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Signal transduction and regulation of T-cell expression in simulated microgravity.    M. Hughes-Fulford , C-F. Li and A. Cogoli, Lab of Cell Growth, UCSF, NCIRE and VAMC, San Francisco, CA and Space Biology, ETH Zurich, Switzerland

   It has been recognized from the early days of spaceflight that microgravity blunts the immune response in humans. Studies by Cogoli have demonstrated that the most likely source of inhibition occurs early in T-cell activation. In preparation for our Soyuz experiment, we have conducted ground studies of signal transduction of  T-cell activation in normal and altered gravity. Since expression of interleukin-2 and its receptor subunits, a, b, g is essential for T lymphocyte proliferation; we investigated early induction of these genes.  IL-2, IL-2Rg and IFNg were significantly induced at 2h, and IL-2Ra at 4h after activation; IL-2Rb expression was constitutive.  The induced gene expression of IL-2, IL-2Ra and IFNg was significantly inhibited by H-89 to levels equal to or greater than 76% inhibition.  PKC inhibition significantly reduced IFNg, IL-2 and IL-2Ra gene expression by approximately 40%, but did not affect IL-2Rb or g subunits. In order to further study regulation of IFNg, IL-2 and IL-2Ra, PMA-stimulated Jurkat cells were analyzed.  We found that H-89 inhibited IFNg, IL-2 and IL-2Ra gene expression, with no effect on 18S.  Analysis of proteins showed that H-89 inhibited synthesis of IFNg, IL-2 and IL-2Ra.   Expression of the key genes were altered in simulated microgravity and suggest that signal  transduction  is altered in the absence of 1g. These results suggest that T-cell activation, which is dependent on IL-2Ra, IL-2 and IFNg  mRNA expression, is in part mediated via the  PKA signaling pathway during early stages of activation, in addition this pathways is reduced in the absence of gravity.  (Supported by NASA grant: NAG-2-1286 and by ESA Contract 13634/NL/VJ (IC) to A. Cogoli)