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Clinorotation differentially inhibits T-lymphocyte transcription factor activation

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Summary

T lymphocytes cultured under the low-shear stress environment of modeled microgravity demonstrate an inhibition of activation in response to T-cell receptor (TCR)-mediated signaling. Modeled microgravity culture-induced inhibition mimics the inhibition observed during spaceflight. This work investigates the molecular signaling events of interleukin 2 transcription activation in modeled microgravity as generated with clinorotation. Under normal conditions, NFAT (nuclear factor of activated T cells) is dephosphorylated and activated with sustained calcium (Ca++) influx and calcineurin activity, whereas AP-1 is activated by protein kinase C (PKC) and Ras-mediated pathways. Purified human T lymphocytes are shown to exhibit differential inhibition of transcription factor activation in modeled microgravity. Activation of AP-1 is blocked with clinorotation, whereas NFAT dephosphorylation occurs. This work supports the theory that modeled microgravity differentially blooks the activation of distinct signaling mechanism.

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References

  • Acuto, O.; Cantrell, D. A. T Cell Activation and the cytoskeleton. Annu. Rev. Immunol. 18:165–184; 2000.

    Article  PubMed  CAS  Google Scholar 

  • Adachi, S.; Iwata, M. Duration of calcineurin and Erk signals regulates CD4/ CD8 lineage commitment of thymocytes. Cell. Immunol. 15:45–53; 2002.

    Article  CAS  Google Scholar 

  • Auphan, N.; Ghosh, S.; Flavell, R. A.; Schmitt-Verhulst, A. M. Differential requirements for NFkB and AP-1 trans-activation in response to minimal TCR engagement by a partial agonist in naive CD8 T cells. J. Immunol. 163:5219–5227; 1999.

    PubMed  CAS  Google Scholar 

  • Bromley, S. K.; Burack, W. R.; Johnson, K. G., et al. The immunological synapse. Annu. Rev. Immunol. 19:375–396; 2001.

    Article  PubMed  CAS  Google Scholar 

  • Cogoli, A.; Cogoli-Greuter, M. Activation and proliferation of lymphocytes and other mammalian cells in microgravity. Adv. Space Biol. Med. 6:33–79; 1997.

    Article  PubMed  CAS  Google Scholar 

  • Cooper, D.; Pellis, N. R. Suppressed PHA activation of T lymphocytes in simulated microgravity is restored by direct activation of protein kinase. C. J. Leukoc. Biol. 63:550–562; 1998.

    CAS  Google Scholar 

  • Cooper, D.; Pride, M. W.; Brown, E. L.; Risin, D.; Pellis, N. R. Suppression of antigen-specific lymphocyte activation in modeled microgravity. In Vitro Cell. Dev. Biol. 37A:63–65; 2001.

    Article  Google Scholar 

  • de Groot, R. P.; Rijken, P. J.; den Hertog, J., et al. Nuclear responses to protein kinase C signal transduction are sensitive to gravity changes. Exp. Cell Res. 197:87–90; 1991.

    Article  PubMed  Google Scholar 

  • Dignam, J. D.; Lebovitz, R. M.; Roeder, R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 11:1475–1489; 1983

    Article  PubMed  CAS  Google Scholar 

  • Flanagan, W. M.; Corthesy, B.; Bram, R. J.; Crabtree, G. R. Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclo-sporin A. Nature 352:803–807; 1991.

    Article  PubMed  CAS  Google Scholar 

  • Hashemi, B. B.; Penkala, J. E.; Vens, C.; Huls, H.; Cubbage, M.; Sams, C. F. T cell activation responses are differentially regulated during clinorotation and in spaceflight. FASEB J. 13:2071–2082; 1999.

    PubMed  CAS  Google Scholar 

  • Hughes-Fulford, M.; Lewis, M. L. Effects of microgravity on osteoblast growth activation. Exp. Cell Res. 224:103–109; 1996.

    Article  PubMed  CAS  Google Scholar 

  • Ingber, D. How cells (might) sense microgravity. FASEB J. 13:3–15; 1999.

    Google Scholar 

  • Jain, J.; McCaffrey, P. G.; Miner, Z., et al. The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature 365:352–355; 1993.

    Article  PubMed  CAS  Google Scholar 

  • Lewis, M. L.; Reynolds, J. L.; Cubano, L. A.; Hatton, J. P.; Lawless, B. D.; Piepmeier, E. H. Spaceflight alters microtubules and increases apoptosis in human lymphocytes (Jurkat). FASEB J. 12: 1007–1018; 1998.

    PubMed  CAS  Google Scholar 

  • Mondino, A.; Whaley, C. D.; DeSilva, D. R.; Li, W.; Jenkins, M. K.; Mueller, D. L. Defective transcription of the IL-2 gene is associated with impaired expression of c-Fos, FosB, and JunB in anergic T helper 1 cells. J. Immunol. 157:2048–2057; 1996.

    PubMed  CAS  Google Scholar 

  • Nussenzweig, M.; Allison, J. P. Lymphocyte activation and effector functions. How signals are integrated in the immune system. Curr. Opin. Immunol. 9:293–295; 1997.

    Article  PubMed  CAS  Google Scholar 

  • Papaseit, C.; Pochon, N.; Tabony, J. Microtubule self-organization is gravity dependent. Proc. Natl. Acad. Sci. USA 97:8364–8368; 2000.

    Article  PubMed  CAS  Google Scholar 

  • Rao, A.; Luo, C.; Hogan, P. G. Transcription factors of the NFAT family: regulation and function. Annu. Rev. Immunol. 15:707–747; 1997.

    Article  PubMed  CAS  Google Scholar 

  • Rayter, S. I.; Woodrow, M.; Lucas, S. C.; Cantrell, D. A.; Downward, J. p21ras mediates control of IL-2 gene promoter function in T cell activation. EMBO J. 11: 4549–4556; 1992.

    PubMed  CAS  Google Scholar 

  • Sambrook, J.; Fritsch, E. F.; Maniatis, T. Molecular cloning: a laboratory manual. 2nd ed. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1989.

    Google Scholar 

  • Schreiber, S. L.; Crabtree, G. R. The mechanism of action of cyclosporin A and FK506. Immunol. Today. 13:136–142; 1992.

    Article  PubMed  CAS  Google Scholar 

  • Schwarz, R. P.; Goodwin, T. J.; Wolf, D. A. Cell culture for three-dimensional modeling in rotating-wall vessels: an application of simulated microgravity. J. Tissue Cult. Methods 14:51–57; 1992.

    Article  PubMed  CAS  Google Scholar 

  • Sciola, L.; Cogoli-Greuter, M.; Cogoli, A.; Spano, A.; Pippia, P. Influence of microgravity on mitogen binding and cytoskeleton in Jurkat cells. Adv. Space Res. 24:801–805; 1999.

    Article  PubMed  CAS  Google Scholar 

  • Serfling, E.; Avots, A.; Neumann, M. The architecture of the interleukin-2 promoter: a reflection of T lymphocyte activation. Biochim. Biophys. Acta 1263:181–200; 1995.

    PubMed  Google Scholar 

  • Sundaresan, A.; Risin, D.; Pellis, N. R. Loss of signal transduction and inhibition of lymphocyte locomotion in a ground-based model of microgravity. In Vitro Cell Dev. Biol 38A:118–122; 2002

    Article  Google Scholar 

  • Sundaresan, A.; Risin, D.; Pellis, N. R. Modeled microgravity-induced protein kinase C isoform expression in human lymphocytes. J. Appl. Physiol. 96:2028–2033; 2004.

    Article  PubMed  CAS  Google Scholar 

  • Ullman, K. S.; Northrop, J. P.; Verweij, C. L.; Crabtree, G. R. Transmission of signals from the T lymphocyte antigen receptor to the genes responsible for cell proliferation and immune function: the missing link. Annu Rev. Immunol. 8:421–452; 1990.

    Article  PubMed  CAS  Google Scholar 

  • Unsworth, B. R.; Lelkes, P. I. Growing tissues in microgravity. Nat. Med. 4:901–907; 1998.

    Article  PubMed  CAS  Google Scholar 

  • Uva, B. M.; Masini, M. A.; Sturla, M.; Prato, P.; Passalacqua, M.; Giuliani, M.; Tagliafierro, G.; Strollo, F. Clinorotation-induced weightlessness influences the cytoskeleton of glial cells in culture. Brain Res. 934:132–139; 2002.

    Article  PubMed  CAS  Google Scholar 

  • Vassy, J.; Portet, S.; Beil, M., et al. The effect of weightlessness on cyto-skeleton architecture and proliferation of human breast cancer cell line MCF-7. FASEB J. 15:1104–1106; 2001.

    PubMed  CAS  Google Scholar 

  • Walther, I.; Pippia, P.; Meloni, M. A.; Turrini, F.; Mannu, F.; Cogoli, A. Simulated microgravity inhibits the genetic expression of interleukin-2 and its receptor in mitogen-activated T lymphocytes. FEBS Lett. 436:115–118; 1998.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Maureen A. Morrow.

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Morrow, M.A. Clinorotation differentially inhibits T-lymphocyte transcription factor activation. In Vitro Cell.Dev.Biol.-Animal 42, 153–158 (2006). https://doi.org/10.1290/0601011.1

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