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Effects of moderate aerobic exercise training on inflammatory status of the colon during acute ulcerative colitis
PNIRS meeting abstracts / Brain, Behavior, and Immunity 25 (2011) S179–S242
Women exhibit immunological memory resulting from immunizations and natural antigen exposure prior to pregnancy. To determine if immune memory influences development of offspring in a murine model of maternal immune stimulation, C57BL/6 (B6) female mice were immunized with allogeneic female Balb/c spleen cells. Immune and immunologically naı¨ve wild-type (WT) B6 and IL-6 KO females were mated with WT B6 males and injected i.p. with PBS or poly(I:C) on gestational day 12. Higher levels of IL-6 were seen in maternal sera and amniotic fluids of immune vs naı¨ve poly(I:C)-injected WT dams. However, in matings between IL-6 KO (IL-6 / ) females and WT (IL-6+/+) B6 males, significantly higher levels of IL-6 were found in amniotic fluids. Analysis of supernatants from cultured placental cell preparations revealed significant IL-6 production from the heterozygous (IL-6+/ ) fetal component. Splenocytes from immune (vs. naı¨ve) WT B6 pregnant females also showed higher proliferative responses to the CD4+ T cell restricted epitope of a male H-Y-encoded antigen. Moreover, FACS analysis of activated spleen cells from offspring of immune (vs. naı¨ve) poly(I:C)-injected WT dams showed >fivefold increase in Th17 cells. These results indicate that immune stimulation during pregnancy in females with immunological memory leads to development of a Th17 cell repertoire in offspring, which could mediate immunopathology similar to that reported in mouse models of human autoimmune diseases (e.g., EAE, RA, IBD). doi:10.1016/j.bbi.2011.07.080
78. Impaired glucocorticoid receptor dimerization exacerbates LPS-induced sickness behavior and inflammation in mice M.N. Silverman a, B.D. Revenis a, J.H. Doran a, B.E. Ballard a, E. Belyavskaya a, P. Mukhopadhyay b, J. Tam c, L.H. Tonelli d, P. Pacher b, E.M. Sternberg a a
Section on Neuroendocrine Immunology & Behavior, National Institute of Mental Health, National Institutes of Health, Rockville, MD 20852, USA b Section on Oxidative Stress and Tissue Injury, NIAAA, NIH, USA c Section on Neuroendocrinology, NIAAA, NIH, USA d Mood & Anxiety Program, Dept. of Psychiatry, University of Maryland, USA Glucocorticoid resistance and enhanced inflammation have been associated with a variety of behavioral disorders, although their relation has not been fully elucidated. As a model of impaired glucocorticoid receptor (GR) function, we are using the GRdim mouse, in which absent GR dimerization contributes to impaired GR-DNA binding-dependent mechanisms but intact protein-protein interactions. Mice were injected with lipopolysaccharide (LPS; i.p.; 0.25 mg/kg) and subsequent behavioral, neuroendocrine and inflammatory profiles were investigated over a 72 h period. LPS-GRdim mice exhibited greater and sustained sickness behavior (lethargy, piloerection, ptosis), locomotor activity impairment, hypothermia and body weight loss relative to LPS-WT mice. LPS-induced plasma corticosterone levels initially rose to a similar amplitude in both genotypes, but were slower to return to baseline in the GRdim mice. LPS-induced plasma TNF-alpha responses showed the same kinetic profile in both genotypes, whereas, plasma IL-6 responses in the LPS-GRdim mice were elevated at early time points and showed delayed recovery relative to LPS-WT. In contrast, LPS-GRdim mice exhibited elevated hippocampal and hypothalamic expression of TNF-alpha, IL-1beta and IL-6 mRNA at early time points relative to LPS-WT mice. These results suggest that intact GR-DNA bindingdependent mechanisms are essential for the proper regulation and recovery of inflammatory, HPA axis and behavioral responses to an
S201
immune challenge and can inform the development of novel therapeutic agents to improve GR function for inflammatory-related behavioral disorders. doi:10.1016/j.bbi.2011.07.081
79. Effects of moderate aerobic exercise training on inflammatory status of the colon during acute ulcerative colitis M. Cook, S. Martin, J.A. Woods University of Illinois Urbana Champaign, Department of Kinesiology, Freer Hall, 906 S. Goodwin Ave, Champaign, IL 61801, USA Inflammatory bowel diseases, such as ulcerative colitis, significantly reduce physical functioning and decrease the quality of life in afflicted patients. Preliminary studies show that moderate exercise training reduces symptoms and disease activity, improving the patients quality of life. Local inflammation in the periphery results in inflammation within the brain to alter behavior. The purpose of this study was to understand whether exercise reduced inflammation and sickness behavior associated with colitis using a mouse model. UC was induced by dextran sodium sulfate treatment in treadmill exercised (8–12 m/min for 6 weeks–5/week) or sedentary C57Bl/6 male mice (n = 13/group). DSS was given at 2% in drinking water over five days. Sickness behaviors were assessed by changes in food and fluid intake, body weight (BW), and locomotor activity (LMA). Mice were euthanized and colons were harvested at disease peak (Day 8) for analysis of pro- and anti-inflammatory gene expression. Surprisingly, we found that 6 weeks of prior exercise training caused intensified local inflammation of the colon as measured by significant (p < 0.05) increases in IL-6, IL-1b and TNFa gene expression. While DSS-treated mice exhibited reductions in food and fluid intake, BW, LMA when compared to the water-only group, prior exercise training did not exacerbate these symptoms associated with colitis. We are in the process of examining brain cytokines and the histology of the colons to address this paradox. doi:10.1016/j.bbi.2011.07.082
80. The relationship between inhibited temperament and leukocyte sensitivity to glucocorticoids in Rhesus macaques K. Chun, L.A. Miller, J.P. Capitanio California National Primate Research Center, Department of Psychology, University of California, Davis, One Shields Ave, Davis, CA 95616, USA Behavioral inhibition reflects a disposition to react warily to novel situations, can involve altered regulation of the hypothalamic–pituitary–adrenal axis, and has been associated with atopic diseases such as asthma. We tested hypotheses about whether behaviorally inhibited rhesus monkeys show altered glucocorticoid regulation of cytokine gene expression that could help illuminate the pathways mediating these relationships. Whole blood was cultured ex vivo for 24-hours with either anti-CD3/anti-CD28 antibodies (3/28), which stimulate T-cells, or Staphyloccal Enterotoxin B (SEB), which stimulates antigen presenting cells (APCs) and T-cells. Cultures also contained varying molar concentrations of dexamethasone. Real-time PCR was used to quantify gene expression of cytokines IL-4, IL-10, IL-12, and IFN-c. In the 3/28 cultures, ANOVA [a = 0.05, df = 5/52] indicated that dexamethasone-suppressed IL-4 and IFN-c expression, but not IL-10 or IL-12 expression, and no temperament effects were found. In the SEB cultures, however,
Women exhibit immunological memory resulting from immunizations and natural antigen exposure prior to pregnancy. To determine if immune memory influences development of offspring in a murine model of maternal immune stimulation, C57BL/6 (B6) female mice were immunized with allogeneic female Balb/c spleen cells. Immune and immunologically naı¨ve wild-type (WT) B6 and IL-6 KO females were mated with WT B6 males and injected i.p. with PBS or poly(I:C) on gestational day 12. Higher levels of IL-6 were seen in maternal sera and amniotic fluids of immune vs naı¨ve poly(I:C)-injected WT dams. However, in matings between IL-6 KO (IL-6 / ) females and WT (IL-6+/+) B6 males, significantly higher levels of IL-6 were found in amniotic fluids. Analysis of supernatants from cultured placental cell preparations revealed significant IL-6 production from the heterozygous (IL-6+/ ) fetal component. Splenocytes from immune (vs. naı¨ve) WT B6 pregnant females also showed higher proliferative responses to the CD4+ T cell restricted epitope of a male H-Y-encoded antigen. Moreover, FACS analysis of activated spleen cells from offspring of immune (vs. naı¨ve) poly(I:C)-injected WT dams showed >fivefold increase in Th17 cells. These results indicate that immune stimulation during pregnancy in females with immunological memory leads to development of a Th17 cell repertoire in offspring, which could mediate immunopathology similar to that reported in mouse models of human autoimmune diseases (e.g., EAE, RA, IBD). doi:10.1016/j.bbi.2011.07.080
78. Impaired glucocorticoid receptor dimerization exacerbates LPS-induced sickness behavior and inflammation in mice M.N. Silverman a, B.D. Revenis a, J.H. Doran a, B.E. Ballard a, E. Belyavskaya a, P. Mukhopadhyay b, J. Tam c, L.H. Tonelli d, P. Pacher b, E.M. Sternberg a a
Section on Neuroendocrine Immunology & Behavior, National Institute of Mental Health, National Institutes of Health, Rockville, MD 20852, USA b Section on Oxidative Stress and Tissue Injury, NIAAA, NIH, USA c Section on Neuroendocrinology, NIAAA, NIH, USA d Mood & Anxiety Program, Dept. of Psychiatry, University of Maryland, USA Glucocorticoid resistance and enhanced inflammation have been associated with a variety of behavioral disorders, although their relation has not been fully elucidated. As a model of impaired glucocorticoid receptor (GR) function, we are using the GRdim mouse, in which absent GR dimerization contributes to impaired GR-DNA binding-dependent mechanisms but intact protein-protein interactions. Mice were injected with lipopolysaccharide (LPS; i.p.; 0.25 mg/kg) and subsequent behavioral, neuroendocrine and inflammatory profiles were investigated over a 72 h period. LPS-GRdim mice exhibited greater and sustained sickness behavior (lethargy, piloerection, ptosis), locomotor activity impairment, hypothermia and body weight loss relative to LPS-WT mice. LPS-induced plasma corticosterone levels initially rose to a similar amplitude in both genotypes, but were slower to return to baseline in the GRdim mice. LPS-induced plasma TNF-alpha responses showed the same kinetic profile in both genotypes, whereas, plasma IL-6 responses in the LPS-GRdim mice were elevated at early time points and showed delayed recovery relative to LPS-WT. In contrast, LPS-GRdim mice exhibited elevated hippocampal and hypothalamic expression of TNF-alpha, IL-1beta and IL-6 mRNA at early time points relative to LPS-WT mice. These results suggest that intact GR-DNA bindingdependent mechanisms are essential for the proper regulation and recovery of inflammatory, HPA axis and behavioral responses to an
S201
immune challenge and can inform the development of novel therapeutic agents to improve GR function for inflammatory-related behavioral disorders. doi:10.1016/j.bbi.2011.07.081
79. Effects of moderate aerobic exercise training on inflammatory status of the colon during acute ulcerative colitis M. Cook, S. Martin, J.A. Woods University of Illinois Urbana Champaign, Department of Kinesiology, Freer Hall, 906 S. Goodwin Ave, Champaign, IL 61801, USA Inflammatory bowel diseases, such as ulcerative colitis, significantly reduce physical functioning and decrease the quality of life in afflicted patients. Preliminary studies show that moderate exercise training reduces symptoms and disease activity, improving the patients quality of life. Local inflammation in the periphery results in inflammation within the brain to alter behavior. The purpose of this study was to understand whether exercise reduced inflammation and sickness behavior associated with colitis using a mouse model. UC was induced by dextran sodium sulfate treatment in treadmill exercised (8–12 m/min for 6 weeks–5/week) or sedentary C57Bl/6 male mice (n = 13/group). DSS was given at 2% in drinking water over five days. Sickness behaviors were assessed by changes in food and fluid intake, body weight (BW), and locomotor activity (LMA). Mice were euthanized and colons were harvested at disease peak (Day 8) for analysis of pro- and anti-inflammatory gene expression. Surprisingly, we found that 6 weeks of prior exercise training caused intensified local inflammation of the colon as measured by significant (p < 0.05) increases in IL-6, IL-1b and TNFa gene expression. While DSS-treated mice exhibited reductions in food and fluid intake, BW, LMA when compared to the water-only group, prior exercise training did not exacerbate these symptoms associated with colitis. We are in the process of examining brain cytokines and the histology of the colons to address this paradox. doi:10.1016/j.bbi.2011.07.082
80. The relationship between inhibited temperament and leukocyte sensitivity to glucocorticoids in Rhesus macaques K. Chun, L.A. Miller, J.P. Capitanio California National Primate Research Center, Department of Psychology, University of California, Davis, One Shields Ave, Davis, CA 95616, USA Behavioral inhibition reflects a disposition to react warily to novel situations, can involve altered regulation of the hypothalamic–pituitary–adrenal axis, and has been associated with atopic diseases such as asthma. We tested hypotheses about whether behaviorally inhibited rhesus monkeys show altered glucocorticoid regulation of cytokine gene expression that could help illuminate the pathways mediating these relationships. Whole blood was cultured ex vivo for 24-hours with either anti-CD3/anti-CD28 antibodies (3/28), which stimulate T-cells, or Staphyloccal Enterotoxin B (SEB), which stimulates antigen presenting cells (APCs) and T-cells. Cultures also contained varying molar concentrations of dexamethasone. Real-time PCR was used to quantify gene expression of cytokines IL-4, IL-10, IL-12, and IFN-c. In the 3/28 cultures, ANOVA [a = 0.05, df = 5/52] indicated that dexamethasone-suppressed IL-4 and IFN-c expression, but not IL-10 or IL-12 expression, and no temperament effects were found. In the SEB cultures, however,