One of the side effects of treatment of manic depressive disease with lithium salts is the triggering or aggravation of psoriasis. In a murine model, subcutaneous (s.c.) injection of a combination of tumor necrosis factor (TNF) and lithium chloride (LiC1) induces a psoriasiform inflammatory reaction. Recent studies suggest that interleukin (1L)-6 and its inducer TNF may play an important role in the pathophysiology of psoriasis. To understand the mechanism involved in the exacerbation of psoriasis by lithium salts, the IL-1, IL-6 and granulocytemacrophage colony-stimulating factor (GM-CSF) levels in murine skin injected with TNF in combination with LiCl were studied. IL-6 levels in skin extracts of mice treated S.C. with a combination of TNFand LiCl were considerably increased as compared to the levels found in skin extracts from mice treated with TNF or LiCl alone. In contrast, in the same skin extracts IL-1 levels were not changed and GM-CSF was even not detectable. Although less pronounced, increased IL-6 levels could also be found in the sera of mice treated S.C. with TNF and LiCl. Injection with IL-1, interferon-y, lipopolysaccharide, or phorbol 12-myristate 13-acetate also induced IL-6 in murine skin. However, these IL-6 levels were not enhanced by co-treatment with LiCl. Likewise, no inflammatory reaction could be seen in mice treated with these agents. These results suggest a role for endogenous TNF and IL-6 in the triggering or aggravation of psoriasis in lithium-treated patients.