Levamisole induces interleukin-18 and shifts type 1/type 2 cytokine balance

Immune responses can be classified, according to the predominant cytokines involved, into type 1 (featuring interferon-gamma, IFN-gamma) and type 2 (f eaturing interleukin-4, IL-4); imbalance between type 1 and type 2 cytokine compartments has been implicated in many human diseases. Levamisole is a d rug with an unknown mode of action that has been used to boost immunity in infectious diseases including leprosy, and in some cancers. To test the hyp othesis that levamisole acts by inducing a shift to a type 1 immune respons e, we used Brown Norway (BN) rats, which are markedly biased to type 2 resp onses. BN rats treated with levamisole showed a dose-dependent rise in seru m IFN-gamma and fall in serum immunoglobulin E (IgE) level. Detailed analys is of cytokine gene expression showed upregulation of IFN-gamma and downreg ulation of IL-4 messenger RNA. This coincided with marked upregulation of I L-18, a recently characterized cytokine with potent activity in stimulating IFN-gamma production. IL-12 was not induced. Further, the type 2 response induced in BN rats by mercuric chloride was markedly attenuated when rats w ere pretreated with levamisole: there was a 2-log reduction in maximum seru m IgE level and marked attenuation of IL-4 gene upregulation. These data in dicate that levamisole acts by resetting the immune balance towards a type 1 response via induction of IL-18. Our findings provide a direction for dev elopment of more specific immunomodulating therapy.