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Antagonist of Phorbol Ester Receptor-mediated Chemotaxis in Mouse Peritoneal Macrophages¹

Department of Pharmacology and Toxicology, Medical College of Virginia, Richmond, Virginia 23298

Biologically active phorbol ester derivatives displace [³H]phorbol-12,13-dibutyrate from thioglycollate-elicited mouse peritoneal macrophages in a time-, temperature-, and concentration-dependent manner. Scatchard analysis revealed an apparent K_d of 54.1 nM and 8.0 x 10⁵ sites/cell, indicating that these macrophages possess saturable, high-affinity phorbol ester-binding sites. These derivatives also act as chemoattractants for the macrophage at equivalent concentrations. A notable exception to this pattern is phorbol-12,13-diacetate. Phorbol-12,13-diacetate inhibits specific binding of [³H]phorbol-12,13-dibutyrate (concentration required for a 50% inhibition of the maximum specific binding of [³H]phorbol-12,13-dibutyrate, 2.6 µM) and chemotaxis to phorbol-12-myristate, 13-acetate (concentration required for a 50% inhibition of the maximum chemotactic response, 0.39 µM) while exhibiting no activity as a chemoattractant at concentrations up to 10^-5 M. The data indicate that phorbol-12,13-diacetate may be an antagonist for receptor-mediated chemotaxis to phorbol-12-myristate, 13-acetate in the macrophage.

¹ Supported by grants from the American Cancer Society (IN-105G), the National Institute of Dental Research (5P50DE05139) and the United States Environmental Protection Agency (R-808861010).

² Postdoctoral trainee supported by National Institute of Environmental Health Services Training Grant T32E507087. To whom requests for reprints should be addressed.

³ Predoctoral trainees supported by National Institute of Environmental Health Services Training Grant T32E507087.

⁴ Present address: The Wistar Institute of Anatomy and Biology, Philadelphia, Pa. 19104.

⁵ Recipient of NIH Research Career Development Award K04AM00565.

Received 9/ 8/82. Accepted 7/ 1/83.