Spaceflight Influences both Mucosal and Peripheral Cytokine Production in PTN-Tg and Wild Type Mice

Spaceflight is associated with several health issues including diminished immune efficiency. Effects of long-term spaceflight on selected immune parameters of wild type (Wt) and transgenic mice over-expressing pleiotrophin under the human bone-specific osteocalcin promoter (PTN-Tg) were examined using the novel Mouse Drawer System (MDS) aboard the International Space Station (ISS) over a 91 day period. Effects of this long duration flight on PTN-Tg and Wt mice were determined in comparison to ground controls and vivarium-housed PTN-Tg and Wt mice. Levels of interleukin-2 (IL-2) and transforming growth factor-beta1 (TGF-β1) were measured in mucosal and systemic tissues of Wt and PTN-Tg mice. Colonic contents were also analyzed to assess potential effects on the gut microbiota, although no firm conclusions could be made due to constraints imposed by the MDS payload and the time of sampling. Spaceflight-associated differences were observed in colonic tissue and systemic lymph node levels of IL-2 and TGF-β1 relative to ground controls. Total colonic TGF-β1 levels were lower in Wt and PTN-Tg flight mice in comparison to ground controls. The Wt flight mouse had lower levels of IL-2 and TGF-β1 compared to the Wt ground control in both the inguinal and brachial lymph nodes, however this pattern was not consistently observed in PTN-Tg mice. Vivarium-housed Wt controls had higher levels of active TGF-β1 and IL-2 in inguinal lymph nodes relative to PTN-Tg mice. The results of this study suggest compartmentalized effects of spaceflight and on immune parameters in mice.

[1]  Manolo Gouy,et al.  SEAVIEW and PHYLO_WIN: two graphic tools for sequence alignment and molecular phylogeny , 1996, Comput. Appl. Biosci..

[2]  S. Fagarasan Intestinal IgA synthesis: a primitive form of adaptive immunity that regulates microbial communities in the gut. , 2006, Current topics in microbiology and immunology.

[3]  Wanjun Chen,et al.  TGF-beta1 on osteoimmunology and the bone component cells , 2013, Cell & Bioscience.

[4]  F. Powrie,et al.  Regulatory lymphocytes and intestinal inflammation. , 2009, Annual review of immunology.

[5]  Matthew C. Thomas,et al.  Diets enriched in oat bran or wheat bran temporally and differentially alter the composition of the fecal community of rats. , 2009, The Journal of nutrition.

[6]  Louis S Stodieck,et al.  Shifts in bone marrow cell phenotypes caused by spaceflight. , 2009, Journal of applied physiology.

[7]  Jian-xin Lin,et al.  IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. , 2011, Current opinion in immunology.

[8]  M. Pecaut,et al.  Spaceflight induces changes in splenocyte subpopulations: effectiveness of ground-based models. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[9]  William G. Mckendree,et al.  ESPRIT: estimating species richness using large collections of 16S rRNA pyrosequences , 2009, Nucleic acids research.

[10]  A. J. Macpherson,et al.  Compartmentalization of the Mucosal Immune Responses to Commensal Intestinal Bacteria , 2004, Annals of the New York Academy of Sciences.

[11]  F. S. Ambesi-Impiombato,et al.  The Impact of Long-Term Exposure to Space Environment on Adult Mammalian Organisms: A Study on Mouse Thyroid and Testis , 2012, PloS one.

[12]  B. Crucian,et al.  Altered cytokine production by specific human peripheral blood cell subsets immediately following space flight. , 2000, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[13]  L. Hooper,et al.  Symbiotic Bacteria Direct Expression of an Intestinal Bactericidal Lectin , 2006, Science.

[14]  B. Haas,et al.  Chimeric 16S rRNA sequence formation and detection in Sanger and 454-pyrosequenced PCR amplicons. , 2011, Genome research.

[15]  M. Mushipe,et al.  Effects of Pleiotrophin (PTN) Over-expression on Mouse Long Bone Development, Fracture Healing and Bone repair , 2005, Calcified Tissue International.

[16]  D. Zawieja,et al.  Inhibition of active lymph pump by simulated microgravity in rats. , 2006, American journal of physiology. Heart and circulatory physiology.

[17]  T. Mukai,et al.  Bone mass loss due to estrogen deficiency is compensated in transgenic mice overexpressing human osteoblast stimulating factor-1. , 1997, Biochemical and biophysical research communications.

[18]  Louis S Stodieck,et al.  Spaceflight effects on T lymphocyte distribution, function and gene expression. , 2009, Journal of applied physiology.

[19]  Z. Allebban,et al.  Effects of spaceflight on the number of rat peripheral blood leukocytes and lymphocyte subsets , 1994, Journal of leukocyte biology.

[20]  R T Turner,et al.  The skeletal effects of spaceflight in growing rats: Tissue‐specific alterations in mrna levels for TGF‐β , 1995, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[21]  Y. Belkaid,et al.  A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism , 2007, The Journal of experimental medicine.

[22]  Millie Hughes-Fulford,et al.  Reduction of anabolic signals and alteration of osteoblast nuclear morphology in microgravity , 2006, Journal of cellular biochemistry.

[23]  T. Jukes CHAPTER 24 – Evolution of Protein Molecules , 1969 .

[24]  A. Musarò,et al.  Adaptation of Mouse Skeletal Muscle to Long-Term Microgravity in the MDS Mission , 2012, PloS one.

[25]  D. Barritault,et al.  Growth factors in skeletal muscle regeneration. , 1996, Cytokine & growth factor reviews.

[26]  N. Dawson Rate of passage of a non-absorbable marker through the gastrointestinal tract of the mouse (Mus musculus). , 1972, Comparative biochemistry and physiology. A, Comparative physiology.

[27]  Richard A Flavell,et al.  Transforming growth factor-beta regulation of immune responses. , 2006, Annual review of immunology.

[28]  K. Nakao,et al.  Pleiotrophin triggers inflammation and increased peritoneal permeability leading to peritoneal fibrosis. , 2012, Kidney international.

[29]  F. Sutterwala,et al.  Transforming growth factor-beta controls T helper type 1 cell development through regulation of natural killer cell interferon-gamma. , 2005, Nature immunology.

[30]  S. Jeffery Evolution of Protein Molecules , 1979 .

[31]  R. Cancedda,et al.  Bone Turnover in Wild Type and Pleiotrophin-Transgenic Mice Housed for Three Months in the International Space Station (ISS) , 2012, PloS one.

[32]  K. Ohya,et al.  Inhibition of HSP70 and a Collagen‐Specific Molecular Chaperone (HSP47) Expression in Rat Osteoblasts by Microgravity , 2003, Annals of the New York Academy of Sciences.

[33]  A. Régnault,et al.  TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells. , 1999, Journal of immunology.

[34]  K. Honda,et al.  Induction of Colonic Regulatory T Cells by Indigenous Clostridium Species , 2011, Science.

[35]  V. Apostolopoulos,et al.  Cytokine profile and induction of T helper type 17 and regulatory T cells by human peripheral mononuclear cells after microbial exposure , 2012, Clinical and experimental immunology.

[36]  E R Morey,et al.  Inhibition of bone formation during space flight. , 1978, Science.

[37]  G Sonnenfeld,et al.  Effects of spaceflight and PEG-IL-2 on rat physiological and immunological responses. , 1999, Journal of applied physiology.

[38]  D. Lane 16S/23S rRNA sequencing , 1991 .

[39]  S. Tuck,et al.  The cell biology of bone metabolism , 2008, Journal of Clinical Pathology.

[40]  A T Ichiki,et al.  Effects of spaceflight on rat peripheral blood leukocytes and bone marrow progenitor cells , 1996, Journal of leukocyte biology.

[41]  R. Flavell,et al.  Abrogation of TGFβ Signaling in T Cells Leads to Spontaneous T Cell Differentiation and Autoimmune Disease , 2000 .

[42]  J. Tiedje,et al.  Naïve Bayesian Classifier for Rapid Assignment of rRNA Sequences into the New Bacterial Taxonomy , 2007, Applied and Environmental Microbiology.

[43]  M. Icaza-Chávez,et al.  Gut microbiota in health and disease , 2013 .

[44]  Angela Maria Rizzo,et al.  Effects of Long-Term Space Flight on Erythrocytes and Oxidative Stress of Rodents , 2012, PloS one.

[45]  Martin Hartmann,et al.  Introducing mothur: Open-Source, Platform-Independent, Community-Supported Software for Describing and Comparing Microbial Communities , 2009, Applied and Environmental Microbiology.

[46]  A. Mastro,et al.  The effect of a 10-day space flight on the function, phenotype, and adhesion molecule expression of splenocytes and lymph node lymphocytes. , 1995, Experimental cell research.

[47]  H. Roach,et al.  Pleiotrophin/Osteoblast‐Stimulating Factor 1: Dissecting Its Diverse Functions in Bone Formation , 2002, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[48]  K. Wise,et al.  Altered cytokine expression in tissues of mice subjected to simulated microgravity , 2004, Molecular and Cellular Biochemistry.

[49]  J. Green-Johnson Immunological responses to gut bacteria. , 2012, Journal of AOAC International.

[50]  Vittorio Cotronei,et al.  The Mice Drawer System (MDS) Experiment and the Space Endurance Record-Breaking Mice , 2012, PloS one.

[51]  Proto Pippia,et al.  Space flight affects motility and cytoskeletal structures in human monocyte cell line J‐111 , 2011, Cytoskeleton.

[52]  M. Rescigno,et al.  Human intestinal epithelial cells promote the differentiation of tolerogenic dendritic cells , 2009, Gut.

[53]  R T Turner,et al.  Effects of orbital spaceflight on human osteoblastic cell physiology and gene expression. , 2000, Bone.

[54]  C. Cann,et al.  Bone resorption and mineral excretion in rats during spaceflight. , 1983, The American journal of physiology.

[55]  E. W. Beals,et al.  Bray-curtis ordination: an effective strategy for analysis of multivariate ecological data , 1984 .

[56]  L. Bonewald,et al.  Role of active and latent transforming growth factor beta in bone formation. , 1994, Journal of cellular biochemistry.

[57]  S. Dowd,et al.  Evaluation of the bacterial diversity in cecal contents of laying hens fed various molting diets by using bacterial tag-encoded FLX amplicon pyrosequencing. , 2009, Poultry science.

[58]  M. Hornef,et al.  The impact of perinatal immune development on mucosal homeostasis and chronic inflammation , 2011, Nature Reviews Immunology.

[59]  Ronald J. White,et al.  Humans in space , 2001, Nature.

[60]  Lynda F. Bonewald,et al.  Role of active and latent transforming growth factor β in bone formation , 1994 .