We studied the effects of interleukins (IL) on in vitro IgM and IgG anti-DNA antibody production by splenic B cells from autoimmune disease-prone NZB×NZW (NZB/W) FI mice. It was found that different interleukins regulate phenotypically distinct B cells producing separate isotype of anti-DNA antibodies. IL-2 slightly but significantly inhibited the production of IgM anti-DNA antibodies. IL-4 and IL-6 significantly enhanced the antibody production, but the effects were not so marked and inconsistent, particularly with respect to IL-6. By contrast. the effects of IL-5 were remarkable, particularly on splenic B cells from young mice. As for IgG anti-DNA antibodies. IL-6. but not other interleukins, markedly up-regulated the antibody production by splenic B cells from mice over 6 months of age, in a dose dependent fashion. Thus, the ability of B cells to produce IgC anti-DNA antibodies appears to be dependent on the surface expression of IL-6 receptor (IL-6R) at the ages when the mice begin to develop the disease. Studies of the surface phenotypes showed that while the IL-5-sensitive major IgM anti-DNA producers were CD5+Lp-3(CD43)-sIgM+. the IL-6-sensitive major IgG anti-DNA producers were CDS−p-3+sIgM−. However, significant amounts of IgG antibodies were also produced, in the presence of IL-6, by CDS+Lp−3+sIgM+, but not by CDS−Lp-3+sIgM+B cells from 6-month-old mice. We suggest that surface phenotypes of anti-DNA antibody producers change from CD5+Lg 35−-sIgM+IL-5R+. CD5+Lp−3+sIgM'IL-6R+and subsequently to CD5−-Lp-3−-sIgM-(sIgG+)IL-6R+in NZB/W FI mice with aging.