NITRIC-OXIDE PRODUCTION IN SJL MICE BEARING THE RCSX LYMPHOMA - A MODEL FOR IN-VIVO TOXICOLOGICAL EVALUATION OF NO-CENTER-DOT

SJL mice spontaneously develop pre-B-cell lymphoma that we hypothesize d might stimulate macrophages to produce nitric oxide (NO.). Transplan tation of an aggressive lymphoma (RcsX) was used to induce tumor forma tion. Urinary nitrate excretion was measured as an index of NO. produc tion and was found to increase 50-fold by 13 days after tumor injectio n. NO. production was prevented by the addition of a nitric oxide synt hase (NOS) inhibitor. The expression of inducible NOS (iNOS) in variou s tissues was estimated by Western blot analysis and localized by immu nohistochemistry. The synthase was detected in the spleen, lymph nodes , and liver of treated but not control mice. To assess whether the iNO S-staining cells were macrophages, spleen sections from RcsX-bearing a nimals were costained with anti-iNOS antibody and the anti-macrophage antibody moma-2. Expression of iNOS was found to be limited to a subse t of the macrophage population. The concentration of gamma-interferon, a cytokine known to induce NO. production by macrophages, in the seru m of tumor-bearing mice, was measured and found to be elevated 25-fold above untreated mice. The ability of RcsX-activated macrophages to in hibit splenocyte growth in primary culture was estimated and macrophag e-derived NO. was found to inhibit cell division 10-fold. Our findings demonstrate that RcsX cells stimulate NO. production by macrophages i n the spleen and lymph nodes of SJL mice, and we believe this experime ntal model will prove useful for study of the toxicological effects of NO. under physiological conditions.