagonist attenuates increases in inflammatory cytokine levels and decreases in immunosuppressive cytokine production within the CNS associated with an established in vivo S. pneumoniae infection. Furthermore, we have shown that treatment with an NK-1 receptor antagonist reverses infection-associated pathology in the absence of effects on bacterial burden within the CNS. These results provide the first demonstration that the therapeutic targeting of SP/NK-1 receptor interactions can limit progressive neuroinflammation and neurological damage associated with bacterial infections of the CNS. NK-1 receptor antagonists could, therefore, represent a new strategy for the treatment of potentially lethal CNS inflammation.
Identification of a role for TLR3 in the inflammatory response to Chlamydia infection of murine oviduct epithelial cells. (162.11)
Authors: Derbigny Wilbert , Shobe LaTasha , Kamran Jasmine 
Published: January 2023

Abstract
Because epithelial cells are the major cell type productively infected with Chlamydia during genital tract infections, the overall goal of our research is to understand the contribution of the infected-epithelial cells to the host defense. We showed that TLR3 is the critical PRR in oviduct epithelial (OE) cells that is stimulated during Chlamydia infection, resulting in the synthesis of IFN-β. Our ELISA data indicate that expression of other innate immune modulators including IL-6, CXCL-10, CXCL-16, and CCL-5 were induced in the infected wild-type OE cells; however, this induction was not observed in the TLR3-deficient OE cells. Pre-treatment of the TLR3-deficient OE cells with 50 U/ml IFN-β prior to infection restored the ability of Chlamydia infection to induce IL-6, CXCL10, and CCL-5 expression; however CXCL-16 induction was not restored by IFN-β pre-incubation in the TLR3-deficient cells. Our findings were corroborated in pathway-focused PCR arrays which demonstrated a plethora of different inflammatory genes that were defectively regulated during Chlamydia infection of the TLR3-deficient OE cells, and that some of these genes were induced only when IFN-β was added prior to infection. Our OE cell data implicate TLR3 as an essential inducer of INF-β and other inflammatory mediators during Chlamydia infection, and highlights the importance of the role of TLR3 during the inflammatory cytokine response.
Pegylated leptin antagonist ameliorates chronic colitis by inducing regulatory T cells (Tregs) partially mediated by TGF-beta induction (162.4)
Authors: Singh Udai , Singh Narendra , Singh Balwan , Price Robert , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
IIBD is a chronic intestinal inflammation caused by hyper activated effector immune cells that affects millions of people around the world. Several lines of evidence support an important role for TGF-beta in the induction of tolerance and control gut inflammation. Leptin is satiety hormone produced primarily by adipose tissue, which increases during IBD progression. We investigated the effect of pegylated leptin antagonist mediated inhibition of chronic colitis in IL-10-/- mice. In the present study, we report that pegylated leptin antagonist (mutant L39A/D40A/F41A) effectively attenuated the overall clinical score, reversed colitis-associated pathogenesis including a decrease in body weight, systemic serum amyloid A (SAA), and leptin levels. The percentage of Tregs in the spleen, mesenteric lymph node (MLN) and intestinal lamina propria (LP) of colitis mice was increased after leptin antagonist treatment as compared to control mice. Similarly, the percentage of TGF-beta in the MLN and LP of colitis mice increased after leptin antagonist treatment. Leptin antagonist also reduced systemic and mucosal cytokines as well as increased the insulin level as compared to control mice. These findings suggest that leptin antagonist ameliorates chronic colitis by inducing TGF-beta, which mediates the induction of Tregs and reduces both mucosal and systemic cytokines. The intricate interaction among leptin, TGF-beta and Tregs might provide new strategies for therapeutic interventions.
IL-10 production by B cells is not required for B cell-mediated suppression of contact allergy (163.24)
Authors: Surianarayanan Sangeetha , Karp Christopher L. , Muller Werner , Roers Axel 
Published: January 2023

Abstract
B cells play important roles in the activation of T cells. On the other hand, regulatory functions have been ascribed to B cells based on findings in animal models. Enhanced autoimmunity and contact allergy was found in B cell deficient mice. These data supported the concept of distinct subsets of regulatory B cells specialized in the suppression of immune responses. IL-10 was proposed as one of the key suppressive mechanisms of such cells. An IL-10 producing subpopulation of B cells characterized by expression of CD5 and CD1d, B10 cells, was reported to suppress the T cell response to contact allergens and to ameliorate experimental autoimmune encephalitis. Unexpectedly, our analysis of conditional B cell-specific IL-10 deficient mice revealed no deregulation of contact allergy. This was not due to inefficient Cre/loxP-mediated inactivation of the IL-10 gene in the CD5+CD1d+ B cell subset or in conventional B cells as shown by cell sorting and single cell PCR. We conclude that IL-10 production is not required for regulation of contact allergy by B cells.
Novel strategies to suppress NF-κB in experimental autoimmune encephalomyelitis (164.17)
Authors: Janardhanam Srihari , Srinivasan Mythili 
Published: January 2023

Abstract
Biological strategies that selectively harness the therapeutic benefits of glucocorticoids (GC) are highly attractive in the management of inflammatory conditions such as multiple sclerosis (MS). Glucocorticoid induced leucine zipper (GILZ), is a GC induced protein that binds the p65 subunit of nuclear factor kappa B(NF-κB, prevents its nuclear translocation and suppress inflammatory cytokines. GILZ over-expressing mice exhibit reduced T-bet expression and IFN-γ secretion, a canonical Th1 transcription factor and prototype Th1 cytokine respectively. We hypothesized that the intracellular delivery of GILZ protein may suppress delayed type hypersensitivity reaction, a Th1 response that mimic inflammation in MS. IFN-γ and IL-12 secretion was significantly reduced and that of IL-10 was elevated in human peripheral blood mononuclear cells stimulated with protein peptide derivative in the presence of GC or exogenous GILZ. We next investigated the therapeutic potential of GILZ supplement in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Groups of SJL/J mice induced EAE and administered GILZ protein exhibited significantly reduced clinical disease than vehicle treated mice. Upon re-stimulation with CNS antigens lymphocytes from GILZ protein administered mice exhibited significantly lower proliferation and inflammatory cytokine secretion (TNF-α and IL-12). These observations suggest a therapeutic potential for exogenous GILZ in MS.
Identification of new cancer/testis antigens in non-small cell lung cancer (165.16)
Authors: Chiriva Maurizio , Mirandola Leonardo , Yu Yuefei , Kim Minji , Alalawi Raed , Asawa Chompunut , Jumper Cynthia , Cobos Everardo 
Published: January 2023

Abstract
Lung cancer is the leading cause of cancer death in both genders worldwide. The incidence is only second to prostate cancer in men and breast cancer in women. The lethality of the disease highlights the urgent need for innovative therapeutic options. Immunotherapy can afford efficient and specific targeting of tumor cells, reducing the need for invasive conventional treatments. We have previously reported the aberrant expression of cancer/testis antigens (CTA) in multiple myeloma and ovarian cancer. Here, we show that the CTA, SP17, AKAP-4 and PTTG-1 are aberrantly expressed in lung cancer cell lines and primary cells from patients by RT-PCR, immunohistochemistry and flow cytometry. Our results provide for the first time that CTA/SP17-AKAP-4-PTTG-1 are expressed and are highly immunogenic in advanced non-small cell lung cancer. Further work is warranted to develop CTA tailored immunotherapeutic strategies for non-small cell lung cancer.
Development of an attenuated interleukin-2 cytokine fusion protein that can be activated by tumor expressed matrix metalloproteinases (165.19)
Authors: Skrombolas Denise , Puskas John , Sedlacek Abigail , Lord Edith , Frelinger John 
Published: January 2023

Abstract
Cytokines have been used to treat tumors, however, side effects often limit their use when delivered systemically. We set out to develop an approach in which cytokines would be preferentially activated at the site of growing tumors. We have constructed a novel fusion protein (FP) consisting of the cytokine interleukin-2 (IL-2) joined to a specific inhibitor moiety, the interleukin-2 receptor alpha chain separated by a protease cleavage sequence recognized by matrix metalloproteinases (MMPs). The rationale is that the cytokine would be relatively inactive in the intact fusion protein but its biological activity would increase after protease cleavage. We analyzed a baculovirus expressed FP biochemically by immunoblot analyses and functionally using the IL-2 dependent CTLL-2 cell line. IL-2 activity is attenuated over 50 fold in the intact FP compared to the same molar amount of IL-2. MMP cleavage releases IL-2 resulting in an increase in the amount of biologically available IL-2. Additionally, the FP showed efficacy in vivo using a peritoneal tumor model employing Colon 38. This general approach may be applicable to other cytokines as well as other proteases.
PI3K-Akting in crosstalk between Notch1-Jagged2 and CD28-B7 pathways in dendritic cells (165.21)
Authors: Koorella Chandana , Nair Jayakumar , Carlson Louise , Murray Megan , Rozanski Cheryl , Lee Kelvin 
Published: January 2023

Abstract
Survival of myeloma cells is characterized by their critical interaction with bone marrow stromal cells, which produce IL-6. At the cellular level, dendritic cells (DC) in the bone marrow microenvironment and at the molecular level the CD28-B7 and Notch1-Jagged2 pathways were separately implicated by us in myeloma induced IL-6 production. While Notch signaling leading to IL-6 production in DC is well understood, the mechanism of “backsignaling” via B7, a ligand with a short cytoplasmic tail, is largely uncharacterized. Inhibiting Notch signaling using pharmacological inhibitors and blocking antibodies leads to a significant decrease in CD28 mediated IL-6 production by DC suggesting crosstalk between the Notch1-Jagged2 and CD28-B7 pathways. To underline the molecular mechanism of crosstalk, we blocked PI3K and PKC activity using Ly294002 and Bis respectively and observed a significant decrease in IL-6 production upon B7 crosslinking. Additionally, CD28 mediated crosslinking of B7 in DC leads to activation of P-Akt(Thr 308) thus implicating the PI3K-Akt pathway downstream of B7 which is a novel finding. We are examining the potential role of PTEN downstream of Notch signaling in crosstalk in both human and murine DC by testing its effect on P-Akt expression. Targeting IL-6 induced by crosstalk between these two pathways prompts not only clinical evaluation to improve MM patient outcome but also extends to advancing knowledge in T-cell biology and normal plasma cell biology.
Identification of FOXO3A as a regulator of dendritic cell tolerogenicity in human and murine prostate cancer (165.22)
Authors: Watkins Stephanie , Zhu Ziqiang , Ambs Stefan , Hurwitz Arthur 
Published: January 2023

Abstract
The limited success of cancer immunotherapies is often attributed to the loss of antigen-specific T cell function in situ. In this study, we demonstrate a novel mechanism of tolerance induction by tumor-associated dendritic cells (TADCs) in human and mouse prostate cancer. TADCs from human prostate cancer patients and TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice expressed elevated levels of FOXO3A which correlated with expression of suppressive genes that negatively regulate T cell function. Similar results were observed in both a B16 melanoma and a RENCA renal cell carcinoma model. Furthermore, TADC isolated from tumors in Foxo3a-/- mice had reduced tolerogenic function. Additionally, silencing Foxo3a with siRNAs abrogated the ability of TADCs to tolerize and induce suppressive activity by T cells. This was associated with diminished expression of tolerogenic mediators, indoleamine-2,3-dioxygenase, arginase, and TGF-beta and up-regulated expression of co-stimulatory molecules and pro-inflammatory cytokines. In TRAMP mice, provision of tumor-specific CD4+ T cell help abrogated TADC tolerogenicity which was associated with reduced FOXO3A expression. These findings demonstrate that FOXO3A plays a critical role in mediating TADC-induced immune suppression. Moreover, our results identify a novel target for preventing CTL tolerance and enhancing immune responses to cancer by modulating the immunosuppressive activity of TADC found in the tumor microenvironment.
Syk survival signals in Epstein-Barr virus + B cell lymphomas (165.27)
Authors: Hatton Olivia , Lambert Stacie , Krams Sheri , Martinez Olivia 
Published: January 2023

Abstract
EBV latent membrane protein 2a (LMP2a) is a B cell receptor mimic that provides a constitutive survival signal to virally-infected cells through Syk; however, the precise downstream mechanisms executing this survival signal have yet to be elucidated. Previously, we have shown that Syk inhibition induces apoptosis and reduces PI3K/Akt and Erk downstream signals in our EBV+ B cell lymphoma lines. Small molecule inhibitors for the Syk, PI3K/Akt and Erk pathway, or a DMSO vehicle control, were used to interrogate the function of each pathway. Survival of EBV+ B cell lymphoma lines was dependent on PI3K/Akt, but not Erk, as assayed by Annexin-V staining. Akt signaling can promote survival by directly phosphorylating molecules that inhibit apoptosis, including FOXO, Bad, and XIAP. XIAP is degraded after Syk and PI3K/Akt, but not Erk, inhibition, as assayed by Western blot. Treatment of EBV+ B cell lymphoma lines with an inhibitor of the XIAP protease Omi/HtrA2 rescued XIAP degradation and apoptosis induced by Syk inhibition. Our data supports a model in which Syk signaling in EBV+ B cell lymphomas activates Akt, which subsequently stabilizes XIAP and prevents its degradation. Small molecule, peptidic, substrate mimetic inhibition strategies for XIAP, Akt, and Syk are currently in clinical development and present potential new treatment strategies for EBV+ B cell lymphomas that target these EBV-driven survival signals.
Increased expression and cleavage of amyloid precursor-like protein 2 in pancreatic cancer and regulation of fragment stability by major histocompatibility complex class I molecules (165.4)
Authors: Peters Haley , Tuli Amit , Wang Xiaojian , Pan Zenggang , Liu Cuiling , Ouellette Michel , MacDonald Richard , Solheim Joyce 
Published: January 2023

Abstract
Particularly in neurological systems, amyloid precursor-like protein 2 (APLP2) has been linked to cellular growth, adhesion and migration. Our laboratory has demonstrated that several human pancreatic cancer cell lines, as well as pancreatic cancer tissue, express a high level of APLP2. Furthermore, we showed that oncogene-induced transformation of pancreatic cells resulted in increased levels of full-length APLP2 and 12-15 kDa APLP2 C-terminal cleavage fragments. Additionally, in pancreatic cancer cell lines we have noted association of APLP2 C-terminal fragments and major histocompatibility complex (MHC) class I molecules, the proteins responsible for the presentation of tumor antigens. The APLP2 C-terminal fragments associated with MHC class I molecules had prolonged stability compared to unassociated fragments. Incubation with calyculin A, which enhances serine/threonine phosphorylation, increased the rate of APLP2 C-terminus turnover. In agreement with our earlier finding, the APLP2 C-termini associated with MHC class I molecules underwent relatively slower degradation in the presence of calyculin A. Thus, MHC class I molecules have a previously unrecognized function of regulating APLP2 homeostasis. Overall, our discoveries have established that APLP2 expression and cleavage are up-regulated in pancreatic cancer, and have led to a new understanding of the involvement of MHC class I molecules in the regulation of APLP2 C-terminal fragments in pancreatic cancer cells.
Role of CD91 in HSP-mediated innate immunity (165.9)
Authors: Pawaria Sudesh , Binder Robert 
Published: January 2023

Abstract
The immunogenic HSPs gp96, hsp70 and calreticulin are known to chaperone antigenic peptides and elicit strong immunity against tumors and pathogens. The peptide bound form of the HSP bind to and are endocytosed by CD91 on antigen presenting cells leading to the cross-presentation of the chaperoned peptides. We show here that CD91 gets phosphorylated in response to HSPs and results in activation of downstream signals. By selective mutation of the two phosphorylation sites of CD91, we observed that HSPs appear to utilize different sites resulting in different downstream signaling pathways. As a result the cytokine profiles released from stimulated APCs are different for each HSP leading to priming of differential T helper responses including Th17 cells. These results are important in understanding how T cell responses are initiated when HSPs are released into the extracellular environment from dying tumor or infected cells or introduced via vaccination.
Novel model of colitis induced by a non-inflammatory small bowel infection (166.10)
Authors: Dann Sara , Le Christine , Nguyen Kim , Dann Raymond , Hanson Elaine , Eckmann Lars 
Published: January 2023

Abstract
Introduction: Chronic colitis is sustained by aberrant T cells responding to normal microbiota, although how these cells develop is poorly understood. Our aim was to evaluate whether Giardia, a parasite that infects the small intestine but does not elicit inflammation, triggers colitis in a susceptible host and to elucidate mechanisms governing decisions leading to disease. Methods: IL-10-/- mice were infected with Giardia and evaluated up to 12 wks after infection. T cells and DC were isolated and characterized by FACS. Mechanistic studies were performed using neutralizing antibodies and double knockout mice. Results: Within 2 wks of Giardia infection, IL-10-/- mice developed colitis, which persisted after parasite eradication. Infection resulted in Th1 and Th17 expansion and increased expression of neutrophil-recruiting chemokines. Surprisingly, a similar response was measured in infected WT mice, which did not develop colitis. Mechanistic studies revealed that absence of T cells or Myd88 in IL-10-/- mice prevented Giardia-induced colitis. Giardia infection induced expansion of the colonic DC population and ablation of DC led to reduced severity of inflammation. Conclusions: These results suggest that Giardia functions as a microbial trigger of colitis in IL-10-/- mice. This is a powerful new model of chronic intestinal inflammation that can provide fresh insight into mechanisms controlling homeostasis and the development of colitogenic T cells.
Role of Axl receptor tyrosine kinase in the generation of intestinal γδ T cells (166.13)
Authors: Park Min , Lee Eun-Hee , Kang Hyung-Sik 
Published: January 2023

Abstract
Axl receptor tyrosine kinase has been known to play a crucial role in cell survival, proliferation, and migration, but little is yet known about its regulatory role in the generation of γδ T cells. Here we investigated the role of Axl in the generation of intraepithelial γδ T cells. The γδ T cell population was increased in intraepithelial lymphocytes (IELs) of Axl-/- mice compared to them of wild type mice. In addition, upregulaton of IL-7α Rexpression was observed in both IELs and γδ T cells purified from IELs of Axl-/- mice. In electrophoretic mobility shift assay, IELs of Axl-/- mice showed the reduced AP-1 activation due to the dephosphorylation of its upstream signaling molecules, c-Jun and JNK. Taken together, these results suggested that Axl is required for the generation of intestinal γδ T cells by the transcriptional regulation of IL-7Rα via the JNK pathway.
A murine model of the immune responses to trauma and transfusion (169.36)
Authors: Jackman Rachael , Muench Marcus , Heitman John , Utter Garth , Busch Michael , Norris Philip 
Published: January 2023

Abstract
Traumatic injury is immunosuppressive, and we have previously observed major fluctuations in plasma cytokines following trauma in humans with notable differences between those that are transfused or not. It has been difficult, however, to distinguish the effects of blood loss, injury, and other patient characteristics from those of allogeneic transfusion on immune function in human subjects. We have developed a murine model to understand the relative contributions of traumatic blood loss and allogeneic transfusion on immunomodulation. BALB/c mice were bled 25-30% of their estimated total blood volume to model traumatic blood loss, and transfusions of saline-diluted C57B6 blood or saline alone were administered IV into these mice as well as into mice without injury. Serum cytokines and chemokines were evaluated 4 hours after treatment. Several proteins, including IL-6, IL-10, MMP-9, and KC were elevated after traumatic blood loss (p&lt;0.05), with some of these increases reduced or prevented by transfusion. Some proteins were elevated in response to transfusion alone (such as sE-Selectin, p&lt;0.05), and still others responded to both blood loss and/or transfusion (such as IL-5 and MCP-1, p&lt;0.05). Saline administration alone produced intermediate changes compared with allogeneic blood transfusion. These results are consistent with our clinical observations in humans and demonstrate clear roles for both blood loss and transfusion in modulating the early immune response to trauma.