EFFECTS OF IL-12 ON IN-VIVO CYTOKINE GENE-EXPRESSION AND IG ISOTYPE SELECTION

The effects of murine rIL-12 on cytokine gene expression and Ig secret ion were studied in vivo. In untreated mice IL-12 enhanced IFN-gamma a nd IL-10 gene expression and protein secretion, reduced base line IL-3 and IL-4 gene expression, and increased serum IgG2a concentration. In mice that had been injected with goat anti-mouse IgD antibody (Galpha Mdelta) to induce increases in IL-3, IL-4, and IL-10 gene expression a nd serum IgE, IgG1, IgG2a, and IgG3 concentrations, the simultaneous i njection of IL-12 enhanced IFN-gamma and IL-10 gene expression and sup pressed IL-3 and IL-4 gene expression and serum IgG and IgE responses. Anti-IFN-gamma mAb neutralized most, but not all, IFN-gamma produced by mice treated with GalphaMdelta and IL-12. Anti-IFN-gamma mAb enhanc ed IL-3 and IL-4 gene expression, did not affect IL-10 or IFN-gamma ge ne expression, and increased serum IgG1, IgG2a, and IgG3 levels, but h ad relatively little effect on serum IgE in these mice. In contrast to its effects in GalphaMdelta-treated mice, IL-1 2 failed to inhibit th e IgE response to GalphaMepsilon antibody, which stimulates mIgE+ B ce lls to secrete IgE. These observations demonstrate that: 1) IL-12 may limit its own effects by inducing the production of a cytokine (IL-10) that down-regulates both IL-12 production and IL-12-induced IFN-gamma production; 2) IL-1 2 inhibits the production of at least one cytokin e, IL-3, that is not generally regarded to be strictly Th1- or Th2-ass ociated; 3) IL-1 2 inhibits switching to IgE secretion to a greater ex tent-than it inhibits switching to other Ig isotypes; and 4) the in vi vo effects of IL-12 are, to a large extent, IFN-gamma-dependent.