Monoclonal non-specific suppressor factor (MNSF), a lymphokine produced by a murine hybridoma, was originally found to inhibit the generation of lipopolysaccharide (LPS)-induced Ig-secreting cells. Most recently, we demonstrated the recombinant form of the ubiquitin-like segment (rUbi-L) or MNSF beta, an isoform of MNSF, has a MNSF activity. To investigate the possible role of rUbi-L, a 8.5 kDa ubiquitin-like polypeptide, in the regulation of Ig isotype secretion, rUbi-L was added to purified B cell cultures stimulated with LPS plus IL-4. rUbi-L notable suppressed the IgE and IgG1 responses when added at culture initiation. In addition, rUbi-L had a strong effect on IgG3 production and a little effect on IgM production by LPS-stimulated B cells, whereas the level of other isotypes (IgG2a, IgG2b and IgA) was not affected. These findings demonstrate the isotype-specific suppression, but not pan-suppression, of Ubi-L. IFN-alpha and IFN-gamma, which are also known to inhibit the IgE response, showed a synergistic effect with Ubi-L, albeit the effects of IFN-alpha were smaller. The action was reversed by the addition of neutralizing antibodies of these cytokines. Therefore, Ubi-L, a ubiquitin-like protein, may have an important immunoregulatory role on the IgE response.