A FETAL SHEEP LIVER EXTRACT REVERSES AGE-RELATED INCREMENTS IN SPONTANEOUS AND INDUCED CYTOKINE PRODUCTION BY INDIRECT ENVIRONMENTAL-EFFECTS

BALB/c, DBA/2 and C57BL/6 mice of different ages (ranging from 8 to 11 0 weeks of age) were used as spleen cell donors to assay cytokine prod uction from ConA activated spleen and Peyer's Patch (PP) lymphocytes. As reported in an earlier publication, there was an age-related declin e in IL-2 production in all strains, with a general increase in IL-4 a nd IL-10 production with age, this being particularly marked for PP ce ll preparations. Similar conclusions were reached from independent ana lysis of CD44(hi) and CD44(lo) cell populations in these groups (memor y vs. naive cells, respectively). Interestingly, IL-6 production was d ramatically increased (some 4-5-fold in the different strains) and sig nificantly increased levels of IL-6 were detected in the serum of aged mice. A previously described sheep fetal liver extract was able to re verse, to varying degrees, these cytokine changes associated with agin g. Interestingly, when cells from aged mice were adoptively transferre d to lethally irradiated young (8 week) recipients, the cytokine produ ction phenotype of cells harvested from recipient mice 3 weeks later w as that of the aged donor, unless recipients were treated continually with extract. Treatment of the donor alone produced minimal changes in cytokine production 3 weeks following adoptive transfer. The effect o f extract was reversed in treated aged mice by concomitant daily intra venous infusion of the competitive inhibitor of nitric oxide synthesis (NG-monomethyl-L-arginine (NMMA)), which also decreased the increased serum nitrate levels in mice treated with extract. Our data suggest a n important role for reactive nitrogen products, themselves induced by fetal liver extract, in age-associated changes in cytokine production . (C) 1998 Elsevier Science B.V. All rights reserved.