TENIDAP MODULATES CYTOPLASMIC PH AND INHIBITS ANION TRANSPORT IN-VITRO .2. INHIBITION OF IL-1-BETA PRODUCTION FROM ATP-TREATED MONOCYTES AND MACROPHAGES

IL-1 beta is an important inflammatory mediator produced by monocytes and macrophages after LPS stimulation. In the absence of a secondary s timulus, however, little IL-1 beta is released into the medium. Previo usly, ATP was shown to promote the release and proteolytic maturation of IL-1 beta from LPS-stimulated murine peritoneal macrophages. Tenida p, a new anti-inflammatory and antiarthritic agent, inhibited the rele ase and maturation of IL-1 beta induced in vitro by ATP treatment of m urine peritoneal macrophages. Tenidap's inhibitory activity was mimick ed by other agents that blocked anion transport, such as UK5099 and DI DS. In contrast, cyclooxygenase-inhibiting nonsteroidal anti-inflammat ory drugs, such as piroxicam and naproxen, did not impair ATP-induced post-translational processing. Human monocytes responded to LPS to pro duce IL-1 beta, but externalized little of their newly synthesized cyt okine. ATP at concentrations greater than or equal to 2 mM promoted IL -1 beta release from these cells. The degree to which the released cyt okine was proteolytically processed to its biologically active 17-kDa species, however, depended on the pH of the medium; a greater processi ng efficiency was observed at slightly acidic (pH 6.9) values. Tenidap and other anion transport inhibitors effectively prevented the ATP re sponse of cultured human monocytes. Likewise, LPS-stimulated human alv eolar macrophages responded to ATP by releasing 17-kDa IL-1 beta, and tenidap inhibited this response. The ATP-induced release and maturatio n of IL-1 beta from human monocytes and macrophages, therefore, was su ppressed by anion transport inhibitors, suggesting that anion conducta nce is a necessary component of the ATP-promoted externalization mecha nism. In view of IL-1's importance as an inflammatory mediator, tenida p may demonstrate novel anti-inflammatory activities by virtue of its inhibition of the post-translational release and maturation of this cy tokine.