IL-12 INHIBITS IN-VITRO IMMUNOGLOBULIN PRODUCTION BY HUMAN LUPUS PERIPHERAL-BLOOD MONONUCLEAR-CELLS (PBMC)

Systemic lupus erythematosus (SLE) is a prototypical autoimmune diseas e characterized by polyclonal B cell activation and by the production of anti-double-stranded (ds) DNA antibodies. Given the inhibitory effe cts of IL-12 on humoral immune responses, we investigated whether IL-1 2 displayed such an activity on in vitro immunoglobulin production by SLE PBMC. Spontaneous IgG, IgG1, IgG2, IgG3 and IgM antibody productio n was dramatically reduced by addition of IL-12. These results were co nfirmed by Elispot assays detecting IgG- and anti-dsDNA-secreting cell s. While IL-6 and TNF titres measured in PBMC supernatants were not mo dified by addition of IL-12, interferon-gamma (IFN-gamma) titres were up-regulated and IL-10 production down-regulated. Since addition of IF N-gamma did not down-regulate immunoglobulin production and since the inhibitory activity of IL-12 on immunoglobulin synthesis was not suppr essed by anti-IFN-gamma antibody, we concluded that the effect of IL-1 2 on immunoglobulin production was not mediated through IFN-gamma. Our data also argue against the possibility that down-regulation of endog enous IL-10 production was responsible for the effect of IL-12. Thus, inhibition of IL-10 production by IFN-gamma was not accompanied by inh ibition of immunoglobulin production, and conversely, restoration of I L-10 production by anti-IFN-gamma antibody did not suppress the inhibi tory activity exerted by IL-12 on immunoglobulin production. Taken tog ether, our data indicate that reduction of excessive immunoglobulin an d anti-dsDNA antibody production by lupus PBMC can be achieved in vitr o by IL-12, independently of IFN-gamma and IL-10 modulation.