IL-12 directly stimulates expression of IL-10 by CD5+ B cells and IL-6 by both CD5+ and CD5- B cells: possible involvement in age-associated cytokine dysregulation

Constitutive expression of p35 and p40 IL-12 mRNA was detected in splenicmacrophages isolated from aged mice. Macrophages were also implicated asthe cell type responsible for the dysregulated IL-6 and tumor necrosisfactor (TNF)-alpha commonly observed to be constitutively produced bylymphoid cells from aged donors. A role for IL-12 in the aging process wassuggested when it was found that recombinant IL-12 (rIL-12) directlystimulated splenic CD5+ B cells to secrete IL-10, and both CD5+ and CD5- Bcells could be directly induced to produce IL-6 in response to rIL-12.Furthermore, splenocytes from aged animals cultured in the presence ofanti-IL-12 antibodies demonstrated a significant reduction in spontaneousIL-6, IL-10 and IFN- gamma production. Based on these observations it wasconcluded that IL- 12 might be responsible for the dysregulated productionof IL-10 and IFN-gamma known to occur in aged animals. Treatment of agedanimals with low doses of dehydroepiandrosterone sulfate, previouslyestablished to be immunocorrective in immunosenescent animals, reduced theage-associated alterations in IL-12 mRNA and protein expression. Themechanisms responsible for the abnormal constitutive expression ofinflammatory cytokines by the macrophages of aged animals may play animportant afferent role in establishing the immunosenescent phenotype.