Browsing by Subject "Tumor Necrosis Factor-alpha"

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    The altered mononuclear cell-derived cytokine response to glucose ingestion is not regulated by excess adiposity in polycystic ovary syndrome
    (The Endocrine Society, 2014-11) González, Frank; Sia, Chang Ling; Shepard, Marguerite K.; Rote, Neal S.; Minium, Judi; Department of Obstetrics & Gynecology, IU School of Medicine
    CONTEXT: Excess adipose tissue is a source of inflammation. Polycystic ovary syndrome (PCOS) is a proinflammatory state and is often associated with excess abdominal adiposity (AA) alone and/or frank obesity. OBJECTIVE: To determine the effect of glucose ingestion on cytokine release from mononuclear cells (MNC) in women with PCOS with and without excess AA and/or obesity. DESIGN: A cross-sectional study. SETTING: Academic medical center. PATIENTS: Twenty-three women with PCOS (seven normal weight with normal AA, eight normal weight with excess AA, eight obese) and 24 ovulatory controls (eight normal weight with normal AA, eight normal weight with excess AA, eight obese). INTERVENTION: Three-hour 75-g oral glucose tolerance test (OGTT). MAIN OUTCOME MEASURES: Body composition was measured by dual energy x-ray absorptiometry. Insulin sensitivity was derived from the OGTT (ISOGTT). TNFα, IL-6, and IL-1β release was measured in supernatants of cultured MNC isolated from blood samples drawn while fasting and 2 hours after glucose ingestion. RESULTS: Insulin sensitivity was lower in obese subjects regardless of PCOS status and in normal-weight women with PCOS compared with normal-weight controls regardless of body composition status. In response to glucose ingestion, MNC-derived TNFα, IL-6, and IL-1β release decreased in both normal-weight control groups but failed to suppress in either normal-weight PCOS group and in obese women regardless of PCOS status. For the combined groups, the cytokine responses were negatively correlated with insulin sensitivity and positively correlated with abdominal fat and androgens. CONCLUSIONS: Women with PCOS fail to suppress MNC-derived cytokine release in response to glucose ingestion, and this response is independent of excess adiposity. Nevertheless, a similar response is also a feature of obesity per se. Circulating MNC and excess adipose tissue are separate and distinct sources of inflammation in this population.
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    Cellular metabolism constrains innate immune responses in early human ontogeny
    (Nature Research, 2018-11-16) Kan, Bernard; Michalski, Christina; Fu, Helen; Au, Hilda H.T.; Lee, Kelsey; Marchant, Elizabeth A.; Cheng, Maye F.; Anderson-Baucum, Emily; Aharoni-Simon, Michal; Tilley, Peter; Mirmira, Raghavendra G.; Ross, Colin J.; Luciani, Dan S.; Jan, Eric; Lavoie, Pascal M.; Medicine, School of Medicine
    Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny.
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    Evidence of mononuclear cell preactivation in the fasting state in polycystic ovary syndrome
    (Elsevier, 2014-12) González, Frank; Kirwan, John P.; Rote, Neal S.; Minium, Judi; Department of Obstetrics and Gynecology, IU School of Medicine
    OBJECTIVE: We evaluated mononuclear cell (MNC) preactivation in women with polycystic ovary syndrome (PCOS) by examining the effect of in vitro lipopolysaccharide (LPS) exposure on cytokine release in the fasting state. STUDY DESIGN: Twenty women with PCOS (10 lean, 10 obese) and 20 weight-matched controls (10 lean, 10 obese) volunteered for study participation. Tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) release was measured from mononuclear cells isolated from fasting blood samples and cultured in the presence and absence of LPS. Plasma IL-6 was measured from the same fasting blood samples. Insulin sensitivity was derived from an oral glucose tolerance test using the Matsuda index, and truncal fat was measured by dual-energy x-ray absorptiometry. RESULTS: The percent change from baseline in TNF-α and IL-6 release from MNC following LPS exposure was increased (P < .04) in lean and obese women with PCOS and obese controls compared with lean controls. Plasma IL-6 was increased (P < .02) in obese women with PCOS compared with lean women with PCOS, which in turn was increased (P < .02) compared with lean controls. The MNC-derived TNF-α and IL-6 responses from MNCs were negatively correlated with insulin sensitivity (P < .03) and positively correlated with testosterone (P < .03) and androstenedione (P < .006) for the combined groups. Plasma IL-6 was positively correlated with percentage truncal fat (P < .008). CONCLUSION: In PCOS, increased cytokine release from MNCs following LPS exposure in the fasting state reveals the presence of MNC preactivation. Importantly, this phenomenon is independent of obesity and may contribute to the development of insulin resistance and hyperandrogenism in PCOS. In contrast, the source of plasma IL-6 elevations in PCOS may be excess adiposity.
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    Hyperandrogenism induces a proinflammatory TNFα response to glucose ingestion in a receptor-dependent fashion
    (The Endocrine Society, 2014-05) González, Frank; Sia, Chang Ling; Bearson, Dawn M.; Blair, Hilary E.; Department of Obstetrics and Gynecology, IU School of Medicine
    CONTEXT: Hyperandrogenism and inflammation are related in polycystic ovary syndrome (PCOS). Hyperandrogenemia can induce inflammation in reproductive-age women, but the mechanism for this phenomenon is unclear. OBJECTIVE: We examined the in vivo and in vitro effects of hyperandrogenism on mononuclear cell (MNC)-derived androgen receptor (AR) status and TNFα release. DESIGN: This study combined a randomized, controlled, double-blind protocol with laboratory-based cell culture experiments. SETTING: This work was performed in an academic medical center. PARTICIPANTS: Lean, healthy, reproductive-age women were treated with 130 mg of dehydroepiandrosterone (DHEA) or placebo (n = 8 subjects each) for 5 days and also provided untreated fasting blood samples (n = 12 subjects) for cell culture experiments. MAIN OUTCOME MEASURES: AR mRNA content and TNFα release were measured before and after DHEA administration in the fasting state and 2 hours after glucose ingestion. TNFα release in the fasting state was also measured in cultured MNCs exposed to androgens with or without flutamide preincubation. RESULTS: At baseline, subjects receiving DHEA or placebo exhibited no significant difference in androgens and TNFα release from MNCs before and after glucose ingestion. Compared with placebo, DHEA administration raised levels of T, androstenedione, and DHEA sulfate, and increased MNC-derived AR mRNA content and TNFα release in the fasting state and in response to glucose ingestion. Compared with MNC exposure to baseline concentrations of DHEA (175 ng/dL) or T (50 ng/dL), the absolute change in TNFα release increased after exposure to T concentrations of 125 and 250 ng/dL and a DHEA concentration of 1750 ng/dL. Preincubation with flutamide reduced the TNFα response by ≥ 60% across all T concentrations. CONCLUSION: Androgen excess in vivo and in vitro comparable to what is present in PCOS increases TNFα release from MNCs of lean healthy reproductive-age women in a receptor-dependent fashion. Hyperandrogenemia activates and sensitizes MNCs to glucose in this population.
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    Neutralizing negative epigenetic regulation by HDAC5 enhances human haematopoietic stem cell homing and engraftment
    (Nature Publishing Group, 2018-07-16) Huang, Xinxin; Guo, Bin; Liu, Sheng; Wan, Jun; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
    Enhancement of hematopoietic stem cell (HSC) homing and engraftment is clinically critical, especially for cord blood (CB) hematopoietic cell transplantation. Here we report that specific HDAC5 inhibition highly upregulates CXCR4 surface expression in human CB HSCs and progenitor cells (HPCs). This results in enhanced SDF-1/CXCR4-mediated chemotaxis and increased homing to the bone marrow environment, with elevated SCID-repopulating cell (SRC) frequency and enhanced long-term and secondary engraftment in NSG mice. HDAC5 inhibition increases acetylated p65 levels in the nucleus, which is important for CXCR4 transcription. Inhibition of nuclear factor-κB (NF-κB) signaling suppresses HDAC5-mediated CXCR4 upregulation, enhanced HSC homing, and engraftment. Furthermore, activation of the NF-κB signaling pathway via TNFα also results in significantly increased CXCR4 surface expression, enhanced HSC homing, and engraftment. These results demonstrate a previously unknown negative epigenetic regulation of HSC homing and engraftment by HDAC5, and allow for a new and simple translational strategy to enhance HSC transplantation.
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    The role of SHIP in the development and activation of mouse mucosal and connective tissue mast cells
    (The American Association of Immunologists, 2012-04-15) Ruschmann, Jens; Antignano, Frann; Lam, Vivian; Snyder, Kim; Kim, Connie; Essak, Martha; Zhang, Angela; Lin, Ann Hsu-An; Mali, Raghuveer Singh; Kapur, Reuben; Krystal, Gerald; Department of Pediatrics, IU School of Medicine
    Although SHIP is a well-established suppressor of IgE plus Ag-induced degranulation and cytokine production in bone marrow-derived mast cells (BMMCs), little is known about its role in connective tissue (CTMCs) or mucosal (MMCs) mast cells. In this study, we compared SHIP's role in the development as well as the IgE plus Ag and TLR-induced activation of CTMCs, MMCs, and BMMCs and found that SHIP delays the maturation of all three mast cell subsets and, surprisingly, that it is a positive regulator of IgE-induced BMMC survival. We also found that SHIP represses IgE plus Ag-induced degranulation of all three mast cell subsets and that TLR agonists do not trigger their degranulation, whether SHIP is present or not, nor do they enhance IgE plus Ag-induced degranulation. In terms of cytokine production, we found that in MMCs and BMMCs, which are poor producers of TLR-induced cytokines, SHIP is a potent negative regulator of IgE plus Ag-induced IL-6 and TNF-α production. Surprisingly, however, in splenic or peritoneal derived CTMCs, which are poor producers of IgE plus Ag-induced cytokines, SHIP is a potent positive regulator of TLR-induced cytokine production. Lastly, cell signaling and cytokine production studies with and without LY294002, wortmannin, and PI3Kα inhibitor-2, as well as with PI3K p85α(-/-) BMMCs and CTMCs, are consistent with SHIP positively regulating TLR-induced cytokine production via an adaptor-mediated pathway while negatively regulating IgE plus Ag-induced cytokine production by repressing the PI3K pathway.
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