INTERLEUKIN-12 PRIMES MACROPHAGES FOR NITRIC-OXIDE PRODUCTION IN-VIVOAND RESTORES DEPRESSED NITRIC-OXIDE PRODUCTION BY MACROPHAGES FROM TUMOR-BEARING MICE - IMPLICATIONS FOR THE ANTITUMOR-ACTIVITY OF INTERLEUKIN-12 AND OR INTERLEUKIN-2/

Interleukin-12 (IL-12) is a recently described immunoregulatory cytoki ne with potent therapeutic activity in various preclinical models of i nfectious or malignant disease, As part of our ongoing evaluation of p otential mechanisms accounting for the potent antitumor activity of IL -12, we have investigated the influence of IL-12 administration on tot al serum nitrate/nitrite (NOx-) levels and the production of nitric ox ide (NO) by peritoneal macrophages from normal and tumor-bearing mice. We report here that IL-12 administration to either normal or tumor-be aring mice for periods of time ranging from 7-19 days induced progress ive increases in serum NOx- levels and primed peritoneal macrophages f or NO production on subsequent exposure to lipopolysaccharide or IL-2 ex vivo. Treatment of resident peritoneal macrophages of the macrophag e cell line ANA-1 with IL-12 alone or IL-12 in combination with variou s other stimuli failed to induce NO production, suggesting that the ef fects of IL-12 occurred via an indirect mechanism. Furthermore, we hav e shown that not only was the production of NO by macrophages from unt reated long-term, tumor-bearing mice suppressed compared with control mice treated with vehicle or IL-12, but also that IL-12 administration overcame this suppression and delayed tumor growth. Lastly, we have s hown that administration of weekly pulses of IL-2 in combination with IL-12 additively enhanced the priming of macrophages for NO production ex vivo and delayed tumor growth far more effectively than either age nt alone. These observations and reports in the literature regarding t he potential influence of NO on development of the immune response and on the regulation of tumor growth and vascularization suggest that NO may play a significant role in the antitumor activity of IL-12 and IL -2.