In susceptible H-2S mice, mercuric chloride (HgCl2) induces an autoimmune syndrome characterized by production of anti-nucleolar antibodies (ANoA) and increased serum levels of IgG1 and IgE antibodies. The increase in serum IgG1 and IgE, which are under IL-4 control, suggests a role for the Th2 subset in the induction of this syndrome. We have previously shown that administration of IL-12, a potent Th1-promoting cytokine, resulted in a dramatic reduction of the HgCl2-induced anti-nucleolar antibody titres and inhibited serum IgG1 increase. These results suggest that Th1 T cells can down-regulate ANoA, and support a role for the Th2 subset in ANoA production, possibly via IL-4. To examine the role of IL-4 in this syndrome, C57Bl/6 mice (H-2b) with a targeted deletion of the IL-4 gene were mated with A.SW mice (H-2S) to yield H-2S mice lacking IL-4. We then analysed ANoA and serum immunoglobulin levels in these mice after HgCl2 treatment. While mercury-treated IL-4(-/-) H-2S mice had virtually no detectable serum IgG1 or IgE, and very low levels of IgG1 ANoA, these mice had levels of IgG2a and IgG2b class ANoA comparable to mercury-treated IL-4+ H-2S mice, indicating that IL-4 is not required for the ANoA response in mercury-induced autoimmunity.