Inflammation impacts androgen receptor signaling in basal prostate stem cells through interleukin 1 receptor antagonist.

Chronic prostate inflammation in patients with benign prostate hyperplasia (BPH) correlates with the severity of symptoms. How inflammation contributes to prostate enlargement and/or BPH symptoms and the underlying mechanisms remain unclear. In this study, we utilize a unique transgenic mouse model that mimics chronic non-bacterial prostatitis in men and investigate the impact of inflammation on androgen receptor (AR) in basal prostate stem cells (bPSC) and their differentiation in vivo.

Inflammation Impacts Androgen Receptor Signaling in Basal Prostate Stem Cells Through Interleukin 1 Receptor Antagonist.

The majority of patients with benign prostate hyperplasia (BPH) exhibit chronic prostate inflammation and the extent of inflammation correlates with the severity of symptoms. How inflammation contributes to prostate enlargement and/or BPH symptoms and the underlying mechanisms are not clearly understood. We established a unique mouse model Prostate Ovalbumin Expressing Transgenic 3 (POET3) that mimics chronic non-bacterial prostatitis in men to study the role of inflammation in prostate hyperplasia.

Folate Receptor Beta Designates Immunosuppressive Tumor-Associated Myeloid Cells That Can Be Reprogrammed with Folate-Targeted Drugs.

Although immunotherapies of tumors have demonstrated promise for altering the progression of malignancies, immunotherapies have been limited by an immunosuppressive tumor microenvironment (TME) that prevents infiltrating immune cells from performing their anticancer functions. Prominent among immunosuppressive cells are myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) that inhibit T cells via release of immunosuppressive cytokines and engagement of checkpoint receptors. Here, we explore the properties of MDSCs and TAMs from freshly isolated mouse and human tumors and find that an immunosuppressive subset of these cells can be distinguished from the nonimmunosuppressive population by its upregulation of folate receptor beta (FRβ) within the TME and its restriction to the TME.

Cholesterol Sulfotransferase SULT2B1b Modulates Sensitivity to Death Receptor Ligand TNFα in Castration-Resistant Prostate Cancer.

Cholesterol sulfotransferase, SULT2B1b, has been demonstrated to modulate both androgen receptor activity and cell growth properties. However, the mechanism(s) by which SULT2B1b alters these properties within prostate cancer cells has not been described. Furthermore, specific advantages of SULT2B1b expression in prostate cancer cells are not understood.

Targeting the Hsp90 C-terminal domain to induce allosteric inhibition and selective client downregulation.

Background: Inhibition of Hsp90 is desirable due to potential downregulation of oncogenic clients. Early generation inhibitors bind to the N-terminal domain (NTD) but C-terminal domain (CTD) inhibitors are a promising class because they do not induce a heat shock response. Here we present a new structural class of CTD binding molecules with a unique allosteric inhibition mechanism.

Cholesterol Sulfonation Enzyme, SULT2B1b, Modulates AR and Cell Growth Properties in Prostate Cancer.

Unlabelled: Cholesterol accumulates in prostate lesions and has been linked to prostate cancer incidence and progression. However, how accumulated cholesterol contributes to prostate cancer development and progression is not completely understood. Cholesterol sulfate (CS), the primary sulfonation product of cholesterol sulfotransferase (SULT2B1b), accumulates in human prostate adenocarcinoma and precancerous prostatic intraepithelial neoplasia (PIN) lesions compared with normal regions of the same tissue sample.

Expression of Cationic Amino Acid Transporter 2 Is Required for Myeloid-Derived Suppressor Cell-Mediated Control of T Cell Immunity.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature cells that expand during benign and cancer-associated inflammation and are characterized by their ability to inhibit T cell immunity. Increased metabolism of l-Arginine (l-Arg), through the enzymes arginase 1 and NO synthase 2 (NOS2), is well documented as a major MDSC suppressive mechanism. Therefore, we hypothesized that restricting MDSC uptake of l-Arg is a critical control point to modulate their suppressor activity.

Impact of prostate inflammation on lesion development in the POET3(+)Pten(+/-) mouse model of prostate carcinogenesis.

Evidence linking prostatitis and prostate cancer development is contradictory. To study this link, the POET3 mouse, an inducible model of prostatitis, was crossed with a Pten-loss model of prostate cancer (Pten(+/-)) containing the ROSA26 luciferase allele to monitor prostate size. Prostatitis was induced, and prostate bioluminescence was tracked over 12 months, with lesion development, inflammation, and cytokine expression analyzed at 4, 8, and 12 months and compared with mice without induction of prostatitis.

Use of graphene as protection film in biological environments.

Corrosion of metal in biomedical devices could cause serious health problems to patients. Currently ceramics coating materials used in metal implants can reduce corrosion to some extent with limitations. Here we proposed graphene as a biocompatible protective film for metal potentially for biomedical application.

Early growth response-1 (EGR-1) and nuclear factor of activated T cells (NFAT) cooperate to mediate CD40L expression in megakaryocytes and platelets.

Increasing evidence implicates circulating platelets as mediators of chronic inflammatory and autoimmune diseases via the expression and release of CD40L, an important modulator of inflammation and adaptive immune responses traditionally associated with activated T cells. Emerging evidence suggests that platelet CD40L is dynamically regulated in several chronic inflammatory and autoimmune diseases and may mediate progression and secondary pathology associated with those disease states. The present study identifies NFATc2 as a key transcriptional modulator of CD40L expression in megakaryocytes and inflammatory activity of platelets.

An inducible model of abacterial prostatitis induces antigen specific inflammatory and proliferative changes in the murine prostate.

Background: Prostatitis is a poorly understood disease and increasing evidence suggests inflammation is involved in other prostatic diseases including prostate cancer.

Methods: The ability of pre-activated CD8 T cells to induce prostatitis was examined by adoptive transfer of prostate antigen specific CD8 T cells into POET-3 mice or POET-3/Luc/Pten(-/+) mice. Characterization of the inflammatory response was determined by examining leukocyte infiltration by histological analysis, flow cytometry and by evaluating cytokine and chemokine levels in prostate tissue.

In vivo suppressive function of myeloid-derived suppressor cells is limited to the inflammatory site.

Current paradigms suggest that, despite the heterogeneity of myeloid-derived suppressor cells (MDSC), all Gr-1(+) CD11b(+) cells can exert suppressive function when exposed to inflammatory stimuli. In vitro evaluation shows that MDSC from multiple tissue sites have suppressive activity, and in vivo inhibition of MDSC enhances T-cell function; however, the relative capacity of MDSC present at localized inflammatory sites or in peripheral tissues to suppress T-cell responses in vivo has not been directly evaluated. In the current study, we observed that during a tissue-specific inflammatory response, MDSC inhibition of CD8(+) T-cell proliferation and IFN-γ production was restricted to the inflammatory site.

Platelet CD40L at the interface of adaptive immunity.

Initiated by the finding that platelets express functional CD40 ligand (CD40L, CD154), many new roles for platelets have been discovered in unanticipated areas, including the immune response. When current literature is considered as a whole, the picture that is emerging begins to show that platelets are able to significantly affect, for better or worse, the overall health and condition of the mammalian host. Animal models have made significant contributions to our expanding knowledge of platelet function, much of which is anticipated to be clinically relevant.

Platelet influence on T- and B-cell responses.

Understanding the adaptive immune response is an area of research critically important in medicine. Several positive regulators of B- and T-cell activation exist to eliminate pathogens, in which CD40 ligand (CD154) plays a fundamental role. It is well documented that CD154 expressed by CD4 T helper cells can be critical in the proper activation of dendritic cells for the productive stimulation of CD8 T cells and is required for proper T-dependent B-cell immunity.

Platelet-derived CD154 enables T-cell priming and protection against Listeria monocytogenes challenge.

Collagen exposure in tissue activates platelets, initiates wound healing, and modulates adaptive immunity. In this report, data are presented to demonstrate a requirement for platelet-derived CD154 for both collagen-induced augmentation of T-cell immunity and induction of pro-tective immunity to Listeria challenge. Specifically, we demonstrate that Ad5 encoding the membrane-bound form of ovalbumin (Ad5-mOVA) delivered in collagen induces higher ovalbumin-specific cytotoxic T lymphocyte (CTL) activity in a dose-dependent manner compared with Ad5-mOVA delivered in PBS.

Platelet-mediated modulation of adaptive immunity: unique delivery of CD154 signal by platelet-derived membrane vesicles.

Although mounting evidence indicates that platelets participate in the modulation of both innate and adaptive immunity, the mechanisms by which platelets exert these effects have not been clearly defined. The study reported herein uses a previously documented adoptive transfer model to investigate the ability of platelet-derived membrane vesicles to communicate activation signals to the B-cell compartment. The findings demonstrate for the first time that platelet-derived membrane vesicles are sufficient to deliver CD154 to stimulate antigen-specific IgG production and modulate germinal center formation through cooperation with responses elicited by CD4(+) T cells.

Nuclear factor of activated T cells (NFAT) mediates CD154 expression in megakaryocytes.

Platelets are an abundant source of CD40 ligand (CD154), an immunomodulatory and proinflammatory molecule implicated in the onset and progression of several inflammatory diseases, including systemic lupus erythematosus (SLE), diabetes, and cardiovascular disease. Heretofore considered largely restricted to activated T cells, we initiated studies to investigate the source and regulation of platelet-associated CD154. We found that CD154 is abundantly expressed in platelet precursor cells, megakaryocytes.

Expression of TNF-related apoptosis-inducing ligand (TRAIL) in megakaryocytes and platelets.

Objective: Platelets are known to play an important role in hemostasis, thrombosis, wound healing, and inflammation. Platelet-induced modulation of inflammation and adaptive immune responses are mediated in part through tumor necrosis factor (TNF) family member ligands, including CD154, Fas ligand, and TNFalpha, that are expressed upon platelet activation. The present study investigated whether platelets and megakaryocytes also express TNF-related apoptosis-inducing ligand (TRAIL), another pro-apoptotic member of the TNF superfamily.

Structure/function analysis of the murine CD95L promoter reveals the identification of a novel transcriptional repressor and functional CD28 response element.

CD28 costimulation, an important second signal for antigen-mediated T cell activation, is known to enhance expression of several genes important for the regulation of CD4+ T cell effector function including interleukin-2 and CD154. Previous studies demonstrate CD28-mediated enhancement of the transcription and expression of Fas ligand (CD95L) in T cell lines, suggesting a regulatory link between CD28 and CD95L expression. These results served as the basis for structure/function analysis of the CD95L promoter to elucidate the mechanism for CD28-mediated enhancement of CD95L.

Interleukin-6 production by human bladder tumor cell lines is up-regulated by bacillus Calmette-Guérin through nuclear factor-kappaB and Ap-1 via an immediate early pathway.

Purpose: The expression of interleukin-6 (IL-6) by normal and malignant urothelium in response to bacillus Calmette-Guerin (BCG) may have direct and indirect effects on the antitumor activity of BCG. We evaluated the molecular signaling pathway through which BCG induces IL-6 expression in human transitional cell carcinoma lines.

Materials And Methods: We evaluated IL-6 messenger RNA and protein expression by human transitional carcinoma cell lines in response to BCG.