Tenidap modulates cytoplasmic pH and inhibits anion transport in vitro. II. 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 stimulus, however, little IL-1 beta is released into the medium. Previously, ATP was shown to promote the release and proteolytic maturation of IL-1 beta from LPS-stimulated murine peritoneal macrophages. Tenidap, a new anti-inflammatory and antiarthritic agent, inhibited the release and maturation of IL-1 beta induced in vitro by ATP treatment of murine peritoneal macrophages. Tenidap's inhibitory activity was mimicked by other agents that blocked anion transport, such as UK5099 and DIDS. In contrast, cyclooxygenase-inhibiting nonsteroidal anti-inflammatory drugs, such as piroxicam and naproxen, did not impair ATP-induced post-translational processing. Human monocytes responded to LPS to produce IL-1 beta, but externalized little of their newly synthesized cytokine. ATP at concentrations > or = 2 mM promoted IL-1 beta release from these cells. The degree to which the released cytokine was proteolytically processed to its biologically active 17-kDa species, however, depended on the pH of the medium; a greater processing efficiency was observed at slightly acidic (pH 6.9) values. Tenidap and other anion transport inhibitors effectively prevented the ATP response of cultured human monocytes. Likewise, LPS-stimulated human alveolar macrophages responded to ATP by releasing 17-kDa IL-1 beta, and tenidap inhibited this response. The ATP-induced release and maturation of IL-1 beta from human monocytes and macrophages, therefore, was suppressed by anion transport inhibitors, suggesting that anion conductance is a necessary component of the ATP-promoted externalization mechanism. In view of IL-1's importance as an inflammatory mediator, tenidap may demonstrate novel anti-inflammatory activities by virtue of its inhibition of the post-translational release and maturation of this cytokine.
Laliberte
R
R
Department of Immunology and Infectious Diseases, Pfizer, Inc., Central Research Division, Groton, CT 06340.
Perregaux
D
D
Svensson
L
L
Pazoles
C J
CJ
Gabel
C A
CA
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D000838:Anions / Q000378:metabolism*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000494:pharmacology*; D007375:Interleukin-1 / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D000078183:Oxindoles; D011499:Protein Processing, Post-Translational / Q000187:drug effects
D000838:Anions; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007211:Indoles; D007375:Interleukin-1; D000078183:Oxindoles; D000255:Adenosine Triphosphate; C062866:tenidap