Most normal human diploid cells have no detectable telomerase; however, expression of the catalytic subunit of telomerase is sufficient to induce telomerase activity and, in many cases, will bypass normal senescence. We and others have previously demonstrated in vitro assembly of active telomerase by combining the purified RNA component with the reverse transcriptase catalytic component synthesized in rabbit reticulocyte extract. Here we show that assembly of active telomerase from in vitro-synthesized components requires the contribution of proteins present in reticulocyte extracts. We have identified the molecular chaperones p23 and Hsp90 as proteins that bind to the catalytic subunit of telomerase. Blockade of this interaction inhibits assembly of active telomerase in vitro. Also, a significant fraction of active telomerase from cell extracts is associated with p23 and Hsp90. Consistent with in vitro results, inhibition of Hsp90 function in cells blocks assembly of active telomerase. To our knowledge, p23 and Hsp90 are the first telomerase-associated proteins demonstrated to contribute to telomerase activity.

Summary. In this study, we examined the effect of injecting various cytokines. We report here that tumour necrosis factor (TNF)\g=a\,\g=g\-interferon and interleukin 2 (IL-2) can, in some circumstances, increase fetal resorption rates in abortionprone (CBA/J \m=x\DBA/2) and non-abortion prone (CBA/J \m=x\BALB/c,C3H \m=x\DBA/2) matings: 1000 units TNF enhanced resorptions from 43 to 79% in CBA \m=x\DBA/2, from 7 to 89% in CBA \m=x\ BALB/c, from 5 to 47% in C3H \m=x\ DBA/2. The effect was both gestational age-and dose-dependent. Gamma interferon and R-IL-2 enhanced resorptions from 38 to 68% and 76% respectively in the CBA/J \m=x\ DBA/2 mating combination, whereas the rates in CBA/J \m=x\ BALB/c matings were enhanced from 6 to 44% and 55%. Lipopolysaccharride (LPS), which is known to lead to the release of TNF-\g=a\, had a similar effect, leading to gestational age-and dose-dependent enhancement of resorptions up to 100%.However, cytokines of the CSF family, including IL-3 and GM-CSF, increased the chances of fetal survival when injected into abortion-prone mice, e.g. reducing resorption rates in the abortion-prone CBA/J \m=x\ DBA/2 mating combination from 55 to 22% (IL-3), and 47 to 8% (GM-CSF). They also increased fetal and placental weight and, in particular, expanded the spongiotrophoblast zone in the placenta. The latter observations may be due to a direct trophic influence on placental cells, perhaps through a cytokine cascade, or an indirect effect due to inhibition of natural killer (NK)-like cells, or both. Whatever the mechanism, these results may find practical application in influencing reproductive outcome in women and other species.

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